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Purpose: Acute kidney injury (AKI) is a severe complication in medical and surgical intensive care units accounting for a high morbidity and mortality. Incidence, risk factors, and prognostic impact of this deleterious condition are well established in this setting. Data concerning the neurocritically ill patients is scarce. Therefore, aim of this study was to determine the incidence of AKI and elucidate risk factors in this special population.
Methods: Patients admitted to a specialized neurocritical care unit between 2005 and 2011 with a length of stay above 48 hours were analyzed retrospectively for incidence, cause, and outcome of AKI (AKI Network-stage ≥2).
Results: The study population comprised 681 neurocritically ill patients from a mixed neurosurgical and neurological intensive care unit. The prevalence of chronic kidney disease (CKD) was 8.4% (57/681). Overall incidence of AKI was 11.6% with 36 (45.6%) patients developing dialysis-requiring AKI. Sepsis was the main cause of AKI in nearly 50% of patients. Acute kidney injury and renal replacement therapy are independent predictors of worse outcome (hazard ratio [HR]: 3.704; 95% confidence interval [CI]: 1.867-7.350; P < .001; and HR: 2.848; CI: 1.301-6.325; P = .009). Chronic kidney disease was the strongest independent risk factor (odds ratio: 12.473; CI: 5.944-26.172; P < .001), whereas surgical intervention or contrast agents were not associated with AKI.
Conclusions: Acute kidney injury in neurocritical care has a high incidence and is a crucial risk factor for mortality independently of the underlying neurocritical condition. Sepsis is the main cause of AKI in this setting. Therefore, careful prevention of infectious complications and considering CKD in treatment decisions may lower the incidence of AKI and hereby improve outcome in neurocritical care.
Artificial intelligence (AI)1, together with big data, is the driving force behind the ever-accelerating digital revolution. AI has what it takes to call into question our fundamental concepts and processes of political, social, economic etc. order (Macron, 2018; Zuboff, 2018), and the law will not be spared. Therefore, all societal actors (inter alia from politics, the economy, legal practice and academia) must take responsibility for the crucial twin tasks of determining the right, balanced relationship between AI and the law, and even to hybridise them. ...
Does economic policy uncertainty affect household stockholding? To answer this question we create a novel measure of household exposure to economic policy uncertainty news by combining survey information on the hours a household spends in reading newspapers and the frequency of such news in the popular press during a household’s pre-interview period. After controlling for household fixed effects, month-year fixed effects and time-varying cognitive skills, we find that households with a higher exposure to economic policy uncertainty news are less likely to invest in stocks held directly or through mutual funds. This effect is independent from the market volatility index and household (first-moment) expectations about the stock market index.
Background: Immigration has a strong impact on the development of health systems, medicine and science worldwide. Therefore, this article provides a descriptive study on the overall research output.
Methods: Utilizing the scientific database Web of Science, data research was performed. The gathered bibliometric data was analyzed using the established platform NewQIS, a benchmarking system to visualize research quantity and quality indices.
Findings: Between 1900 and 2016 a total of 6763 articles on immigration were retrieved and analyzed. 86 different countries participated in the publications. Quantitatively the United States followed by Canada and Spain were prominent regarding the article numbers. On comparing by additionally taking the population size into account, Israel followed by Sweden and Norway showed the highest performance. The main releasing journals are the Public Health Reports, the Journal of Immigrant and Minority Health and Social Science & Medicine. Over the decades, an increasing number of Public, Environmental & Occupational Health articles can be recognized which finally forms the mainly used subject area.
Conclusion: Considerably increasing scientific work on immigration cannot only be explained by the general increase of scientific work but is also owed to the latest development with increased mobility, worldwide crises and the need of flight and migration. Especially countries with a good economic situation are highly affected by immigrants and prominent in their publication output on immigration, since the countries’ publication effort is connected with the appointed expenditures for research and development. Remarkable numbers of immigrants throughout Europe compel medical professionals to consider neglected diseases, requires the public health system to restructure itself and finally promotes science.
Ein Hauptziel dieser Arbeit war die spektroskopische Charakterisierung einer neuartigen photolabilen Schutzgruppe (Photocage). Diese besteht aus dem weitverbreiteten (7-Diethylaminocumarin)methyl (DEACM), welches zusätzlich mit einer Art Antenne (ATTO 390) ausgestattet ist. Letztere soll die Zwei-Photonen-Absorption (2PA) erleichtern, was neben dem Energietransfer von der Antenne zur photolabilen Schutzgruppe sowie die Freisetzungsreaktion eines gebundenen Effektormoleküls untersucht wurde. Der Nachweis der erhöhten 2PA wurde durch Zwei-Photonen-induzierte Fluoreszenz erbracht, welche die Bestimmung des Zwei-Photonen-Einfangquerschnitts ermöglicht. Die 2PA wurde durch Messungen mit variierender Anregungsenergie an Rhodamin B und dem neuartigen Antennen-Photocage-System bestätigt, welche eine fast perfekte quadratische Abhängigkeit der Fluoreszenzintensität nach vorangegangener 2PA widerspiegelten. Die Werte des Zwei-Photonen-Einfangquerschnitts der neuartigen photolabilen Schutzgruppe sind über alle Wellenlängen hinweg größer als die von DEACM-OH. Der Beweis eines intramolekularen Energietransfers von der Antenne zu DEACM erfolgte durch transiente Absorptionsspektroskopie. Hierfür wurde der Photocage mit 365nm angeregt, was überwiegend die Antenne adressiert. Ein intramolekularer Energietransfer konnte mit einer Zeitkonstante von 20 ps beobachtet werden, welcher wahrscheinlich von einem nachgelagerten Ladungstransfer von DEACM auf ATTO 390 begleitet wurde. Die Funktionalität des neuartigen Photocages wurde durch Aufnahme von Absorptionsspektren im IR-Bereich während kontinuierlicher Belichtung bei 365 nm untersucht. Hierbei konnte die Entstehung der intensiven Absorption von Kohlendioxid aufgrund der Photodecarboxylierung detektiert werden. Absorptionsänderungen während kontinuierlicher Belichtung wurden ebenfalls im UV/Vis-Bereich detektiert, in welchen eine hypsochrome Verschiebung der langwelligen Absorptionsbande sowie ein Anstieg der Absorption festgestellt wurden. Hieraus konnte eine Quantenausbeute der Freisetzungsreaktion von 1,5% ermittelt werden. Die Ergebnisse zum Antennen-Photocage-System zeigen auf, dass durch Anbringen einer Antenne die 2PA verbessert werden kann, ohne die Funktionalität des Freisetzungsprozesses negativ zu beeinflussen. In einem nächsten Schritt zielen Verbesserungen des untersuchten Photocages darauf ab, den Ladungstransfer zu unterdrücken. Die Validierung dieses Ansatzes sollte die Einführung anderer Antennen mit erhöhten Zwei-Photonen-Einfangquerschnitten, wie z.B. Quantenpunkte, weiter motivieren. Der zweite Ergebnisteil dieser Arbeit konzentriert sich auf drei verschiedene Photosysteme, die sich durch eine sehr kurzlebige Fluoreszenz auszeichnen, welche mit einem Kerrschalter aufgenommen wurde. Das erste der drei untersuchten Systeme umfasst eine kooperative BODIPY-DTE-Dyade(Bordipyrromethen-Dithienylethen), die einen hocheffizienten photochromen Förster-Resonanzenergietransfer aufweist. Dieser wurde durch verkürzte Lebenszeiten der Differenzsignale im transienten Absorptionsspektrum der Dyade im photostationären Zustand abgeleitet. In diesem stellt BODIPY-DTE eine hochkonjugierte Einheit dar, welches durch die geschlossene Form des photochromen DTEs einen Energietransfer vom photoangeregten BODIPY zum DTE ermöglicht. Bei diesem Prozess wird die Fluoreszenz des Donors um einige Größenordnungen reduziert. Die Ergebnisse der transienten Absorptionsmessung wurde durch ein zeitaufgelöstes Fluoreszenzexperimentbestätigt. Die detektierte Fluoreszenztransiente zerfällt mit einer Zeitkonstante von etwa 15 ps und weist somit sehr hohe Ähnlichkeit mit dem Signal des Grundzustandsbleichens (GSB) aus dem transienten Absorptionsexperiment auf. Des Weiteren wurde die photochrome Ringschlussreaktion eines wasserlöslichen Indolylfulgimids spektroskopisch charakterisiert. Transiente Absorptionsmessungen geben einen direkten Einblick in den Mechanismus der Reaktion, in welcher, nach Photoanregung, die Relaxation aus dem Franck-Condon Bereich und die schnelle biphasische Relaxation des Moleküls über die konische Durchschneidung abgeleitet werden kann. Zusätzlich wurden zeitaufgelöste Fluoreszenzmessungen mit Hilfe des Kerrschalters durchgeführt, da die stimulierte Emission (SE) in transienten Absorptionsmessungen durch die Überlagerung mehrerer Signale nicht vollständig zu erkennen war. Die globale Lebensdaueranalyse der mit dem Kerrschalter aufgenommenen Breitband-Fluoreszenz lieferte drei Zeitkonstanten, welche wesentliche Übereinstimmung mit den Zeitkonstanten aus der globalen Lebensdaueranalyse der transienten Absorptionsmessungen aufweisen. Schlussendlich wurde die Deaktivierung des elektronisch angeregten Zustands des flavinbindenden Dodecins aus Mycobacterium tuberculosis mit Hilfe von unterschiedlichen spektroskopischen Methoden charakterisiert. Stationäre Fluoreszenzmessungen bei unterschiedlichen pH-Werten zeigten bei pH 5 eine im Vergleich zu nahezu physiologischen Bedingungen (pH 7,5)reduzierte Fluoreszenz auf. Auffällig ist, dass diese Beobachtungen durch transiente Absorptionsmessungen nicht bestätigt werden konnten, da diese eine große Ähnlichkeit bezüglich der Dynamik und der spektralen Signatur zueinander besaßen. Ein negatives Signal, hervorgerufen durch die SE, wurde hierbei nicht gefunden. Allerdings konnte in den zerfallsassoziierten Spektren eine spektrale Signatur beobachtet werden, die auf eine SE hindeutete, welche allerdings mit größeren positiven Signalen überlagert ist. Dieser Aspekt wurde in einer Kerrschalter-Messung untersucht, in der eine schwache Emission bei pH 7,5 festgestellt werden konnte. Zusätzlich wies die Zerfallsdynamik der Emission Übereinstimmung mit dem GSB-Signal aus den transienten Absorptionsmessungen auf.
Testing for liver-related autoantibodies should be included in the workup of patients with hepatitis or cholestasis of unknown origin. Although most of these autoantibodies are not disease specific, their determination is a prerequisite to diagnose autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC), and they are components of the diagnostic scoring system in these diseases. In primary sclerosing cholangitis (PSC), on the other hand, autoantibodies are frequently present but play a minor role in establishing the diagnosis. In PSC, however, data on antibodies suggest a link between disease pathogenesis and the intestinal microbiota. This review will focus on practical aspects of antibody testing in the three major autoimmune liver diseases AIH, PBC, and PSC.
In AD 79 the town of Herculaneum was suddenly hit and overwhelmed by volcanic ash-avalanches that killed all its remaining residents, as also occurred in Pompeii and other settlements as far as 20 kilometers from Vesuvius. New investigations on the victims' skeletons unearthed from the ash deposit filling 12 waterfront chambers have now revealed widespread preservation of atypical red and black mineral residues encrusting the bones, which also impregnate the ash filling the intracranial cavity and the ash-bed encasing the skeletons. Here we show the unique detection of large amounts of iron and iron oxides from such residues, as revealed by inductively coupled plasma mass spectrometry and Raman microspectroscopy, thought to be the final products of heme iron upon thermal decomposition. The extraordinarily rare preservation of significant putative evidence of hemoprotein thermal degradation from the eruption victims strongly suggests the rapid vaporization of body fluids and soft tissues of people at death due to exposure to extreme heat.
Background: Bacterial meningitis is associated with high mortality and long-term neurological sequelae. Increasing the phagocytic activity of microglia could improve the resistance of the CNS against infections. We studied the influence of activin A, a member of the TGF-β family with known immunoregulatory and neuroprotective effects, on the functions of microglial cells in vitro.
Methods: Primary murine microglial cells were treated with activin A (0.13 ng/ml–13 μg/ml) alone or in combination with agonists of TLR2, 4, and 9. Phagocytosis of Escherichia coli K1 as well as release of TNF-α, IL-6, CXCL1, and NO was assessed.
Results: Activin A dose-dependently enhanced the phagocytosis of Escherichia coli K1 by microglial cells activated by agonists of TLR2, 4, and 9 without further increasing NO and proinflammatory cytokine release. Cell viability of microglial cells was not affected by activin A.
Conclusions: Priming of microglial cells with activin A could increase the elimination of bacteria in bacterial CNS infections. This preventive strategy could improve the resistance of the brain to infections, particularly in elderly and immunocompromised patients.
Lymphangioleiomyomatosis (LAM) is a rare disease that generally affects young women and involves the abnormal proliferation of smooth muscle-like cells (LAM cells) in the lungs (pulmonary LAM) and extrapulmonary sites (extrapulmonary LAM). This disease is rare in males. It is hard to distinguish between lung cancer and pulmonary LAM, especially during early stages. Herein, we present a case of a 66-year-old man with a small nodule in the right upper lobe that was first diagnosed as a lung malignancy using a chest CT scan. After a wedge dissection, a pathologist performed a histologic and immunohistochemical examination, and a diagnosis of pulmonary LAM was made. We further performed a 518-gene panel analysis using next-generation sequencing, and only three genes, BARD1, BLM, and BRCA2, were found to have mutations. We also provide a summary of the diagnosis and treatment of this disease.
Cyclin-dependent kinase (CDK) 4/6 inhibitors have shown great results in numerous clinical trials and have improved the clinical outcome for patients with hormone-receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer significantly. To date, three CDK4/6 inhibitors are approved by the US Food and Drug Administration (FDA): palbociclib, ribociclib and abemaciclib; the first two compounds are aproved by the European Medicines Agency (EMA) as well. In combination with endocrine therapy, all of them led to significantly improved progression-free survival compared with endocrine therapy alone. The aim of this article is to give an overview of the efficacy data and to describe the CDK4/6 inhibitor-based treatment-associated adverse events, including hematological and nonhematological adverse events. In addition, it describes the corrrect approach to patient monitoring and adverse event mangement and summarizes the current recommendations for dose reductions and dose interruptions regarding the key adverse events, such as neutropenia, diarrhea, QTc prolongation and hepatobiliary toxicity. Accurate patient monitoring and management of the side effects is crucial, as several clinical trials in early breast cancer are in progress and may lead to an additional approval in the neo-/adjuvant setting.
BACKGROUND: Adjuvant chemotherapy (ACT) for breast cancer improves relapse-free survival (BCRFS) and overall survival. Differences in terms of efficacy and toxicity could partly be explained by the significant interpatient variability in pharmacokinetics which cannot be captured by dosing according to body surface area. Consequently, tailored dosing was prospectively evaluated in the PANTHER trial.
PATIENTS AND METHODS: PANTHER is a multicenter, open-label, randomized phase III trial which compared tailored, dose-dense (DD) epirubicin/cyclophosphamide (E/C) and tailored docetaxel (D) (tDD) with standard interval 5-fluorouracil/E/C and D. The primary end point was BCRFS and the primary efficacy analysis has been previously published. In this secondary analysis, we aimed to retrospectively explore the concept of dose tailoring. Our two hypotheses were that BCRFS would not vary depending on the cumulative administered epirubicin dose; and that dose tailoring would lead to appropriate dosing and improved outcomes for obese patients, who are known to have worse prognosis and increased toxicity after DD ACT.
RESULTS: Patients treated with tDD had similar BCRFS regardless of the cumulative epirubicin dose (P = 0.495), while obese patients in this group [body mass index (BMI) ≥30] had improved BCRFS compared with nonobese ones (BMI <30) [hazard ratio (HR) = 0.51, 95% confidence interval (CI) 0.30-0.89, P = 0.02]. Moreover, tDD was associated with improved BCRFS compared with standard treatment only in obese patients (HR = 0.49, 95% CI 0.26-0.90, P = 0.022) but not in nonobese ones (HR = 0.79, 95% CI 0.60-1.04, P = 0.089). The differences were not formally statistically significant (P for interaction 0.175). There were no differences in terms of toxicity across the epirubicin dose levels or the BMI groups.
CONCLUSIONS: Dose tailoring is a feasible strategy that can potentially improve outcomes in obese patients without increasing toxicity and should be pursued in further clinical studies.
Background: The management of intraductal papilloma without atypia (IDP) in breast needle biopsy remains controversial. This study investigates the upgrade rate of IDP to carcinoma and clinical and radiologic features predictive of an upgrade. Methods: Patients with a diagnosis of IDP on image-guided (mammography, ultrasound, magnetic resonance imaging) core needle or vacuum-assisted biopsy and surgical excision of this lesion at a certified breast center between 2007 and 2017 were included in this institutional review board-approved retrospective study. Appropriate statistical tests were performed to assess clinical and radiologic characteristics associated with an upgrade to malignancy at excision. Results: For 60 women with 62 surgically removed IDPs, the upgrade rate to malignancy was 16.1% (10 upgrades, 4 invasive ductal carcinoma, 6 ductal carcinoma in situ). IDPs with upgrade to carcinoma showed a significantly greater distance to the nipple (63.5 vs. 36.8 mm; p = 0.012). No significant associations were found between upgrade to carcinoma and age, menopausal status, lesion size, microcalcifications, BI-RADS descriptors, initial BI-RADS category, and biopsy modality. Conclusion: The upgrade rate at excision for IDPs diagnosed with needle biopsy was higher than expected according to some guideline recommendations. Observation only might not be appropriate for all patients with IDP, particularly for those with peripheral IDP.
During a survey of the fishes in the region of the Wonga-Wongué Presidential Reserve, 14 new populations of the subgenus Chromaphyosemion Myers, 1924 were found. These observations extend the previously known distribution range of the subgenus 120 kilometres southward. None of these populations could be related to any described species. Based on the colouration of the males and females, together with a genetic marker (mitochondrial DNA cytochrome b sequences), the populations studied are grouped into six new species which are described in this article, all close to Aphyosemion alpha Huber, 1998 with which they share the presence of a black alpha-shaped mark on the pre- and post-opercular region. The group composed of A. alpha and the six new species is referred to here as the A. alpha species group. All the new species, A. aurantiacum Chirio, Legros & Agnèse sp. nov., A. barakoniense Chirio, Legros & Agnèse sp. nov., A. flammulatum Chirio, Legros & Agnèse sp. nov., A. flavocyaneum Chirio, Legros & Agnèse sp. nov., A. pusillum Chirio, Legros & Agnèse sp. nov. and A. rubrogaster Chirio, Legros & Agnèse sp. nov., are further unambiguously diagnosed by unique combinations of colour patterns, making it possible to generate an identification key for the A. alpha species group. It is likely that the coastal dunes of Wonga-Wongué that form a sandy relief, could have led to the fragmentation and then isolation of the hydrographical networks that flow into the Atlantic Ocean, making possible a significant number of allopatric speciations.
Impaired NO-cGMP signaling has been linked to several neurological disorders. NO-sensitive guanylyl cyclase (NO-GC), of which two isoforms—NO-GC1 and NO-GC2—are known, represents a promising drug target to increase cGMP in the brain. Drug-like small molecules have been discovered that work synergistically with NO to stimulate NO-GC activity. However, the effects of NO-GC stimulators in the brain are not well understood. In the present study, we used Förster/fluorescence resonance energy transfer (FRET)-based real-time imaging of cGMP in acute brain slices and primary neurons of cGMP sensor mice to comparatively assess the activity of two structurally different NO-GC stimulators, IWP-051 and BAY 41-2272, in the cerebellum, striatum and hippocampus. BAY 41-2272 potentiated an elevation of cGMP induced by the NO donor DEA/NO in all tested brain regions. Interestingly, IWP-051 potentiated DEA/NO-induced cGMP increases in the cerebellum and striatum, but not in the hippocampal CA1 area or primary hippocampal neurons. The brain-region-selective activity of IWP-051 suggested that it might act in a NO-GC isoform-selective manner. Results of mRNA in situ hybridization indicated that the cerebellum and striatum express NO-GC1 and NO-GC2, while the hippocampal CA1 area expresses mainly NO-GC2. IWP-051-potentiated DEA/NO-induced cGMP signals in the striatum of NO-GC2 knockout mice but was ineffective in the striatum of NO-GC1 knockout mice. These results indicate that IWP-051 preferentially stimulates NO-GC1 signaling in brain slices. Interestingly, no evidence for an isoform-specific effect of IWP-051 was observed when the cGMP-forming activity of whole brain homogenates was measured. This apparent discrepancy suggests that the method and conditions of cGMP measurement can influence results with NO-GC stimulators. Nevertheless, it is clear that NO-GC stimulators enhance cGMP signaling in the brain and should be further developed for the treatment of neurological diseases.
The neomycin sensing riboswitch is the smallest biologically functional RNA riboswitch, forming a hairpin capped with a U-turn loop—a well-known RNA motif containing a conserved uracil. It was shown previously that a U→C substitution of the eponymous conserved uracil does not alter the riboswitch structure due to C protonation at N3. Furthermore, cytosine is evolutionary permitted to replace uracil in other U-turns. Here, we use molecular dynamics simulations to study the molecular basis of this substitution in the neomycin sensing riboswitch and show that a structure-stabilizing monovalent cation-binding site in the wild-type RNA is the main reason for its negligible structural effect. We then use NMR spectroscopy to confirm the existence of this cation-binding site and to demonstrate its effects on RNA stability. Lastly, using quantum chemical calculations, we show that the cation-binding site is altering the electronic environment of the wild-type U-turn so that it is more similar to the cytosine mutant. The study reveals an amazingly complex and delicate interplay between various energy contributions shaping up the 3D structure and evolution of nucleic acids.
As adapter molecules to convert the nucleic acid information into the amino acid sequence, tRNAs play a central role in protein synthesis. To fulfill this function in a reliable way, tRNAs exhibit highly conserved structural features common in all organisms and in all cellular compartments active in translation. However, in mitochondria of metazoans, certain dramatic deviations from the consensus tRNA structure are described, where some tRNAs lack the D- or T-arm without losing their function. In Enoplea, this miniaturization comes to an extreme, and functional mitochondrial tRNAs can lack both arms, leading to a considerable size reduction. Here, we investigate the secondary and tertiary structure of two such armless tRNAs from Romanomermis culicivorax. Despite their high AU content, the transcripts fold into a single and surprisingly stable hairpin structure, deviating from standard tRNAs. The three-dimensional form is boomerang-like and diverges from the standard L-shape. These results indicate that such unconventional miniaturized tRNAs can still fold into a tRNA-like shape, although their length and secondary structure are very unusual. They highlight the remarkable flexibility of the protein synthesis apparatus and suggest that the translational machinery of Enoplea mitochondria may show compensatory adaptations to accommodate these armless tRNAs for efficient translation.
The statistical model with exact conservation of baryon number, electric charge, and strangeness – the Canonical Statistical Model (CSM) – is used to analyze the dependence of yields of light nuclei at midrapidity on charged pion multiplicity at the LHC. The CSM calculations are performed assuming baryon-symmetric matter, using the recently developed Thermal-FIST package. The light nuclei-to-proton yield ratios show a monotonic increase with charged pion multiplicity, with a saturation at the corresponding grand-canonical values in the high-multiplicity limit, in good qualitative agreement with the experimental data measured by the ALICE collaboration in pp and Pb–Pb collisions at different centralities and energies. Comparison with experimental data at low multiplicities shows that exact conservation of charges across more than one unit of rapidity and/or a chemical freeze-out temperature which decreases with the charged pion multiplicity improves agreement with the data.
Background: Transient elastography (TE) has been validated as an effective noninvasive tool for the assessment of liver fibrosis. The XL probe is a new probe that was initially designed for use in patients with obesity. A meta-analysis was performed to assess the feasibility and efficacy of TE using the XL probe.
Methods: In September 2016, we systematically searched the PubMed and Science Direct search engines. The feasibility of TE was evaluated based on the failure rate and the results of the unreliable liver stiffness measurement (LSM). The efficacy of TE was measured using sensitivity, specificity, and summary receiver-operating characteristic as measures/indices assessed in different stages of fibrosis. Heterogeneity was measured using the chi-squared test and the Q-statistic. We used the 95% confidence interval (95% CI) as an effect measure.
Results: We included 8 studies in the meta-analysis. When the XL was compared to the M probe, the former showed a lower risk of failure rate [relative risk (RR) 0.24, 95% CI 0.14–0.38]. In patients with a body mass index ≥30 kg/m2, the XL probe showed a statistically significantly lower risk of failure rate (RR 0.16, 95% CI 0.08–0.32) but no significant improvement (RR 0.76, 95% CI 0.50–1.16) in the unreliable LSM result. In patients showing liver fibrosis stage ≥F2, the XL probe showed a sensitivity of 0.56 (95% CI 0.39–0.72), specificity of 0.71 (95% CI 0.61–0.79), and an area under the curve (AUC) of 0.71. The results observed in patients with liver fibrosis stage F4 were more promising with a sensitivity of 0.84 (95% CI 0.76–0.90), specificity of 0.78 (95% CI 0.70–0.84), and an AUC of 0.88.
Conclusion: TE using the XL probe demonstrates significant diagnostic utility in patients with liver fibrosis and is likely to be more reliable than the M probe in patients with obesity. Large prospective multicenter studies are, however, necessary to establish the new cut-off values to be used for the XL probe in patients with obesity.
Guide to active recruiting : attract more female faculty increase diversity – optimize quality
(2018)
Neuropogonoid species in the lichen-forming fungal genus Usnea exhibit great morphological variation that can be misleading for delimitation of species. We specifically focused on the species delimitation of two closely-related, predominantly Antarctic species differing in the reproductive mode and representing a so-called species pair: the asexual U. antarctica and the sexual U. aurantiacoatra. Previous studies have revealed contradicting results. While multi-locus studies based on DNA sequence data provided evidence that these two taxa might be conspecific, microsatellite data suggested they represent distinct lineages. By using RADseq, we generated thousands of homologous markers to build a robust phylogeny of the two species. Furthermore, we successfully implemented these data in fine-scale population genomic analyses such as DAPC and fineRADstructure. Both Usnea species are readily delimited in phylogenetic inferences and, therefore, the hypothesis that both species are conspecific was rejected. Population genomic analyses also strongly confirmed separated genomes and, additionally, showed different levels of co-ancestry and substructure within each species. Lower co-ancestry in the asexual U. antarctica than in the sexual U. aurantiacoatra may be derived from a wider distributional range of the former species. Our results demonstrate the utility of this RADseq method in tracing population dynamics of lichens in future analyses.
Authoritarian regimes and religious institutions in the Muslim majority world see eye-to-eye on the topic of atheism. United by their fear of losing control over their populations and their desire for conformity, consecutive governments have pushed for unfair restrictions on their subjects’ beliefs since their inception. But even in society, non-belief remains a taboo. Should atheists in Muslim majority world become more vocal?
The truth lies in Chemnitz?
(2018)
"Germany to the Germans! Foreigners out" was the central slogan of the racist riots in the city of Rostock in 1992. For around three days, neo-Nazis controlled the streets in the plattenbau district of Lichtenhagen where the central registration for asylum-seekers (as well as a housing block of Vietnamese contract workers) were situated. ...
In this research project we aimed to generate genetically modified megakaryocytes and platelets, by targeting protein expression to their secretory alpha-granules to delivery ectopic or therapeutic proteins, to be stored and kept there until an external stimulus triggers platelet activation and platelet secretion takes place. During platelet activation, the therapeutic proteins would then be released to the extracellular space, either as a soluble protein or exposed as a transmembrane protein on the cell surface of platelets. For long-term approaches, genetic modifications must be introduced at the hematopoietic stem cell level.
AIMS: As first approach, we aimed to characterize the lineage-specificity of expression of six different promoter fragments in lentiviral vectors: the murine platelet factor 4 (mPf4) 1222 bp (-1074 to +148), human glycoprotein Ib alpha (hGP1BA) 595 bp (-265 to +330), a short and a longer fragment of the human glycoprotein 6 (hGP6 / hGP6s) 351 bp (-322 to +29) / 726 bp (-697 to +29), as well the human glycoprotein 9 (GP9) promoter 794 bp (-782 to -12). These promoter fragments were included as internal cellular promoters in self-inactivating lentiviral vectors (SIN), using an enhanced green fluorescent protein (eGFP) as gene reporter. GFP detection was evaluated in vitro (in transduced non-megakaryocitc blood cell progenitors and in-vitro differentiated megakaryocytes) and in vivo (Bone marrow cells, blood cells and spleen cells). For targeting of proteins to the secretory alpha granules of megakaryocytes and platelets, we followed two strategies: A) The sorting signal of the cytokine RANTES was fused N-terminally to the destabilized GFP, d2eGFP (RANTES. d2eGFP), to deliver the protein into the granules as soluble cargo. B) The transmembrane granular targeting sequence of P-selectin (the transmembrane domain and cytoplasmic tail (referred as TDCT) was fused to d2eGFP or the B domain deleted codon optimized human coagulation Factor VIII cDNA (referred as BDcohFVIII_TDCT or FVIII_TDCT), to deliver the protein into the membrane of alpha granules. These two strategies were tested in-vitro, from transduced differentiated megakaryocytes in liquid cultures, and in-vivo, by analysis of genetically modified platelets by means of Laser Scanning Confocal Microscopy (LSM) in colocalization analysis (performed at the single cell level) and fluorescence intensity analysis.
RESULTS: GFP expression in blood cells from transplanted mice was significantly higher in platelets, with a smaller background promoter activity in leukocytes and erythrocytes. The highest expression was observed from the mPf4-vector, followed by hGP1BA, hGP6 and hGP6s vectors, identifying the hGP6 vectors as the most restricted to the megakaryocyte and platelet lineage. Analysis in bone marrow cells showed that hGP6-vectors have the lowest activity in the hematopoietic stem and progenitor cells (HSPC) with less than 10% of GFP positive stem cells. Surprisingly, the mPf4 and hGP1BA vectors were both highly active in the HSPC, in a range of 20 to 70% of GFP-positive cells. Polyploidization in later stages of MK-maturation of in-vitro Mks differentiated from Mpl-/- lineage marker negative cells were recovered after gene transfer of the thrombopoietin receptor Mpl, under the control of MK-specific vectors in differentiated into MKs. These results were corroborated in in-vivo analysis, where Mpl-/- mice transplanted with lin-BM cells transduced with the mPf4.Mpl and hGP6.Mpl vectors, showed significantly elevated platelet counts compared to control mice transplanted with a GFP-encoding control vector (PGK-GFP). In the Fluorescent intensity and colocalization analysis of transduced megakaryocytes with the targeting vectors, we observed a significant difference in the GFP targeting compared with those MK transduced with the non-targeting vectors. The median of the WCC values observed from the RANTES.d2eGFP targeting vector was 0.8 (80 % of colocalization) with P-selectin stained granules, and 0.7 (70%) with von Willebrand Factor stained granules. In the case of the non-targeting vector SFFV.d2eGFP the median of the WCC observed were <0.3 (30%) both in P-selectin and von Willebrand Factor stained granules. We observed as well that the GFP signal of MK transduced with the P-selectin.d2eGFP fusion overlapped the signals emitted by P-selectin and von Willebrand factor stained granules, not just in LSM-digitalized images but in the fluorescens intensity analysis as well, indicating a clear signal of GFP colocalization. Likewise, an evident signal overlap between the targeted FVIII (FVIII_TDCT) with the P-selectin / von Willebrand marker was observed. Colocalization and fluorescens intensity analysis performed on activated platelets from transplanted mice with the targeting vectors, corroborated what was previously observed in in-vitro megakaryocytes. The genetic modification of megakaryocyte and platelets will allow in the furture, not just the development of new generation of cells with advanced functions, but it will help us to elucidate new mechanisms and pathways of important cellular processes, by modifying cell function and cell interactions.
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.
Cell-free-synthesized voltage-gated proton channels: Approaches to the study of protein dynamics
(2018)
We often only realize how important health is when diseases manifest themselves through their symptoms and, ultimately, in a diagnosis. Over time, we suffer from many diseases starting with the first childhood disease to colds to gastrointestinal infections. Most diseases pass harmlessly and symptoms fade away. However, not all diseases are so harmless. Alzheimer’s disease, breast cancer, Parkinson’s disease, and colorectal cancer usually cause severe illness with high mortality rates. In pharmaceutical research, efforts are therefore being made to determine the molecular basis of them in order to provide patients with potential relief and, at best, healing. A special group of regulators, involved in the previously mentioned diseases, are voltage-gated proton channels. Thus, the understanding of their structure, function, and potential drug interaction is of great importance for humanity.
Voltage-gated proton channels are localized in the cell membrane. As their name indicates, they are controlled by voltage changes. Depolarization of the cell membrane induces conformational changes that open these channels allowing protons to pass through. Here, the transfer is based on a passive process driven by a concentration gradient between two individual compartments separated by the cell membrane. Voltage-gated proton channels are highly selective for protons and show a temperature- and pH-dependent gating behavior. However, little is known about their channeling mechanism. Previous experimental results are insufficient for understanding the key features of proton channeling.
In this thesis, for the first time, the cell-free production of voltage-sensing domains (VSD) of human voltage-gated proton channels (hHV1) and zebrafish voltage-sensing phosphatases (DrVSP) is described. Utilizing the cell free approach, parameters concerning protein stability, folding and labeling can be easily addressed. Furthermore, the provision of a membrane mimetic in form of detergent micelles, nanodiscs, or liposomes for co-translational incorporations of these membrane proteins is simple and efficient. Both VSDs were successfully produced up to 3 mg/ml. Furthermore, the cell-free synthesis enabled for the first time studies of lipid-dependent co-translational VSD insertions into nanodiscs and liposomes. Cell-free produced VSDs were shown to be active, and to exist mainly as dimers. In addition, also their activation was stated to be lipid-dependent, which has not been described so far. Solution-state NMR experiments were performed with fully and selectively labeled cell-free produced VSDs. With respect to the development of potential drug candidates, I could demonstrate the inhibition of the VSDs by 2-guanidinobenzimidazole (2GBI). Determined KD values were comparable to literature data for the human construct. For the first time, a low affinity for 2GBI of the zebrafish VSD could be described.
In future, the combination of a fast, easy and cheap cell-free production of fully or selectively labeled VSDs and their analysis by solution state NMR will enable structure determinations as well as inhibitor binding studies and protein dynamic investigations of those proteins. The results of these investigations will serve as a basis for example for the development of new drugs. In addition, a detailed description of the lipid-dependent activity might be helpful in controlling the function of voltage-gated proton channels in cancer cells and thereby reducing their growth or disturbing their cell homeostasis in general.
It may indeed seem that while the late 1970s and early 1980s were the period when theory was successfully established in western academic discourse, we have now entered an era "after theory" in which not only 'cultural theory' has come to an end but also a specific culture of theory has vanished from our seminars, departments, and universities: a culture of reflection, abstraction, and self-referentiality that had been at the heart of the humanities from the very beginning. And yet, theory is not so easily abolished but rather stored and maintained within each individual reading of a literary text in spite of empirical trends such as DH or pessimistic manifestos. Therefore, in what follows, Nicolas Pethes is interested in an additional aspect of the textual resistance of theory against the institutional resistance to theory: the relation between theory and practice, that is: the question whether acting is also one of the many languages of theory.
In recent years, the interest in theory which has once been a moving force of academic research in the field of literary studies appears to have decreased. The status of theory, its relevance and appropriateness for the understanding of literature have been put into doubt. Faced with this observation, some critics have even suggested that we have now entered into a new era of research which can retrospectively be identified as the era "after theory". Against the background of such pronouncements and to a certain extent in opposition to them, the investigations proposed here wish to uphold the idea of the utility and indeed the need for theoretical approaches to literature. To appreciate the status of theory and its possible contribution to a deepened understanding of literature, it is useful not to focus exclusively on the distinction or supposed divide between literature and theory. Instead we should pay attention to what links and unites them. This common ground or common denominator of literature and theory consists in the dimension of language. Furnishing, so to speak, the intellectual material from which both domains of articulation are formed, language constitutes at once the key element of literature and a principal concern of theory.
Aim: Participation of medical students in the conceptual development of targeted and attractive teaching content for rural areas.
Method: A questionnaire was developed to gather information on students' views of their current medical studies, career interests, and what requirements should be met by an optional rural health program in general practice. By means of an online survey in summer 2015, all medical students from the fourth preclinical semester onwards (n=2,150) at Goethe University Frankfurt were surveyed on one occasion. Statistical analysis was mainly descriptive. Personal attitudes towards a career as a family practitioner were examined for statistical significance. Further information was gathered on whether a measurable correlation exists between personal background and desired work location.
Results: Of the 2,150 students that were contacted, 617 participated in the survey (response rate=28.7%). The results covered a wide range of ideas and recommendations and were representative both of medical students with a positive attitude toward general practice, as well as those that were rather critical of teaching in general practice. The students expected the planned health program to be of strong practical relevance and to acquaint them with the administrative and economic aspects of running a practice.
Conclusions: By including the target group in the development process, it was possible to tailor the health program to meet the needs of future participants more precisely. Student participation can also be expected to result in greater acceptance of the program. The results on teaching content may also provide other medical faculties with orientation when developing comparable programs.
By the fabrication of periodically arranged nanomagnetic systems it is possible to engineer novel physical properties by realizing artificial lattice geometries that are not accessible via natural crystallization or chemical synthesis. This has been accomplished with great success in two dimensions in the fields of artificial spin ice and magnetic logic devices, to name just two. Although first proposals have been made to advance into three dimensions (3D), established nanofabrication pathways based on electron beam lithography have not been adapted to obtain free-form 3D nanostructures. Here we demonstrate the direct-write fabrication of freestanding ferromagnetic 3D nano-architectures. By employing micro-Hall sensing, we have determined the magnetic stray field generated by our free-form structures in an externally applied magnetic field and we have performed micromagnetic and macro-spin simulations to deduce the spatial magnetization profiles in the structures and analyze their switching behavior. Furthermore we show that the magnetic 3D elements can be combined with other 3D elements of different chemical composition and intrinsic material properties.
Fabrication of three-dimensional (3D) nanoarchitectures by focused electron beam induced deposition (FEBID) has matured to a level that highly complex and functional deposits are becoming available for nanomagnetics and plasmonics. However, the generation of suitable pattern files that control the electron beam’s movement, and thereby reliably map the desired target 3D structure from a purely geometrical description to a shape-conforming 3D deposit, is nontrivial. To address this issue we developed several writing strategies and associated algorithms implemented in C++. Our pattern file generator handles different proximity effects and corrects for height-dependent precursor coverage. Several examples of successful 3D nanoarchitectures using different precursors are presented that validate the effectiveness of the implementation.
Three-dimensional (3D) nanomagnetism, where spin configurations extend into the vertical direction of a substrate plane allow for more complex, hierarchical systems and the design of novel magnetic effects. As an important step towards this goal, we have recently demonstrated the direct-write fabrication of freestanding ferromagnetic 3D nano-architectures of ferromagnetic CoFe in shapes of nano-tree and nano-cube structures by means of focused electron beam induced deposition. Here, we present a comprehensive characterization of the magnetic properties of these structures by local stray-field measurements using a high-resolution micro-Hall magnetometer. Measurements in a wide range of temperatures and different angles of the externally applied magnetic field with respect to the surface plane of the sensor are supported by corresponding micromagnetic simulations, which explain the overall switching behavior of in part rather complex magnetization configurations remarkably well. In particular, the simulations yield coercive and switching fields that are in good quantitative correspondence with the measured coercive and switching fields assuming a bulk metal content of 100 at % consisting of bcc Co 3 Fe. We show that thermally-unstable magnetization states can be repetitively prepared and their lifetime controlled at will, a prerequisite to realizing dynamic and thermally-active magnetic configurations if the building blocks are to be used in lattice structures.
This article pinpoints the double being and doing of weapons, warriors and warrior fraternities as quite possibly a characterising trait from the onset of the Corded Ware period well into the mature Bronze Age and beyond. Exquisitely crafted weapons of bronze – many spirited with a life-energy of their own – were used to wage war and sometimes to hack victims into pieces with strong indications that the beautiful warrior with his trained well-groomed body was capable of extreme violence. The companionship of warrior peers in the fraternity was a social construct enabling effective waging of war as well as fulfilling other roles in Bronze Age society, contributing to rituals and social interaction.
Neuronal calcium signals propagating by simple diffusion and reaction with mobile and stationary buffers are limited to cellular microdomains. The distance intracellular calcium signals can travel may be significantly increased by means of calcium-induced calcium release from internal calcium stores, notably the endoplasmic reticulum. The organelle, which can be thought of as a cell-within-a-cell, is able to sequester large amounts of cytosolic calcium ions via SERCA pumps and selectively release them into the cytosol through ryanodine receptor channels leading to the formation of calcium waves. In this study, we set out to investigate the basic properties of such dendritic calcium waves and how they depend on the three parameters dendrite radius, ER radius and ryanodine receptor density in the endoplasmic membrane. We demonstrate that there are stable and abortive regimes for calcium waves, depending on the above morphological and physiological parameters. In stable regimes, calcium waves can travel across long dendritic distances, similar to electrical action potentials. We further observe that abortive regimes exist, which could be relevant for spike-timing dependent plasticity, as travel distances and wave velocities vary with changing intracellular architecture. For some of these regimes, analytic functions could be derived that fit the simulation data. In parameter spaces, that are non-trivially influenced by the three-dimensional calcium concentration profile, we were not able to derive such a functional description, demonstrating the mathematical requirement to model and simulate biochemical signaling in three-dimensional space.
Continuous blood glucose monitoring reveals enormous circadian variations in pregnant diabetic rats
(2018)
Aim: Diabetes in pregnancy is a major burden with acute and long-term consequences. Its treatment requires adequate diagnosis and monitoring of therapy. Many experimental research on diabetes during pregnancy has been performed in rats. Recently, continuous blood glucose monitoring of non-pregnant diabetic rats revealed an increased circadian variability of blood glucose that made a single blood glucose measurement per day inappropriate to reflect glycemic status. Continuous blood glucose measurement has never been performed in pregnant rats. We wanted to perform continuous blood glucose monitoring in pregnant rats to decipher the influence of pregnancy on blood glucose in diabetic and normoglycemic status.
Methods: We used the transgenic Tet29 diabetes rat model with an inducible knock down of the insulin receptor via RNA interference upon application of doxycycline (DOX) leading to insulin resistant type II diabetes. All Tet29 rats received a HD-XG telemetry implant (Data Sciences International, USA) that measured blood glucose and activity continuously. Rats were divided into four groups and blood glucose was monitored until end of pregnancy or the corresponding period: Tet29 + DOX (diabetic) non-pregnant, Tet29 + DOX (diabetic) pregnant, Tet29 (normoglycemic) non-pregnant, Tet29 (normoglycemic) pregnant.
Results: All analyzed rats displayed a circadian variation in blood glucose concentration. Circadian variability was much more pronounced in pregnant diabetic rats than in normoglycemic pregnant rats. Pregnancy ameliorated variation in blood glucose in diabetic situation. Pregnancy continuously decreased blood glucose during normoglycemic pregnancy. Diabetic rats were less active than normoglycemic rats. We performed a calculation showing that application of continuous blood glucose measurement reduces animal numbers needed to detect a given effect in experimental setting by decreasing variability and SD.
Interpretation: Continuous blood glucose monitoring via a telemetry device in pregnant rats provides a more informative picture of the glycemic situation in comparison to single measurements. This could improve diagnosis and therapy of diabetes, decrease animal numbers within experimental settings, and add another physiological parameter (activity) to the analysis that could be helpful in testing therapeutic concepts targeting blood glucose levels and peripheral muscle function. We propose continuous glucose monitoring as a new tool for the evaluation of pregnant diabetic rats.
NeoBiota, Volume 38 (2018)
(2018)
NeoBiota, Volume 37 (2018)
(2018)
The genetic mutation of the coagulation factor VIII (fVIII) results in a defective or missing protein, leading to a malfunctioning blood coagulation. The resulting disease is called hemophilia A. Depending on the severity of the mutation, affected patients experience an increased risk of pathologic bleeding after minor trauma or even sudden bleeding events. Substitution therapies with extrinsic fVIII exist using plasmatic or recombinant fVIII products. Due to an insufficient immune tolerance towards substituted fVIII, about 30 % of patients develop allogenic neutralizing antibodies (inhibitors) against substituted fVIII products. The gold standard of treating inhibitors is the immune tolerance induction (ITI), where patients are given frequent, high doses of fVIII to induce an immune tolerance. ITI therapy fails in about 30 % of patients. Mechanisms of action of ITI are part of research, as insufficient knowledge about mechanisms and prognostic factors complicate treatment. For example, the development of anti-idiotypic antibodies, which occur naturally as a regulatory mechanism of the immune system, are being studied. Such anti-idiotypes have been detected in immunoglobuline preparations and in patients after successful ITI.
Inhibitors interfere with fVIII function in coagulation by binding functional epitopes within fVIII domains. Inhibitors against the A2 and C2 domain are predominantly found, however also the C1 domain has been shown to be highly immunogenic in some patients. The polyclonality of inhibitors aggravates the understanding and treatment of these. The present project therefore focusses on the selection of synthetic anti-idiotypic antibodies to target inhibitors in patients. The phage display method was applied to, for one, isolate anti-idiotypic single chain variable fragments (scFvs) specific against human polyclonal anti-fVIII antibodies and second against two C1 domain-specific inhibitory monoclonal antibodies (mAbs).
In the first project, anti-fVIII antibodies were purified from human plasma to serve as target molecules. A previous project showed that using full plasma as a target did not yield anti-idiotypic antibodies from phage display. For the purification, protein A chromatography and fVIII coupled Affi Gel® chromatography were applied. The isolated antibodies were next used as targets for the selection of anti-idiotypic scFvs. Analysis revealed that none of the selected phages solely bound the anti-fVIII antibody target. Consequently, the test protocol was modified, which resulted in a reduction of unspecific binders. Yet, no target-specific binders were isolated from phage pools. Reason for this may have been the high diversity of the polyclonal antibody target and the limited diversity of the phage libraries.
The aim of the second project, was the selection and characterization of scFvs, that target the paratopes of C1 domain-specific mAbs GMA8011 and LE2E9. From a therapeutic viewpoint, the preparation of an anti-idiotypic antibody pool, tailored to each patient’s inhibitor population, could help neutralize inhibitors in patients. Ultimately, one GMA8011-specific scFv-carrying phage clone (H2C1) and two specifics to LE2E9 (H3G7, H3F10) were isolated. In further experiments, only the GMA8011-specific scFv showed competitive behavior in presence of fVIII, pointing towards an anti-idiotypic binding to the inhibitor paratope. The LE2E9-specific scFvs did not prevent binding of the inhibitor to fVIII. Hence, no anti-idiotypic behavior could be determined. For further characterization, selected scFvs were genetically fused to Fc antibody fragments and recombinantly produced. In this antibody format, all three scFvs showed concentration dependent binding to the target and the isotype control. The binding specificity to the target, observed in phage context, could not be reproduced. Competition experiments with fVIII confirmed that none of the scFvs bound the paratope of their target inhibitor.
The selection of anti-idiotypic scFvs from phage display libraries proves to be effortful. Polyclonal anti-fVIII antibodies purified from hemophilic plasma appear to be unsuitable as a target for phage display, likely due to the high diversity of the target molecules. Furthermore, the preparation of an individualized anti-idiotypic pools for patients by selecting scFvs against single inhibitory mAbs proves to be difficult. The selection of scFvs against anti-C1 inhibitors GMA8011 and LE2E9 produced three promising scFv-carrying phages. However, analysis could not detect anti-idiotypic behavior. Further research with inhibitors, monoclonal and polyclonal, and anti-idiotypic antibodies should be performed to bring better insight into the highly complex paratope-epitope interaction.
The paper illustrates based on an example the importance of consistency between the empirical measurement and the concept of variables in estimated macroeconomic models. Since standard New Keynesian models do not account for demographic trends and sectoral shifts, the authors proposes adjusting hours worked per capita used to estimate such models accordingly to enhance the consistency between the data and the model. Without this adjustment, low frequency shifts in hours lead to unreasonable trends in the output gap, caused by the close link between hours and the output gap in such models.
The retirement wave of baby boomers, for example, lowers U.S. aggregate hours per capita, which leads to erroneous permanently negative output gap estimates following the Great Recession. After correcting hours for changes in the age composition, the estimated output gap closes gradually instead following the years after the Great Recession.
All lifeforms have to sense changes in their environment and adapt to possibly detrimental conditions. On a cellular level, the highly elaborate proteostasis network (PN) consisting of housekeeping and stress-induced proteins, confers this tolerance against stress and maintains cellular protein homoestasis. This is essential for survival, as an accumulation of stress-induced protein aggregation will eventually affect the functionality of crucial cellular components and ultimately lead to cell death. The guardians of this balance are the molecular chaperones and their activity-regulating co-haperones. They are engaged in all aspects of protein biogenesis, maintenance and degradation, especially during stress.
The heat shock proteins (HSPs) are the major chaperones in mammals and encompass constitutive and stress-induced isoforms. Among them, the HSP70 and the HSP90 family are the most abundant HSPs and their activity is involved in a great variety of homoestasis and stress-induced tasks.
As part of the protein triage the E3 ligase CHIP (C-terminal HSC70-interacting protein) is an essential activity regulating co-chaperone of HSP70 and HSP90 which provides a link between chaperone mediated protein-folding and various degradation pathways. Due to its decisive function, CHIP is involved in a wide array of cellular processes, especially in clearing misfolded HSP70 client proteins that are prone to aggregate. As a consequence, CHIP was reported to confer protection against many aggregation-induced pathologies of the neuronal system. Additionally, CHIP has been identified as a critical factor in various types of cancer and is implied to affect the development and the longevity of mammals.
Despite the significant progress in the understanding of CHIP’s structure and function, many aspects surrounding its chaperone dependency and its substrate recognition remain unclear. Moreover, due to the variety of substrates in diverse cellular pathways, there are yet many connections to elucidate between CHIP and components of the cellular proteostasis network.
The work of this thesis was focused on the role of CHIP in acute stress response and the corresponding status of chaperone association. Moreover, it was investigated if CHIP, as the connecting ligase of folding and degradation systems, might also provide a link between the PN and the reorganisation of the cellular architecture upon stress exposure.
This has become of increasing interest as recent reports highlight the importance of spatial sequestration in protein quality control.
To this end, subcellular distribution of CHIP was analysed by live-cell microscopy during heat stress. It became obvious that during the heat-induced challenge of the chaperone system, CHIP migrated to new cellular sites. Further experiments suggested that the observed migration to the plasma membrane is a chaperone-independent process and in vitro reconstitution of membrane association confirmed the competitive nature of membranes and chaperones for CHIP binding. A detailed in vivo and in vitro analysis of the newly observed membrane association of CHIP revealed a distinct lipid specificity and a novel direct association with lipids. Binding experiments with recombinantly purified deletion mutants of CHIP identified the TPR domain and a positive patch in the coiled-coil domain as main determinants for the lipid association. Through biochemical and biophysical approaches, the structural integrity and functionality of CHIP upon membrane binding was confirmed and further characterised.
Moreover, mass spectrometry analysis provided a high confidence identification of chaperone-free interactors of CHIP at the plasma membrane and other membranous compartments.
In accordance with the lipid specificity, the Golgi apparatus was one of these sites. Only chaperone-free CHIP had a significant effect on the morphology of the organelle, again confirming the competitive role of chaperones and lipids. With respect to the physiological consequences of the changed localisation of CHIP, preliminary results indicated increased cell death when the ligase localises to cellular membranes. The results lead to the conclusion that CHIP acts as an initiator of early stress adaptation and as a sensor for the severity and strength of the stress reaction.
Reactive oxygen species (ROS) are involved in various signalling mechanisms. Redox homeostasis is important in cancer cells, since they are dependent on upregulated antioxidant defence pathways to cope with elevated ROS levels. Therefore, targeting the antioxidant defence system and/ or increasing ROS to a lethal level may be a feasible strategy to counteract cancer cell progression.
Acute lymphoblastic leukaemia (ALL) is the most frequent malignant childhood cancer, displaying on one side resistance to cell death induction and on the other side elevated ROS levels. Therefore, inducing ferroptosis, a ROS- and iron-dependent cell death pathway might be useful to trigger cell death in ALL as a novel treatment strategy. In the first study of this thesis we observed that RSL3, a glutathione (GSH) peroxidase 4 (GPX4) inhibitor, triggered ROS accumulation and lipid peroxidation which contributed to ferroptotic cell death. These observations were based on suppression of RSL3 stimulated cell death using different ferroptosis inhibitors like Ferrostatin-1 (Fer-1), Liproxstatin-1 (Lip-1), as well as iron chelator Deferoxamine (DFO) and the vitamin E derivate α-Tocopherol (α-Toc). RSL3-triggered ROS and lipid peroxide production were also inhibited through Fer-1 and α-Toc. Furthermore, lipoxygenases (LOX) were activated upon RSL3 stimulation and contributed to ferroptotic cell death in ALL as well. Selective inhibition of LOX with the 12/15-LOX inhibitor Baicalein and the pan-LOX inhibitor nordihydroguaiaretic acid (NDGA) abolished RSL3-induced ROS production, lipid peroxidation and cell death. In addition, RSL3 induced lipid peroxide-dependent ferroptotic cell death in FAS-associated Death Domain (FADD)-deficient, death receptor-induced apoptosis resistant cells, demonstrating that ferroptosis might circumvent apoptosis resistance.
The second part of the study revealed that RSL3 and Erastin (Era), a GSH-depleting agent, inhibiting the cystine/glutamate antiporter system xc- and ferroptosis inducer, cooperated with the Smac mimetic BV6 to trigger cell death in ALL cells. RSL3/BV6 and Era/BV6 combination-induced cell death was dependent on ROS accumulation, but independent of caspases and key modulators of necroptosis. RSL3/BV6-treated ALL cells exhibited classical features of ferroptotic cell death with iron-dependency, ROS accumulation and lipid peroxidation which was diminished through either pharmacological inhibition (Fer-1, DFO, α-Toc) or genetic inhibition by overexpressing GPX4. Interestingly, Era/BV6-induced cell death in ALL cells was independent of iron but dependent on ROS accumulation, since α-Toc rescued from Era/BV6-triggered ROS production, lipid peroxidation and cell death. Moreover, inhibition of lipid peroxide formation through the addition of Fer-1 or by overexpressing GPX4 failed to rescue from Era/BV6-triggered cell death, even if Era/BV6-stimulated lipid peroxidation was diminished. Likewise, Fer-1 protected from RSL3/BV6-, but not from Era/BV6-generated ROS production, leading to the assumption that other ROS besides lipid-based ROS contributed to cell death in Era/BV6-treated cells. In summary, while RSL3/BV6 induced ferroptosis in ALL, Era/BV6 stimulated a ROS dependent cell death, which was neither dependent on iron nor caspases or receptor-interacting protein (RIP) kinase 1 nor 3. Additionally, using Erastin alone did not trigger ferroptotic cell death in ALL. Finally, with these two studies we tried to unravel the molecular pathway of ferroptosis by using RSL3 and Erastin as well described ferroptosis stimulators. Here, we demonstrate the possibility of a novel treatment strategy to reactivate programmed cell death by impeding redox homeostasis in ALL.
Since ALL failed to induce ferroptosis upon Erastin treatment, we investigated in the third part of this thesis a new model system to induce ferroptosis upon Erastin and RSL3 exposure. Previous studies revealed that rhabdomyosarcoma (RMS) cells might be susceptible to oxidative stress-induced compounds. To this end, we used Erastin as a prototypic ferroptosis stimulus and GSH-depleting agent and demonstrated that GSH depletion, ROS and lipid ROS accumulation contributed to cell death. Additionally, Fer-1, Lip-1, DFO, lipophilic vitamin E derivate α-Toc and GSH, a cofactor of GPX4, protected from Erastin stimulated ROS accumulation, lipid peroxidation and cell death. Also, the use of a broad spectrum protein kinase C (PKC) inhibitor Bisindolylmaleimide I (Bim1), a PKCα and ß selective inhibitor Gö6976 and siRNA-mediated knockdown of PKCα suppressed Erastin-mediated cell death in RMS. Moreover broad spectrum nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase (NOX) inhibitor Diphenyleneiodonium (DPI) and a more selective NOX1/4 isoform inhibitor GKT137831 abrogated Erastin-generated ROS formation, lipid peroxidation and cell death. With this, we demonstrate that RMS are vulnerable to ferroptotic cell death and investigated the molecular mechanism of ferroptosis by unravelling that PKC and NOX could have a pivotal role in ROS-mediated ferroptosis signalling in RMS. In this regard, ferroptosis inducers may act as a possible novel treatment strategy for RMS, especially those with poor clinical outcome.
The authors relax the standard assumption in the dynamic stochastic general equilibrium (DSGE) literature that exogenous processes are governed by AR(1) processes and estimate ARMA (p,q) orders and parameters of exogenous processes. Methodologically, they contribute to the Bayesian DSGE literature by using Reversible Jump Markov Chain Monte Carlo (RJMCMC) to sample from the unknown ARMA orders and their associated parameter spaces of varying dimensions.
In estimating the technology process in the neoclassical growth model using post war US GDP data, they cast considerable doubt on the standard AR(1) assumption in favor of higher order processes. They find that the posterior concentrates density on hump-shaped impulse responses for all endogenous variables, consistent with alternative empirical estimates and the rigidities behind many richer structural models. Sampling from noninvertible MA representations, a negative response of hours to a positive technology shock is contained within the posterior credible set. While the posterior contains significant uncertainty regarding the exact order, the results are insensitive to the choice of data filter; this contrasts with the authors’ ARMA estimates of GDP itself, which vary significantly depending on the choice of HP or first difference filter.
In Carl Barks' 1963 comic strip "The Invisible Intruder", the bed becomes the main theme of the story. We get to know how Uncle Scrooge became a creative and successful entrepreneur. Since his parents were too poor to provide a proper sleeping place for their son, Scrooge had to sleep in a cabinet drawer. Therefore, Scrooge's only aim was to buy himself a bed. His capitalist creativity is, as he himself admits, driven by the "desire for a better bed." With the economic growth of his company, his bed becomes bigger too. But in the end, he throws out his enormous mattress because it is too sensitive to the vibrations caused by the money rammer in the money bin; and moreover, the investigation into the cause of the vibrations became far too expensive. Eventually, Scrooge is returning to his childhood bed: the cabinet drawer. What is striking about this story is not the idea that objects of everyday culture play a leading role within a narrative; it is the fact that the usual cultural function of furniture is altered in a significant way. The misapplication of the drawer draws attention to the object of everyday culture as signifier of the everyday experience in capitalist societies. The function of the bed is no longer defined by criteria of good sleep but of economic calculation. The bed thereby becomes an agency within the narrative that questions the stability of the cultural and linguistic semantics of the everyday. In the following, I will press the point that the representation of the bed in literary texts from Homer to Kafka can be read as an implicit linguistic theory of cultural signification.
Objective: Imaging studies in diffuse low-grade gliomas (DLGG) vary across centers. In order to establish a minimal core of imaging necessary for further investigations and clinical trials in the field of DLGG, we aimed to establish the status quo within specialized European centers.
Methods: An online survey composed of 46 items was sent out to members of the European Low-Grade Glioma Network, the European Association of Neurosurgical Societies, the German Society of Neurosurgery and the Austrian Society of Neurosurgery.
Results: A total of 128 fully completed surveys were received and analyzed. Most centers (n = 96, 75%) were academic and half of the centers (n = 64, 50%) adhered to a dedicated treatment program for DLGG. There were national differences regarding the sequences enclosed in MRI imaging and use of PET, however most included T1 (without and with contrast, 100%), T2 (100%) and TIRM or FLAIR (20, 98%). DWI is performed by 80% of centers and 61% of centers regularly performed PWI.
Conclusion: A minimal core of imaging composed of T1 (w/wo contrast), T2, TIRM/FLAIR, PWI and DWI could be identified. All morphologic images should be obtained in a slice thickness of ≤ 3 mm. No common standard could be obtained regarding advanced MRI protocols and PET.
Importance of the study: We believe that our study makes a significant contribution to the literature because we were able to determine similarities in numerous aspects of LGG imaging. Using the proposed "minimal core of imaging" in clinical routine will facilitate future cooperative studies.
Bridge International is a for-profit chain of private (pre-)primary schools employing technology to allegedly provide “high-quality, affordable education” in the Global South. Like many other actors, Bridge (cl)aims to bridge the global digital divide and to use information and communication technologies to realize development (“ICT4D”), in particular in sub-Saharan Africa. But are such projects really allowing the region to “catch up” with the rest of the world and strengthen its weak global standing? Not necessarily. Many projects’ implementation mirrors existing global power inequalities and may even reinforce them.1 Moreover, the technologies employed themselves augment these imbalances. The present contribution illustrates this, using Bridge as a case study.
The discussion about the interplay between digital technologies and the process of globalization is often focused around the following question: who has access to global information networks and who benefits from digital communication technologies? These are essential questions and it can hardly be denied that they confront us with a series of political and ethical questions. However, we also need to recognize the ongoing digitalization of the globe, a process where more and more people are put on various kinds of maps...
Europe’s new digital borders
(2018)
The European Union’s (EU) external border framework is not only increasingly reliant on digital databases, but these databases are now set to become interoperable. By 2020, the European Commission (EC) aims to have a fully interconnected new architecture for identity management at the border in place. Based on biometric enrolment of all third-country citizens, Europe’s new digital borders raise a number of concerns, including suspicion, large-scale surveillance, and internal policing that spread well beyond the border site.
Border management today is embedded into a complex network of data collection and data analysis that provides authorities with knowledge about who (or what) attempts to cross the border. While still serving as physical chokepoints for the examination and extraction of dangerous, suspicious, or illegitimate elements from global flows of mobility, border operations therefore increasingly rely on a number of databases...
With the rise of big data, internet-of-things, machine learning, targeted advertising, face recognition algorithms, virtual assistants, cyberbullying, cyberstalking, and cyberwarfare, we find more and more people and policy makers around the world debating whether technological advances are helping us or hurting us. Such debates often focus on trying to figure out a way to balance the need to preserve human values with the desire to not interfere with technological progress. The central problem that arises then is what to do when values and progress come into direct conflict with each other. Should we err on the side of caution and rein in companies like Google, Twitter, and Facebook so they do not interfere with personal privacy and national democracy? Or should we take a more pioneering perspective and view the occasional rights violation as a necessary risk that can be outweighed by the rewards for medicine, manufacturing, and media? Or should we try to find a middle path and have tech companies and policy makers work together to develop guidelines for “responsible research and innovation”?
Almost a decade ago, the internet was celebrated as one of history’s greatest liberation tools. People have unparalleled access to information and a greater deal of freedom to express themselves without fear of censorship or reprisal. This enthusiasm was short-lived, however. Today’s internet is heaving with hate speech, censorship, fake news, misinformation, and all forms of extremism. Governments have tightened their grip on digital spaces, and tech companies have grown into nontransparent empires with immense influence on the world’s politics, economies, and societies. These changes have brought forward new terrains of conflict and have redefined the relationship between the citizen and the state.
Large-scale digitisation has brought cultural heritage objects and materials from the remotest places of the world to our computer screens. At first sight, this innovation seems to make cultural heritage accessible to everyone like never before. However, technological advances have not eliminated social inequalities between powerful and marginalized communities and ethical issues in communicating cultural heritage. These issues became much more vivid and obvious when the spread of cultural heritage reached the global scale.
This paper revisits the macroeconomic effects of the large-scale asset purchase programmes launched by the Federal Reserve and the Bank of England from 2008. Using a Bayesian VAR, we investigate the macroeconomic impact of shocks to asset purchase announcements and assess changes in their effectiveness based on subsample analysis. The results suggest that the early asset purchase programmes had significant positive macroeconomic effects, while those of the subsequent ones were weaker and in part not significantly different from zero. The reduced effectiveness seems to reflect in part better anticipation of asset purchase programmes over time, since we find significant positive macroeconomic effects when we consider shocks to survey expectations of the Federal Reserve’s last asset purchase programme. Finally, in all estimations we find a significant and persistent positive impact of asset purchase shocks on stock prices.
Berühmt sind Benjamins Überlegungen zum bürgerlichen Interieur vor allem im "Passagen-Werk". Weniger bekannt hingegen sind seine Reflexionen über eine eigenartige Form von Erzählraum, der sich in der Mitte seines Erzähler-Aufsatzes lokalisiert. 'Eigenartig' ist er, weil es dort weniger um mündliches oder schriftliches Erzählen geht, als vielmehr um filmische Projektionen. Was projiziert wird, sind nach Benjamin "Ansichten der eigenen Person, unter denen er ohne es inne zu werden, sich selber begegnet ist". Solche Begegnungen gehören weder zur Erfahrung dieser Person noch zu ihrer Selbsterzählung oder Autobiographie. Diese "Out-takes eines Lebens" werden unwissentlich aufgenommen, unbewusst aufbewahrt und am Sterbebett mechanisch projiziert. Benjamin modifiziert in seinem Erzähler-Aufsatz die geläufige, entscheidend filmische Vorstellung, dass einem kurz vor dem Tod noch einmal das ganze Leben vorgeführt werde: Die Vorführung, die hier stattfindet, projiziert nur die Momente, die nie wirklich zum eigenem Leben gehört haben. Um diese andere Erzählart und diesen anderen Erzählraum zu erkunden, muss die betreffende Stelle im Erzähler-Aufsatz zusammen mit Benjamins Schriften zum buckligen Männlein gelesen werden. Was sich durch diese Lektüre manifestiert, ist eine andere Theorie der erzählerischen Autorität und der Tradierbarkeit von "unvergesslichen" Erfahrungen.
With the discovery of light beyond human visibility, scientists strove to extend the range of observation to invisible parts of the light’s spectrum. Realising that light of all frequencies is part the same physical phenomenon, brought a leap in understanding about electromagnetic waves. With the development of more advanced technology, detectors with higher sensitivity for adjacent frequencies to the visible were built. From this, with each new observable wavelength, more insight into otherwise invisible processes and phenomenons were observed. Hand in hand with this went the enhancement of the output power of corresponding sources. This has lead to higher sensitivity setups throughout the spectrum, leading to observations which have given a deeper understanding in various fields of science. Nowadays, detectors and emitters in many different regions of the invisible electro magnetic spectrum have found their way in our every day life. Innovations in technology has lead to practical applications such as X-rays in medicine, motion sensors and remote controls using infrared light, distance sensors and data transmission using radar and radio devices. The frequency regions above infrared are optically generated and below radar can be produced using electric methods. There is no straight line that separates these frequencies. There rather is a whole intermediate region known as the terahertz (THz) regime. Due to the lack of sensitive detectors and efficient sources, the THz frequency region has not been exploited for application use on a widespread basis so far. It combines properties from the surrounding frequency ranges which make it an ideal spectrum for various applications. Consequently, THz radiation and THz imaging are active fields of research.
The work presented in this thesis consists of the development and testing of novel THz imaging concepts, which uses a THz antenna coupled field effect transistor (TeraFET) detector. Two detection principles are applied using two different optical setups. The first uses a pulsed optical parametric oscillator (OPO) THz source where the optical output power is detected. The source relies on a nonlinear effect of a lithium niobate crystal to generate tunable THz pulses from a Q-switched pump laser. The THz signal is detected and amplified by a double stage operational amplifier for monitoring the real time 20 ns pulses on an oscilloscope where a signal to noise ratio (SNR) of ⇠ 25 at a frequency range from 0.75 to 1.1 THz is reached. Imaging of the area of interest with a resolution of 1.2 mm is achieved through raster scanning of the THz pulses. Also spectroscopy with a frequency resolution of ⇠ 50 GHz is demonstrated using a para-aminobenzoic acid sample. The second setup utilises two synchronised electronic multiplier chain sources where their output is mixed on the detector. To form a heterodyne detection setup, the intermediate frequency is fed to a lock-in amplifier which then amplifies the so called beat signal from the TeraFET detector. One source is fixed relative to the detector even through scanning to ensure a stable signal. This detection method allows for amplitude and phase detection for every scanning position, making numerical light field propagation and object reconstruction possible. Numerical focussing is a key feature achieving a lateral resolution of the input transmittance of ⇡ 2 mm.
After the introduction, the second chapter describes the setup, measurement results and challenges which arise using a TeraFET together with the pulsed THz source “Firefly-THz”. In the description of the setup, special attention is given to the shielding of the detector and the electronics. General findings discuss first the overall performance and later spectroscopy and imaging as application examples. Another subsection continues with potential noise sources before the chapter is concluded. Chapter three expands on the topic of Fourier optics from a theoretical point of view. First, parts of the theory of the Fourier Transform (FT) are set out for the reader and how the Fast Fourier Transform (FFT) results from the Discrete Fourier Transform (DFT). This approach is used for theoretical considerations and the implementation of a Fourier optic script that allows for numerical investigations on electro magnetic field propagation through an optical system. The boundary conditions are chosen to be practical relevant to make predictions on measurements presented in chapter four. The following fourth chapter describes the realisation of a heterodyne THz detection setup. Before the measurement results are presented, the setup and its electric configuration are shown. The results come close to the analytical predictions so that the same algorithm which propagates the field from an object to the Fourier plane is used to propagate the measured field back to the object. The influence of phase noise on the measurement results are discussed before simulation and measurement is compared. The last chapter in this thesis concludes on the findings in the pulsed THz detection and the heterodyne THz Fourier imaging and gives an outlook for both configurations.
Different response of Ptch mutant and Ptch wildtype Rhabdomyosarcoma toward SMO and PI3K inhibitors
(2018)
Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma with poor prognosis. RMS frequently show Hedgehog (HH) pathway activity, which is predominantly seen in the embryonal subtype (ERMS). They also show activation of Phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) signaling. Here we compared the therapeutic effectiveness and the impact on HH target gene expression of Smoothened (SMO) antagonists with those of the PI3K inhibitor pictilisib in ERMS with and without mutations in the HH receptor Patched1 (PTCH). Our data demonstrate that growth of ERMS showing canonical Hh signaling activity due to Ptch germline mutations is efficiently reduced by SMO antagonists. This goes along with strong downregulation of the Hh target Gli1. Likewise Ptch mutant tumors are highly responsive toward the PI3K inhibitor pictilisib, which involves modulation of AKT and caspase activity. Pictilisib also modulates Hh target gene expression, which, however, is rather not correlated with its antitumoral effects. In contrast, sporadic ERMS, which usually express HH target genes without having PTCH mutation, apparently lack canonical HH signaling activity. Thus, stimulation by Sonic HE (SHH) or SAG (Smoothened agonist) or inhibition by SMO antagonists do not modulate HH target gene expression. In addition, SMO antagonists do not provoke efficient anticancer effects and rather exert off-target effects. In contrast, pictilisib and other PI3K/AKT/mTOR inhibitors potently inhibit cellular growth. They also efficiently inhibit HH target gene expression. However, of whether this is correlated with their antitumoral effects it is not clear. Together, these data suggest that PI3K inhibitors are a good and reliable therapeutic option for all ERMS, whereas SMO inhibitors might only be beneficial for ERMS driven by PTCH mutations.
The production of hypernuclei is investigated for p̅+A→Λ‾+ΛA reactions in a covariant meson exchange approach. Besides the conventional pseudo-scalar (K) and vector (K*) channels, we study for the first time also contributions from the correlated πK scalar channel, described by the k/K*0 meson. Initial and final state interactions are considered by eikonal theory. The total and angular differential cross sections of the coherent process p̅+AZ→ΛA(Z−1)+Λ̅ are evaluated at the beam momenta 1:5…20 GeV/c within the meson exchange model with bound proton and Λ-hyperon wave functions. It is shown that the shape of the beam momentum dependence of the hypernucleus production cross sections with various discrete Λ states is strongly sensitive to the presence of the scalar k meson exchange in the p̅p→Λ̅Λ amplitude. This can be used as a clean test of the exchange by scalar πK correlation in coherent p̅A reactions.
Africa, UK, and Ireland: Writing Politics and Knowledge Production comprises 6 scholarly/nonfiction essays, 7 short stories, 67 poems, and 2 plays from writers and poets based in the UK, Africa and Ireland the diasporas. It focuses on politics and knowledge production acting as a vehicle in which the production of new knowledge between these three regions/countries intersects in the literary sphere. It dissects the scientific methods of producing knowledge through the act of producing new knowledge, it looks at the management of knowledge, the processing and sharing of knowledge, and dissects, artistically and critically. It further stresses the importance of the ownership of knowledge and how this knowledge shapes politics. The collection contains work from up-and-coming poets and writers, alongside established ones, also included are pieces from academic scholars, essayists, poets, writers of fiction, playwrights. Africa, UK, and Ireland: Writing Politics and Knowledge Production will prove useful to literary and language theorists, poetry collections, political sciences, social sciences and human sciences, general academia and readers, education departments and students.
A Dark Energy
(2018)
Don is the only child of a happy family full of love, but it does not last. At 6 years old Don s parents are burned in a fire through arson, and suspects his father s brother is the culprit. As the family fights over his father's wealth nobody wants anything to do with Don, particularly the Uncle whom he suspects of arson and ends up taking most of his father s wealth. After a difficult upbringing in orphanages and living with an abusive old man Don starts working as an agent in Central Investigations Organisation, Zimbabwe s security intelligence organisation. Despite this apparent success Don never deals with the existential dilemmas he has as a result of his childhood. He becomes a loner, he doesn't believe in love, marriage, or happiness... until he meets Lilian. Soon after he is called into the president s office to cover up an extramarital affair. When a political rival of the president, the corrupt defence minister, bones gets wind of the cover up and unsuccessfully tries to blackmail Don something terrible happens and Don becomes thrown back into the darkness. Straddling literary genres this novel explores themes related to family, love, politics, life and existence. It is the story of a man pushed to breaking point and how that, inevitably, impacts society.
A Conversation : A Contact
(2018)
This English/Shona edtion of How the Twins Grew Up brings authentic biographical stories of two twin brothers. The stories take place in their family circle, at school, at home or in the backyard. It is written as a realistic prose narrative with a humorous intonation, unexpected dramatic twists and interesting punch lines. The stories are short and concise, with effective endings and situations, full of laughter, caricature and absurdity. The book has been translated into 20 languages and has received several awards. For those who love humour and want to return to their childhood, these stories will come as a real refreshment and a unique artistic experience.
In poet and artist Elena Botts new poetry collection: epochs of morning light, we see a shimmering, variegated new voice; we hear: where the trees still talk to each other, and winter feels like a song... (from When I have died we will be here). We feel the weather of her emotions; a contract with the ethereal and the visceral, as when we stand within the short but large poem: blossoms back to under the earth: I felt your ghost move through me out past the Baltic as though you had been in my heart the whole time. In this sensual canvas, beauty never suffers from loneliness, nor the sublime. Each poem herein as Botts wanders memory and weaves tapestries of word worlds, reveals a true and original voice in modern poetry: allowing light to conquer darkness; darkness to defy the estate of the sun, and colors mixed in ways only an artist of the pen could fathom
Logbook written by a drifter
(2018)
Logbook written by a drifter, is a cycle of interlinked poems that deal with life, spirituality, language, philosophy, love and relationships. A main theme are relationships which have changed the character. Those which the character doesn't know how to deal with; which have make the character into a wreck, emotionally, psychologically, or spiritually: he is in a small space. This collection encourages us to keep those spaces, spaces of the drift, until we have faced our challenges, afterall sometimes drifting is all we can do!
Under The Steel Yoke
(2018)
In Under The Steel Yoke I hear the wailing of fellow citizens as leadership subversion takes root. When servants become masters- that is a subversion, waves of despair threaten our people. I attempt to reflect the resilience of fellow Zimbabweans as we fight on for survival, hope refuses to die. The ideals of the true liberators prick our collective conscience. These poems are meant to provoke debate about nation building and they are an assertion that there can never be peace without justice. These poems are the voices heard on the streets, in pubs, factories, churches, homes and wherever our people irk a living. These voices yearn for a glorious future.
This careful selection of short poems, I Threw a Star in a Wine Glass, originally written in Arabic and translated into English can offer you a passport to live for other planets never imagined. With love and soft fragrance, works the poet Fethi Sassi to realize a dream, that was until now, breathing in the depth of his personality.
Another collection of exciting stories, articles and poems by young South Africans. We hope you will enjoy them so much that you #Can't StopReading. All of these pieces have been read and enjoyed by thousands of readers on FunDza's online library. Each piece also has discussion and writing activities for reading clubs and classes.
Social Memory, Silenced Voices, and Political Struggle : Remembering the Revolution in Zanzibar
(2018)
This volume focuses on the cultural memory and mediation of the 1964 Zanzibar revolution, analyzing its continuing reverberations in everyday life. The revolution constructed new conceptions of community and identity, race and cultural belonging, as well as instituting different ideals of nationhood, citizenship, sovereignty. As the commemoration of the 50th anniversary of the revolution revealed, the official versions of events have shifted significantly over time and the legacy of the uprising is still deeply contested. In these debates, the question of Zanzibari identity remains very much at stake: Who exactly belongs in the islands and what historical processes brought them there? What are the boundaries of the nation, and who can claim to be an essential part of this imagined and embodied community? Political belonging and power are closely intertwined with these issues of identity and historyraising intense debates and divisions over precisely where Zanzibar should be situated within the national order of things in a postcolonial and interconnected world. Attending to narratives that have been overlooked, ignored, or relegated to the margins, the authors of these essays do not seek to simply define the revolution or to establish its ultimate meaning. Instead, they seek to explore the continuing echoes and traces of the revolution fifty years on, reflected in memories, media, and monuments. Inspired by interdisciplinary perspectives from anthropology, history, cultural studies, and geography, these essays foreground critical debates about the revolution, often conducted sotto voce and located well off the official stageattending to long silenced questions, submerged doubts, rumors and secrets, or things that cannot be said.
Arguably, one of the most polarising figures in modern times has been Robert Gabriel Mugabe, the former President of the Republic of Zimbabwe. The mere mentioning of his name raises a lot of debate and often times vicious, if not irreconcilable differences, both in Zimbabwe and beyond. In an article titled: Lessons of Zimbabwe, Mahmood Mamdani succinctly captures the polarity thus: It is hard to think of a figure more reviled in the West than Robert Mugabe and his land reform measures, however harsh, have won him considerable popularity, not just in Zimbabwe but throughout southern Africa. This, together with his recent stylised ouster, speaks volumes to his conflicted legacy. The divided opinion on Mugabes legacy can broadly be represented, first, by those who consider him as a champion of African liberation, a Pan-Africanist, an unmatched revolutionary and an avid anti-imperialist who, literally, spoke the truth to Western imperialists. On the other end of the spectrum are those who seemingly paying scant regard to the predicament of millions of black Zimbabweans brutally dispossessed of their land and human dignity since the Rhodesian days have differentially characterised Mugabe as a rabid black fascist, an anti-white racist, an oppressor, and a dictator. Drawing on all these opinions and characterisations, the chapters ensconced in this volume critically reflect on the personality, leadership style and contributions of Robert Mugabe during his time in office, from 1980 to November 2017. The volume is timely in view of the current contested transition in Zimbabwe, and with regard to the ongoing consultations on the Land Question in neighbouring South Africa. It is a handy and richly documented text for students and practitioners in political science, African studies, economics, policy studies, development studies, and global studies.
Kenya's War of Independence restores Kenyas stolen history to its rightful place, stripped of colonial interpretations. In this expanded and revised version of his 1986 booklet, Kimaathi, Mau Mau's First Prime Minister of Kenya, Durrani covers Mau Maus resistance to colonialism and neo-colonialism and reflects on its ideology, organisation and achievements. He sees Mau Mau in the larger context of Kenyas war of independence and looks at the influence of organised, radical trade unions as the engine of resistance, linking economic with political demands of working people. Additional chapters document the post-independence resistance by the underground December Twelve Movement-Mwakenya. Durrani captures the dynamism of transition from colonialism to neo-colonialism: Imperialism replaced colonialism, African elites replaced White Settlers, neo-colonial government replaced colonial government. Resistance changed from the War of Independence to War of Economic Independence. Worker and peasant resistance is evident once again. History is on the march.
This book looks at the third pillar of resistance to British colonialism peoples resistance, the others being Mau Mau and radical trade union movement. It brings together several aspects of peoples resistance to colonialism and imperialism before and after independence and includes resistance by nationalities, women, students, peasants and workers in what can only be described as peoples resistance. While Mau Mau and trade unions were essential in the liberation struggle, on their own they would have faced innumerable difficulties to achieve their goal. Peasants, nationalities, women, children and young people, students, independent churches, independent schools, all played a part in reinforcing the organized and ideology led resistance of Mau Mau and trade unions. Additional material is included to provide thought for reflections. The first two essays deal with the question of nationalities and with the contradictions between capitalism and socialism with the collapse of USSR. They point to the fact that that the struggle in Kenya influences, and is in turn influenced by, developments around the world. The next section is the presentation at the launch of Kenyas War of Independence in Nairobi on February 21, 2018. The final section contains solidarity messages from Shiraz Durrani, Abdilatif Abdalla and Kang'ethe Mungai at the event to commemorate and celebrate the revolutionary work of Karimi Nduthu held on March 24, 2018 at the Professional Centre in Nairobi.The Kenya Resists Series covers different aspects of resistance by people of Kenya to colonialism and imperialism. It reproduces material from books, unpublished reports, research and oral or visual testimonies. The three aspects chosen for the first three publications in the Series Mau Mau, Trade Unions and Peoples Resistance make up the three pillars of resistance of the people of Kenya.
It is due to the success of the trade union movement in the national liberation movement that the colonial government suppressed prominent trade unions and attacked TU leaders like Makhan Singh, Fred Kubai, Pio Gama Pinto and Bildad Kaggia. It also passed on colonial laws to the independent Kenya government so as to ensure that future trade unions were forced to take the non-radical approach to meet worker needs. They thus created imperialist-oriented and led trade unions that bedevil working class politics to this day. There are valuable lessons to be learnt from the history of the militant trade unions in Kenya and also from understanding how colonialism and imperialism enforced changes that made the trade unions ineffective after independence. The selections in this book recall relevant events in the history of the militant trade union movement in Kenya and record the contribution that the trade union movement made to Mau Mau and to Kenya's war of independence. The Kenya Resists Series covers different aspects of resistance by people of Kenya to colonialism and imperialism. It reproduces material from books, unpublished reports, research and oral or visual testimonies. The three aspects chosen for the first three publications in the Series - Mau Mau, Trade Unions and People's Resistance - make up the three pillars of resistance of the people of Kenya.
Background: Histological evidence suggests that autism spectrum disorder (ASD) is accompanied by a reduced integrity of the grey-white matter boundary. This has also recently been confirmed by a structural neuroimaging study in vivo reporting significantly reduced grey-white matter tissue contrast (GWC) in adult individuals (18–42 years of age) with ASD relative to typically developing (TD) controls. However, it remains unknown whether the neuroanatomical differences in ASD at the grey-white matter boundary are stable across development or are age-dependent.
Methods: Here, we examined differences in the neurodevelopmental trajectories of GWC in a cross-sectional sample of 77 male ASD individuals and 76 typically developing (TD) controls across childhood and early adulthood (from 7 to 25 years).
Results: Using nested model comparisons, we first established that the developmental trajectory of GWC is complex in many regions across the cortex and includes linear and non-linear effects of age. Second, while ASD individuals have significantly reduced GWC overall, these differences are age-dependent and are most prominent during childhood (< 15 years).
Conclusions: Taken together, our findings suggest that differences in GWC in ASD are unlikely to reflect atypical grey matter cytoarchitecture alone, but may also represent other aspects of the cortical architecture such as age-dependent variability in myelin integrity.
We use minutes from 17,000 financial advisory sessions and corresponding client portfolio data to study how active client involvement affects advisor recommendations and portfolio outcomes. We find that advisors confronted with acquiescent clients stick to their standards and recommend expensive but well diversified mutual fund portfolios. However, if clients take an active role in the meetings, advisors deviate markedly from their standards, resulting in poorer portfolio diversification and lower Sharpe ratios. Our findings that advisors cater to client requests parallel the phenomenon of doctors prescribing antibiotics to insistent patients even if inappropriate, and imply that pandering diminishes the quality of advice.
Whether Africa is developed or not, depends on how and what one addresses. Development is relative. Nonetheless, the fact is: Africa developed Europe; and thereby became underdeveloped. Addressed academically, the notion of development creates many questions amongst which are: Development in what? Whose development? Development for whom? Who defines development? In this volume, the development dealt with is polygonal; and touches on politico-economic sequels which also affect the social aspect. No doubt. Africa is abundantly rich in terms of resource and culture. Paradoxically, however, Africa is less developed economically compared to Europe thanks to the history of unequal encounters, among other reasons. We cannot emphasise enough the fact that Africas underdevelopment is the price of the development of Europe which is based on historical realities gyrating around Europes criminal past wherein slavery and colonialism enabled Europe to spawn its future capital and investment. How can anyone quibble about Europes development resulting from perpetual plunderage of Africa with impunity committed by European treasure-hunting adventurers? This volume prescribes Africas restorative recompense as the only way forward for the duo and the world.
Jostling Between 'Mere Talk' & Blame Game? : Beyond Africa's Poverty and Underdevelopment Game Talk
(2018)
One of the fundamental challenges in rethinking and remaking development in Africa from a Pan African perspective is that too much mere talk and blame game have played out at the expense of real action. The blame game and mere talk on Africas poverty and underdevelopment jam have remained printed in bold on the face of the continent, yet Africas dire situation warrants nothing less than real emphatic action. This book focuses on the empirics of the production and reproduction of poverty and underdevelopment across Africa in a fashion that warrants urgent pragmatic policy attention and quest for workable homegrown solutions to persistent predicaments. The volume advances the need to recognise the realities of global inequalities and move swiftly in a most informed and transparent manner to address the poverty and underdevelopment conundrum. The book sets the tempo and pace on the need for praxis and pragmatism on the African situation. It is handy to students and practitioners in African studies, poverty and development studies, global studies, policy studies, economics and political science.
Poetic encounter: Rhapsodies from the South is compilation of poems by Southern African Writers from South Africa and Zimbabwe. The poems, were written not only to depict life but also tell tales of socio-political and economic history that Southern African people traversed from colonialism, apartheid to freedom. Therefore, readers from all walks-of-life can identify with themes such as apartheid, economic deprivation, religion and culture, love and so forth that are carefully ensconced in this compilation. The authors invite the readers, to not only indulge the lived injustice and violent nature of both our historic past and trajectory to the current state of affairs, but also appreciate, cry, smile and reminiscence about the life in general as encapsulated in this refreshing and aesthetic work of art - the poetic encounter.
As part of its on-going public dialogue program on progress in Ethiopia's development and public policy the Forum for Social Studies is undertaking a project of research and public dialogue on a number of selected topics on the theme of 'Prospects and Challenges for Inclusive and Participatory Development in Ethiopia'. The aim is to enable researchers and professionals to present evidence-based papers to stimulate debate and reflection. This first book in the program looks at the impact of development or lack of it, on specific social groups, namely women, young people and vulnerable groups that should be entitled to decent social care.
School Development Through Teacher Research : Lesson and Learning Studies in Sweden and Tanzania
(2018)
School Development through Teacher Research - Lesson and Learning Studies in Sweden and Tanzania presents the results from a three-year-long joint research project conducted by educational researchers from Tanzania and Sweden. Even though the country contexts differ in social, economic as well as educational conditions, including teacher education and classroom standards, many recurrent education challenges are shared. These include the tendency to make educational reforms with little or no input from professionals. The new educational reforms in both countries put a much higher responsibility on teachers; teachers must be able to organise teaching that enables all students to develop required abilities/competencies. Thus, teachers need tools to develop knowledge that can contribute to their professional knowledge base. With an overall interest in issues of teaching and action research, this joint project aimed to use Lesson and Learning Study as models for developing and improving the quality of teaching and learning in schools. The research project was realised through four case studies in each country with a focus on students' development of specific capabilities and values Science, Vocational Skills/Home and Consumer Studies, English as second language and Mathematics in grades 6-7. Complementing the cases School Development through Teacher Research - Lesson and Learning Studies in Sweden and Tanzania offers an introductory background to Lesson and Learning Studies as models for teacher-driven research and school development. The book is written to support teachers and teacher educators' wishing to reflect about learning and the struggle of learners to discern various concepts, principles and practices. As well as those who genuinely wish to see serious learning take place, rather than simply seeing content 'covered' - including curriculum designers and developers, educational researchers, educational supervisors and leaders and student-teachers as well as students of pedagogy and didactics. We dedicate the book to teacher educators, teachers and school leaders who are seriously striving to enhance students' learning and understanding in different subject areas.
A Son of Two Countries is a story of struggle for education. Born in 1946 in Rwanda under Belgian colonial rule, the author recounts his early education in Rwanda and later as a refugee in Tanzania. He was naturalized as a Tanzanian citizen in 1980 while doing his undergraduate studies at the University of Dar es Salaam. As he struggled to get education, the author was also grappling with his refugee status, with all the challenges that it entailed. The book gives insights into the contradictions of colonial and post-colonial education, as well as the author's reflections on education in Tanzania, given his long experience in the education sector in that country. Finally, we get some glimpses into the dual identity of the author as a Tanzanian citizen of Rwandan origin and how this shaped his relationship with the two countries he calls home. As he aptly puts it, 'Rwanda gave me my heart; Tanzania gave me my brain. I find it difficult to choose between my heart and my brain'.
It was not the European and American churches which evangelised Africa, but the mission societies. The missions from the Great Awakening such as the London Missionary Society and Church Missionary Society, or the Holy Ghost Fathers and the White Fathers, which started the process of Sub-Saharan Africa becoming a Christian continent are well known and documented. Less known, and less documented are the interdenominational faith missions which began in 1873 with the aim of visiting the still unreached areas of Africa: North Africa, the Sudan Belt and the Congo Basin. Missions such as the Africa Inland Mission or Sudan Interior Mission gave birth to some of the big churches like ECWA in Nigeria and Africa Inland Church in Kenya. It is the aim of this book to describe faith missions and their theology and to present an overview of the early development of faith missions insofar as they touched Africa.
Homosexuality is a cross-cutting challenge to Malawian society with theological, socio-cultural, economic, legal, political, and human rights implications. This book argues that the solution to the homosexuality debate in Malawi does not lie in either the criminalization or decriminalization of homosexuality; neither does it lie in homophobia nor heterophobia. However, the solution to the homosexuality debate lies in achieving a harmonious co-existence of both heterosexuals and homosexuals by practicing mutual tolerance. The book concludes by suggesting various activities to be taken by: The Government of Malawi; Gay Rights Activists; Religious Leaders; Traditional Leaders; and Malawian Society to ensure the aforementioned tolerance and understanding is encouraged.
The missionary work of the Seventh-day Adventist Church started in Southern Malawi in 1902, and histories of churches are usually told from that starting point. This book uses a different approach, it tells the story of Lunjika Mission (earlier called Mombera Mission) which begins in 1932, showing how the SDA Church met a new culture, that of the strongly patrilineal Ngoni and their neighbours to the North, and how it dealt with other churches that had started missionary work in that broad area up to two generations before.
Some scholars classify the Last Church of God and His Christ under the ecclesiastical-cultural bloc known as African Indigenous Churches (AICs). David Barret has divided the world's Christians into seven major ecclesiastical blocs. However, there are many large churches and denominations which do not define themselves under any of these three terms, and often reject all three. As far back as 1549 (Japan) and 1741 (USA), new types of Christianity have emerged that do not fit readily into any of these preceding six major blocs. These consist of denominations, churches and movements that have been initiated, founded and spread by black, Non-White or non-European peoples without European assistance, mainly in the Global South, but also among Black and Non-White minorities in the Western World. The African Indigenous Churches fall under this category. The aim of the book, is to examine the history of the Last Church of God and His Christ International in Malawi from its beginning (1916) through the years and to portray a picture of its current existence in its various branches: What developments and changes have taken place over the years? What has been the relationship of the church to African culture? How has the church grown or expanded? Has the church been able to maintain its unity? And what has been the relationship of the church with other churches?
Stephen Kauta Msiska was ordained to the ministry in 1945 and served the Livingstonia Synod in a number of lakeshore parishes before being appointed ?rst a tutor and later Principal of the united CCAP Theological College at Nkhoma where he taught from 1962 to 1974. His ?rm stand for what he understood to be the principles of the Christian Gospel led to a clash with the one-party regime and he was forced to ?ee to his home village and to live there in relative obscurity. This book makes accessible some of the fruits not only of his years of active pastoral ministry and theological teaching but also of his time of lonely suffering and sorrow. Distinctive in the writing of this pioneering theologian is a profound, though not uncritical, sympathy with the traditional religion of his people combined with a passionate concern for authentic Christian discipleship. Careful readers of this original and thoughtful book will ?nd the 'golden buttons' which Stephen Kauta is determined should not be lost.
Writing Namibia: Literature in Transition is a cornucopia of extraordinary and fascinating material which will be a rich resource for students, teachers and readers interested in Namibia. The text is wide ranging, defining literature in its broadest terms. In its multifaceted approach, the book covers many genres traditionally outside academic literary discourse and debate. The 22 chapters cover literature of all categories in Namibia since independence: written and performance poetry, praise poetry, Oshiwambo orature, drama, novels, autobiography, womens writing, subaltern studies, literature in German, Ju|hoansi and Otjiherero, childrens literature, Afrikaans fiction, story-telling through film, publishing, and the interface between literature and society. The inclusive approach is the books strength as it allows a wide range of subjects to be addressed, including those around gender, race and orature which have been conventionally silenced.
Migration has assumed growing significance in the global development agenda as its potential for economic and social development is increasingly acknowledged. Within the Africa context, perceptions of migration as a negative phenomenon have shifted to recognition of its central role to Africa's transformation. Despite this shift, emerging migration dynamics have not been adequately contextualized and conceptualized, making it difficult to integrate migration into development planning processes. This book attempts to fill the gaps in migration knowledge production, particularly from the perspectives of researchers in the global south and more specifically from Ghana. The chapters provide multi disciplinary perspectives in the contemporary migration landscape in Ghana and Africa. Rather than focus on migration as a problem to be solved, the chapters explore migration as an intrinsic part of the broader processes of structural change in Ghana, which could create opportunities for development if properly harnessed. This reader is an essential resource for migration and development researchers, students, policy makers, practitioners and others interested in the field of development.
Millions of Ghanaians live with diabetes, hypertension, stroke, cancers and other major chronic diseases. Millions more are at risk of getting these conditions. Individuals living with chronic conditions experience many disruptions, especially at the early stages of diagnosis and adjustment. The disruptions are physical (medical complications), psychological (depression), material (impoverishment), social (stigma) and spiritual (struggles with faith and trust). These experiences have an impact on family life and resources, with primary caregivers bearing similar disruptions to their chronically ill loved ones. While chronic conditions cannot be cured, many individuals hope for a cure. This hope drives healthcare seeking across different sectors of Ghanas vibrant pluralistic health system. When hope for a cure meets claims to cure within the herbalist and faith healing sectors, especially, the outcomes for individuals and their families can be catastrophic. The Ghanaian situation is mirrored in many African countries. It is estimated that African chronic non-communicable disease (NCD) prevalence, morbidity and mortality rates will rise faster than rates in Asia and Latin America over the coming decades. The long term and costly nature of NCDs has major implications for individuals, communities, health systems and governments. In this inaugural lecture, Professor Ama de-Graft Aikins discusses the psychology of chronic disease risk, experience and care in Africa. She makes a case for why the problem of NCDs needs to be examined through a psychological lens. She draws on her independent and collaborative work on diabetes representations and experiences among Ghanaians in Ghana and Europe, and the broader African and global health literature, to highlight the complex multi-level context of chronic disease risk, experience and care. She presents a synthesis of the evidence through the concepts of physical ills and ideological ills, arguing that both are interconnected and, as a result, must be addressed through interdisciplinary approaches. She concludes by offering practical solutions for reducing chronic disease risk and improving the quality of long-term experience and care in Ghana, using examples from countries that have implemented successful NCD interventions.
Speaking of Mauritius as an economic miracle has become a cliché, and with good reason: Its development since Independence in 1968 can easily be narrated as a rags-to-riches story. In addition, it is a stable democracy capable of containing the conflict potential inherent in its complex ethnic and religious demography. This book brings together some of the finest scholarship, domestic as well as foreign, on contemporary Mauritius, offering perspectives from constitutional law, cultural studies, sociology, archaeology, economics, social anthropology and more. While celebrating the indisputable, and impressive, achievements of the Mauritian nation on its fiftieth birthday, this book is far from toothless. Looking back inevitably implies looking ahead, and in order to do so, critical self-scrutiny is essential, to be able to learn from the mistakes of the past. The contributors raise fundamental questions concerning a broad range of issues, from the dilemmas of multiculturalism to the marginal role of women in public life, from the question of constitutional reform and the continued problem of corruption to the slow destruction of Mauritius joy and pride, namely the beauty and purity of its natural scenery. Taking stock of the first fifty years, this book also looks ahead to the next fifty years, giving some cues as to where Mauritius can and should aim in the next decades.