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Covalent inhibition has become more accepted in the past two decades, as illustrated by the clinical approval of several irreversible inhibitors designed to covalently modify their target. Elucidation of the structure-activity relationship and potency of such inhibitors requires a detailed kinetic evaluation. Here, we elucidate the relationship between the experimental read-out and the underlying inhibitor binding kinetics. Interactive kinetic simulation scripts are employed to highlight the effects of in vitro enzyme activity assay conditions and inhibitor binding mode, thereby showcasing which assumptions and corrections are crucial. Four stepwise protocols to assess the biochemical potency of (ir)reversible covalent enzyme inhibitors targeting a nucleophilic active site residue are included, with accompanying data analysis tailored to the covalent binding mode. Together, this will serve as a guide to make an educated decision regarding the most suitable method to assess covalent inhibition potency. © 2022 The Authors. Current Protocols published by Wiley Periodicals LLC.
The bromodomain and PHD-finger containing transcription factor (BPTF) is part of the nucleosome remodeling factor (NURF) complex and has been implicated in multiple cancer types. Here, we report the discovery of a potent and selective chemical probe targeting the bromodomain of BPTF with an attractive pharmacokinetic profile enabling cellular and in vivo experiments in mice. Microarray-based transcriptomics in presence of the probe in two lung cancer cell lines revealed only minor effects on the transcriptome. Profiling against a panel of cancer cell lines revealed that the antiproliferative effect does not correlate with BPTF dependency score in depletion screens. Both observations and the multi-domain architecture of BPTF suggest that depleting the protein by proteolysis targeting chimeras (PROTACs) could be a promising strategy to target cancer cell proliferation. We envision that the presented chemical probe and the related negative control will enable the research community to further explore scientific hypotheses with respect to BPTF bromodomain inhibition.
Introduction: The rational development of new therapeutics requires a thorough understanding of how aberrant signalling affects cellular homeostasis and causes human disease. Chemical probes are tool compounds with well-defined mechanism-of-action enabling modulation of, for example, domain-specific protein properties in a temporal manner, thereby complementing other target validation methods such as genetic gain- and loss-of-function approaches.
Areas covered: In this review, the authors summarize recent advances in chemical probe development for emerging target classes such as solute carriers and ubiquitin-related targets and highlight open resources to inform and facilitate chemical probe discovery as well as tool compound selection for target validation and phenotypic screening.
Expert opinion: Chemical probes are powerful tools for drug discovery that have led to fundamental insights into biological processes and have paved the way for the development of first-in-class drugs. Open resources can inform on various aspects of chemical probe development and provide access to data and recommendations on use of chemical probes to catalyse collaborative science and help accelerate drug target identification and validation.
The (mis)management of rapport amongst groups in Niger Delta (ND) communities has become a significant issue, which Ahmed Yerima's Hard Ground (HG) depicts as having the capacity to aid or control the conflicts in the region. Linguistic studies on Yerima's drama from the perspective of pragmatics have tended to use pragmatic acts to identify the discourse value of proverbs and functions of characters' utterances but have not accounted for the politeness strategies utilised for rapport management, especially in conflict situations. This article, drawing on a rapport management model of politeness and aspects of speech act discourse, identifies the face, sociality rights, and interactional goals that characterise the conflict-motivated dialogues sampled in HG, and reveals the rapport management (RM) strategies through which these are managed in the text. Three conflict situations can be observed as prompting different RM strategies: cause-effect identification (CEI), militancy support (MSP), and disagreement (DSG) situations. CEI is marked by incriminating (involving eliciting and informing acts) and exonerating (including complimenting and acknowledging acts) strategies; MSP is indexed by strategies of persuasion (realised with face-enhancing/threatening acts), whereas DSG is typified by requesting (featuring explicit head acts and alerters) and blaming strategies (including insulting and threatening, aggravating moves). Generally, the requesting, blaming, and exonerating strategies are largely used by the ND youth in HG to probe, threaten, or disagree on specific issues, while the incriminating and persuasion strategies are mainly employed by the women to indict, influence, and predict future actions. The study of RM in the conflict situations depicted in the play sheds light on the often neglected cause of conflicts in contemporary Africa.
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.
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.
"Politische Korrektheit" ist als deskriptive wie als normative Kategorie in Bezug auf unterschiedlichste Kommunikations-, mediale und institutionelle Kontexte seit einigen Jahren allgegenwärtig. Zunehmend wird sie nun selbst zum Gegenstand der Debatte. Ursprünglich Ausdruck des Bemühens, ein Bewusstsein für sprachliche Diskriminierungen zu schaffen und auf eine diskriminierungsfreie Sprache hinzuwirken, befindet sich die politische Korrektheit mittlerweile im Spannungsfeld zwischen nahezu obsessiv betriebenen Versuchen einer Beschränkung des Sagbaren einerseits und ebenso programmatisch unternommenen Überschreitungen der Grenzen des Sagbaren andererseits. Verbot und Provokation grundieren nicht zuletzt das politische/ administrative Sprechen bzw. Schreiben sowie erhebliche Anteile von Äußerungsformen im Rahmen der Social Media. In einer historischen Perspektive verbindet die Forderung nach einer mehr oder weniger strikten Reglementierung des Sagbaren die politische Korrektheit mit der staatlichen oder kirchlichen Zensur vor- bzw. nicht-demokratischer Systeme. Während gegenwärtig in der Mehrzahl der westlichen Gesellschaften eine derart institutionalisierte Steuerung des Sagbaren nicht mehr stattfindet, also scheinbar nichts mehr "unsagbar" ist, lassen sich in verschiedenen sozialen Segmenten und Communities sehr wohl selbstauferlegte Sprach- und Verhaltenskodices beobachten, die nach wie vor oder wieder Grenzen des Sagbaren definieren. Als Sprachkodex in diesem Sinn fungiert bisweilen auch die politische Korrektheit. So fragwürdig eine zum Selbstzweck gewordene politisch korrekte Sprache allerdings auch sein mag, so besorgniserregend sind programmatische Verstöße gegen die politische Korrektheit, wo sie offensichtlich auf Diffamierung zielen und in letzter Konsequenz Prozesse der Entsolidarisierung befördern wollen. ...
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.
Tibnīn was an important small Crusader fief and a fortified castle. It was vital for the Kingdom of Jerusalem, because it included fertile agricultural lands, was a tax collection centre, and because it controlled the Damascus-to-Tyre commercial route. Additionally, its castle played defensive and offensive role in the north of the Kingdom of Jerusalem and upper Galilee, and its rulers of Tibnīn played a major role in forming the history of the Latin East. When the Crusaders invaded the Levant at the end of the eleventh century, it was given rise to new demographic, cultural, socio-economic, and architectural features. The present Paper aims at removing some of the mystery concerning the fief of Tibnīn and its castle in the Latin East. This paper thus is a study of the demographic structure of Tibnīn and discusses the socio-economic role of Tibnīn in the Latin east. Moreover, the role of Tibnīn in influencing the relations between Muslims and the Crusaders in the Levant and the architecture of the castle of Tibnīn and its importance in the age of the Crusade will be examined.
In dem folgenden werkgenetischen und forschungskritischen Beitrag geht es um das sonderbare und revisionsbedürftige Schicksal, das eine von Mozart nach dessen Rückkehr aus Mannheim in Salzburg ohne Auftrag begonnene und bis Sommer 1780 fast vollendete Oper durch ihre Rezeption bei der Nachwelt bis heute erlitten hat. Für meine Hypothese, bei Mozarts Zaïde handele es sich um eine ernste (nicht-komische), höchstwahrscheinlich einaktig konzipierte Kurzoper ("Operette", W. A. M.) ohne glücklichen Ausgang, ist es ebenso unmöglich, einen "Nachweis" zu erbringen, wie für die bisher geltende, als einzig denkbare Wahrheit auftretende These, sie sei ein stark fragmentarisches, höchstwahrscheinlich dreiaktiges Singspiel, dem nicht nur die Ouvertüre und die meisten Dialoge fehlten, sondern auch die entweder in mehreren fehlenden Schlussnummern eines zweiten oder in einem dritten Akt sich vollziehen sollende glückliche Wende. Darum wird hier nicht versucht, gegen eine bestehende beanspruchte "Deutungshoheit" eine andere zu setzen, sondern lediglich angezeigt und begründet, warum es ratsam ist, eine andere Interpretationsmöglichkeit bekannter Quellen, von denen einige bisher berücksichtigt, andere vernachlässigt wurden, ins Auge zu fassen. Es kann lediglich anhand von Indizien, welche die Quellen und Teile der bisherigen Forschung aufweisen, eine neue, bisher verworfene Möglichkeit von dem über sie verhängten Verdikt befreit werden. ...
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.
Purpose: DINO and DACOTA were prospective, noninterventional studies assessing the health status and quality of life of patients with COPD newly treated with roflumilast 500 µg once-daily add-on therapy.
Patients and methods: Patients were evaluated over 6 months. Clinical COPD questionnaire (CCQ) and COPD assessment test (CAT) scores were recorded at baseline and after 3 and 6 months. In DACOTA, post-bronchodilator FEV1 was recorded at each time point.
Results: Of 5,462 and 3,645 patients recruited into DINO and DACOTA, respectively, 3,274 patients in DINO and 916 patients in DACOTA completed the 6-month visit. Almost all patients had severe or very severe airway obstruction; mean baseline CCQ total score was 3.9 in DINO and 3.7 in DACOTA. Overall, 33.8% of patients in DACOTA and 30.6% in DINO discontinued treatment prematurely. Significant and clinically relevant improvements in CCQ total scores were observed in both studies (mean change from baseline of 1.36 in DINO and 0.91 in DACOTA at Month 6 [all P<0.001]). Changes in CAT total score from baseline to Month 6 indicated that the average clinical impact of COPD was reduced from a severe (score: 21–30) to a moderate (score: 11–20) impairment. In DACOTA, mean change in post-bronchodilator FEV1 was 202 mL (P<0.001). Diarrhea, nausea, and weight decrease were the most frequently reported adverse drug reactions.
Conclusion: In real-life clinical practice, roflumilast treatment as an add-on therapy is associated with clinically relevant improvements in health status and quality of life.
Sprachen, Epochen und Gattungen stellt die Literaturwissenschaften immer wieder vor die Frage, wie sie diese Entwicklung mitgestalten und zu ihrem Vorteil nutzen können. Dabei ist digital nicht gleich digital, sondern es existiert eine Vielzahl sehr unterschiedlicher, digitaler Repräsentationsformen von Text. Nur wenige dieser Repräsentationsformen werden literaturwissenschaftlichen Anforderungen tatsächlich gerecht, darunter diejenige, die den Richtlinien der Text Encoding Initiative folgt. Der vorliegende Beitrag vergleicht zunächst einige derzeit gängige digitale Repräsentationsformen von Text. Für literaturwissenschaftliche Forschung besonders geeignet erweist sich hierbei eine Repräsentationsform, die den Richtlinien der Text Encoding Initiative folgt. Daher informiert der Beitrag anschließend über deren Nutzen für die literaturwissenschaftliche Arbeit, sowohl im Bereich der wissenschaftlichen Textedition als auch im Bereich der Analyse und Interpretation von Texten. Nur wenn die Literaturwissenschaften in ihrer Breite den Nutzen von offenen, expressiven, flexiblen und standardisierten, langfristig nutzbaren Formaten für die Forschung erkennen, können sie sich mit dem erforderlichen Nachdruck für deren Verbreitung einsetzen und durch die zunehmende Verfügbarkeit von Texten in solchen Formaten für die eigene Forschung und Lehre davon profitieren.
Der Artikel stellt aktuelle stilometrische Studien im Delta-Kontext vor. Diskutiert wird, warum die Verwendung des Kosinus-Abstands zu einer Verbesserung der Erfolgsquote führt; durch Experimente zur Vektornormalisierung gelingt es, die Funktionsweise von Delta besser zu verstehen. Anhand von mittelhochdeutschen Texten wird gezeigt, dass auch metrische Eigenschaften zur Autorschaftsattribution eingesetzt werden können. Zudem wird untersucht, inwieweit die mittelalterliche, nicht-normierte Schreibung die Erfolgsquote von Delta beeinflusst. Am Beispiel von arabisch-lateinischen Übersetzungen wird geprüft, inwieweit eine selektive Merkmalseliminierung dazu beitragen kann, das Übersetzersignal vom Genresignal zu isolieren.
Schiller and Goethe have very different conceptions of tragedy. In his play Don Carlos, Schiller, especially in the character of Philip II, shows us the conflict between blood and positive law. In Goethe´s novel Elective Affinities, the individual will is ignorant of fate and helpless against it. So to speak, Schiller applies the "Antigone´s Model" and Goethe applies the "Oedipus Model". In his dramatic vision of the conflict, Schiller is inspired by Shakespeare´s plays. However, Goethe´s point of view is based on his reflections on Natural Philosophy.
Expression of surfactant protein B is dependent on cell density in H441 lung epithelial cells
(2017)
Background: Expression of surfactant protein (SP)-B, which assures the structural stability of the pulmonary surfactant film, is influenced by various stimuli, including glucocorticoids; however, the role that cell-cell contact plays in SP-B transcription remains unknown. The aim of the current study was to investigate the impact of cell-cell contact on SP-B mRNA and mature SP-B expression in the lung epithelial cell line H441.
Methods: Different quantities of H441 cells per growth area were either left untreated or incubated with dexamethasone. The expression of SP-B, SP-B transcription factors, and tight junction proteins were determined by qPCR and immunoblotting. The influence of cell density on SP-B mRNA stability was investigated using the transcription inhibitor actinomycin D.
Results: SP-B mRNA and mature SP-B expression levels were significantly elevated in untreated and dexamethasone-treated H441 cells with increasing cell density. High cell density as a sole stimulus was found to barely have an impact on SP-B transcription factor and tight junction mRNA levels, while its stimulatory ability on SP-B mRNA expression could be mimicked using SP-B-negative cells. SP-B mRNA stability was significantly increased in high-density cells, but not by dexamethasone alone.
Conclusion: SP-B expression in H441 cells is dependent on cell-cell contact, which increases mRNA stability and thereby potentiates the glucocorticoid-mediated induction of transcription. Loss of cell integrity might contribute to reduced SP-B secretion in damaged lung cells via downregulation of SP-B transcription. Cell density-mediated effects should thus receive greater attention in future cell culture-based research.
Neural responses to heartbeats in the default network encode the self in spontaneous thoughts
(2016)
The default network (DN) has been consistently associated with self-related cognition, but alsoto bodily state monitoring and autonomic regulation. We hypothesized that these two seemingly disparate functional roles of the DN are functionally coupled, in line with theories proposing that selfhood is grounded in the neural monitoring of internal organs, such as the heart. We measured with magnetoencephalograhy neural responses evoked by heartbeats while human participants freely mind-wandered. When interrupted by a visual stimulus at random intervals, participants scored the self-relatedness of the interrupted thought. They evaluated their involvement as the firstperson perspective subject or agent inthethought (“I”), and on another scaleto what degreethey werethinking aboutthemselves (“Me”). During the interrupted thought, neural responses to heartbeats in two regions of the DN, the ventral precuneus and the ventromedial prefrontal cortex, covaried, respectively, with the “I” and the “Me” dimensions of the self, even at the single-trial level. No covariation between self-relatedness and peripheral autonomic measures (heart rate, heart rate variability, pupil diameter, electrodermal activity, respiration rate, and phase) or alpha power was observed. Our results reveal a direct link between selfhood and neural responses to heartbeats in the DN and thus directly support theories grounding selfhood in the neural monitoring of visceral inputs. More generally, the tight functional coupling between self-related processing and cardiac monitoring observed here implies that, even in the absence of measured changes in peripheral bodily measures, physiological and cognitive functions have to be considered jointly in the DN.
Background: Kyrgyzstan, where HIV is concentrated in prisons and driven by injection drug use, provides a prison-based methadone maintenance therapy program as well as abstinence-oriented therapeutic community based on the 12-step model called the “Clean Zone.” We aimed to qualitatively assess how prisoners navigate between these treatment options to understand the persistence of the Clean Zone despite a lack of evidence to support its effectiveness in treating opioid use disorders.
Methods: We conducted an analysis of policy documents and over 60 h of participant observation in February 2016, which included focus groups with a convenience sample of 20 therapeutic community staff members, 110 prisoners across three male and one female prisons, and qualitative interviews with two former Clean Zone participants. Field notes containing verbatim quotes from participants were analyzed through iterative reading and discussion to understand how participants generally perceive the program, barriers to entry and retention, and implications for future treatment within prisons.
Results: Our analyses discerned three themes: pride in the mission of the Clean Zone, idealism regarding addiction treatment outcomes against all odds, and the demonization of methadone.
Conclusion: Despite low enrollment and lack of an evidence base, the therapeutic community is buttressed by the strong support of the prison administration and its clients as an “ordered” alternative to what is seen as chaotic life outside of the Clean Zone. The lack of services for Clean Zone patients after release likely contributes to high rates of relapse to drug use. The Clean Zone would benefit from integration of stabilized methadone patients combined with a post-release program.
Earliest expansion of animal husbandry beyond the Mediterranean zone in the sixth millennium BC
(2017)
Since their domestication in the Mediterranean zone of Southwest Asia in the eighth millennium BC, sheep, goats, pigs and cattle have been remarkably successful in colonizing a broad variety of environments. The initial steps in this process can be traced back to the dispersal of farming groups into the interior of the Balkans in the early sixth millennium BC, who were the first to introduce Mediterranean livestock beyond its natural climatic range. Here, we combine analysis of biomolecular and isotopic compositions of lipids preserved in prehistoric pottery with faunal analyses of taxonomic composition from the earliest farming sites in southeast Europe to reconstruct this pivotal event in the early history of animal husbandry. We observe a marked divergence between the (sub)Mediterranean and temperate regions of Southeast Europe, and in particular a significant increase of dairying in the biochemical record coupled with a shift to cattle and wild fauna at most sites north of the Balkan mountain range. The findings strongly suggest that dairying was crucial for the expansion of the earliest farming system beyond its native bioclimatic zone.
Unequivocal international guidelines regarding the diagnosis and management of patients with acute appendicitis are lacking. The aim of the consensus meeting 2015 of the EAES was to generate a European guideline based on best available evidence and expert opinions of a panel of EAES members. After a systematic review of the literature by an international group of surgical research fellows, an expert panel with extensive clinical experience in the management of appendicitis discussed statements and recommendations. Statements and recommendations with more than 70 % agreement by the experts were selected for a web survey and the consensus meeting of the EAES in Bucharest in June 2015. EAES members and attendees at the EAES meeting in Bucharest could vote on these statements and recommendations. In the case of more than 70 % agreement, the statement or recommendation was defined as supported by the scientific community. Results from both the web survey and the consensus meeting in Bucharest are presented as percentages. In total, 46 statements and recommendations were selected for the web survey and consensus meeting. More than 232 members and attendees voted on them. In 41 of 46 statements and recommendations, more than 70 % agreement was reached. All 46 statements and recommendations are presented in this paper. They comprise topics regarding the diagnostic work-up, treatment indications, procedural aspects and post-operative care. The consensus meeting produced 46 statements and recommendations on the diagnostic work-up and management of appendicitis. The majority of the EAES members supported these statements. These consensus proceedings provide additional guidance to surgeons and surgical residents providing care to patients with appendicitis.
Background: Only few authors have analyzed the impact of workplace conflicts and the resulting stress on the risk of developing cardiovascular disorders. The goal of this study was to analyze the association between workplace conflicts and cardiovascular disorders in patients treated by German general practitioners.
Methods: Patients with an initial documentation of a workplace conflict experience between 2005 and 2014 were identified in 699 general practitioner practices (index date). We included only those who were between the ages of 18 and 65 years, had a follow-up time of at least 180 days after the index date, and had not been diagnosed with angina pectoris, myocardial infarction, coronary heart diseases, or stroke prior to the documentation of the workplace mobbing. In total, the study population consisted of 7,374 patients who experienced conflicts and 7,374 controls for analysis. The main outcome measure was the incidence of angina pectoris, myocardial infarction, and stroke correlated with workplace conflict experiences.
Results: After a maximum of five years of follow-up, 2.9% of individuals who experienced workplace conflict were affected by cardiovascular diseases, while only 1.4% were affected in the control group (p-value <0.001). Workplace conflict was associated with a 1.63-fold increase in the risk of developing cardiovascular diseases. Finally, the impact of workplace conflict was higher for myocardial infarction (OR=2.03) than for angina pectoris (OR=1.79) and stroke (OR=1.56).
Conclusions: Overall, we found a significant association between workplace conflicts and cardiovascular disorders.
Body image dissatisfaction is a serious, global problem that negatively affects life satisfaction. Several claims have been made about the possible psychological benefits of naturist activities, but very little empirical research has investigated these benefits or any plausible explanations for them. In three studies—one large-scale, cross-sectional study (n = 849), and 2 prospective studies (n = 24, n = 100) this research developed and applied knowledge about the possible benefits of naturist activities. It was found that more participation in naturist activities predicted greater life satisfaction—a relationship that was mediated by more positive body image, and higher self-esteem (Study 1). Applying these findings, it was found that participation in actual naturist activities led to an increase in life satisfaction, an effect that was also mediated by improvements in body image and self-esteem (Studies 2 and 3). The potential benefits of naturism are discussed, as well as possible future research, and implications for the use of naturist activities.
In evidence-based weight-loss programs weight regain is common after an initial weight reduction. Eating slowly significantly lowers meal energy intake and hunger ratings. Despite this knowledge, obese individuals do not implement this behaviour. We, thus tested the hypothesis of changing eating behaviour with an intra-oral medical device leading to constant weight reduction in overweight and obesity.
Six obese patients (6 men, age 56 ± 14, BMI 29 ± 2 kg / m2) with increased CVRF profile were included in this prospective study. All patients had been treated for obesity during the last 10 years in a single centre and had at least 3 frustrate evidence-based diets. Patients received a novel non-invasive intra-oral medical device to slow eating time. Further advice included not to count calories, to avoid any other form of diet, to take their time with their meals, and to eat whatever they liked.
This device was used only during meals for the first 4 to 8 weeks for a total of 88 [20–160] hours. Follow-up period was 23 [15–38] months. During this period, patients lost 11% [5–20%] (p<0.001) of their initial weight. At 12 months, all patients had lost >5%, and 67% (4/6) achieved a >10% bodyweight loss. In the course of the study, altered eating patterns were observed. There were no complications with the medical device. Of note, all patients continued to lose weight after the initial intervention period (p<0.001) and none of them had weight regain.
With this medical device, overweight and obese patients with a history of previously frustrating attempts to lose weight achieved a significant and sustained weight loss over two years. These results warrant the ongoing prospective randomised controlled trial to prove concept and mechanism of action.
Decreased STARD10 expression is associated with defective insulin secretion in humans and mice
(2017)
Genetic variants near ARAP1 (CENTD2) and STARD10 influence type 2 diabetes (T2D) risk. The risk alleles impair glucose-induced insulin secretion and, paradoxically but characteristically, are associated with decreased proinsulin:insulin ratios, indicating improved proinsulin conversion. Neither the identity of the causal variants nor the gene(s) through which risk is conferred have been firmly established. Whereas ARAP1 encodes a GTPase activating protein, STARD10 is a member of the steroidogenic acute regulatory protein (StAR)-related lipid transfer protein family. By integrating genetic fine-mapping and epigenomic annotation data and performing promoter-reporter and chromatin conformational capture (3C) studies in β cell lines, we localize the causal variant(s) at this locus to a 5 kb region that overlaps a stretch-enhancer active in islets. This region contains several highly correlated T2D-risk variants, including the rs140130268 indel. Expression QTL analysis of islet transcriptomes from three independent subject groups demonstrated that T2D-risk allele carriers displayed reduced levels of STARD10 mRNA, with no concomitant change in ARAP1 mRNA levels. Correspondingly, β-cell-selective deletion of StarD10 in mice led to impaired glucose-stimulated Ca2+ dynamics and insulin secretion and recapitulated the pattern of improved proinsulin processing observed at the human GWAS signal. Conversely, overexpression of StarD10 in the adult β cell improved glucose tolerance in high fat-fed animals. In contrast, manipulation of Arap1 in β cells had no impact on insulin secretion or proinsulin conversion in mice. This convergence of human and murine data provides compelling evidence that the T2D risk associated with variation at this locus is mediated through reduction in STARD10 expression in the β cell.
The article consists in a comparative reading of three novels: Um rio chamado tempo by Mia Couto, Le pain des corbeaux by Lhoussain Azergui and Paw królowej by Dorota Masłowska. In spite of the difference of the historical circumstances of Mozambique, Morocco and Poland, these three books meet at an intersecting point: the emergence of an intelligentsia that uses literacy and writing as an instrument to deconstruct the post-colonial concept of nation and to operate a trans-colonial renegotiation of identity. By the notion of trans-colonial, I understand the opposition against new kinds of symbolic violence that emerged after the end of the colonial period; here this new form of oppression is related to the concept of national unity – an artificial construct that leaves no place for a dualism or pluralism of cultural reality (two shores of the Zambezi river, Arab and Berber dualism in Morocco, "small homelands" in Poland).
The young heroes of the novels grasp the pen in order to break through the falseness or the taboos created by the fathers, establishing, at the same time, the relation of solidarity with the world of the grandfathers. The act of writing becomes an actualization of the ancestral universe of magic. The settlement of accounts with the parental generation concerns the vision of nation built upon the resistance against the colonizer (it also refers to the Polish cultural formation, based on the tradition of uprisings and resistance against the Russians).
A three-dimensional gridded climatology of carbon monoxide (CO) has been developed by trajectory mapping of global MOZAIC-IAGOS in situ measurements from commercial aircraft data. CO measurements made during aircraft ascent and descent, comprising nearly 41 200 profiles at 148 airports worldwide from December 2001 to December 2012, are used. Forward and backward trajectories are calculated from meteorological reanalysis data in order to map the CO measurements to other locations and so to fill in the spatial domain. This domain-filling technique employs 15 800 000 calculated trajectories to map otherwise sparse MOZAIC-IAGOS data into a quasi-global field. The resulting trajectory-mapped CO data set is archived monthly from 2001 to 2012 on a grid of 5° longitude × 5° latitude × 1 km altitude, from the surface to 14 km altitude.
The mapping product has been carefully evaluated, firstly by comparing maps constructed using only forward trajectories and using only backward trajectories. The two methods show similar global CO distribution patterns. The magnitude of their differences is most commonly 10 % or less and found to be less than 30 % for almost all cases. Secondly, the method has been validated by comparing profiles for individual airports with those produced by the mapping method when data from that site are excluded. While there are larger differences below 2 km, the two methods agree very well between 2 and 10 km with the magnitude of biases within 20 %. Finally, the mapping product is compared with global MOZAIC-IAGOS cruise-level data, which were not included in the trajectory-mapped data set, and with independent data from the NOAA aircraft flask sampling program. The trajectory-mapped MOZAIC-IAGOS CO values show generally good agreement with both independent data sets.
Maps are also compared with version 6 data from the Measurements Of Pollution In The Troposphere (MOPITT) satellite instrument. Both data sets clearly show major regional CO sources such as biomass burning in Central and southern Africa and anthropogenic emissions in eastern China. While the maps show similar features and patterns, and relative biases are small in the lowermost troposphere, we find differences of ∼ 20 % in CO volume mixing ratios between 500 and 300 hPa. These upper-tropospheric biases are not related to the mapping procedure, as almost identical differences are found with the original in situ MOZAIC-IAGOS data. The total CO trajectory-mapped MOZAIC-IAGOS column is also higher than the MOPITT CO total column by 12–16 %.
The data set shows the seasonal CO cycle over different latitude bands and altitude ranges as well as long-term trends over different latitude bands. We observe a decline in CO over the northern hemispheric extratropics and the tropics consistent with that reported by previous studies using other data sources.
We anticipate use of the trajectory-mapped MOZAIC-IAGOS CO data set as an a priori climatology for satellite retrieval and for air quality model validation and initialization.
A three-dimensional gridded climatology of carbon monoxide (CO) has been developed by trajectory mapping of global MOZAIC-IAGOS in situ measurements from commercial aircraft data. CO measurements made during aircraft ascent and descent, comprising nearly 41 200 profiles at 148 airports worldwide from December 2001 to December 2012 are used. Forward and backward trajectories are calculated from meteorological reanalysis data in order to map the CO measurements to other locations, and so to fill in the spatial domain. This domain-filling technique employs 15 800 000 calculated trajectories to map otherwise sparse MOZAIC-IAGOS data into a quasi-global field. The resulting trajectory-mapped CO dataset is archived monthly from 2001–2012 on a grid of 5° longitude × 5° latitude × 1 km altitude, from the surface to 14 km altitude.
The mapping product has been carefully evaluated, by comparing maps constructed using only forward trajectories and using only backward trajectories. The two methods show similar global CO distribution patterns. The magnitude of their differences is most commonly 10 % or less, and found to be less than 30 % for almost all cases. The trajectory-mapped CO dataset has also been validated by comparison profiles for individual airports with those produced by the mapping method when data from that site are excluded. While there are larger differences below 2 km, the two methods agree very well between 2 and 10 km with the magnitude of biases within 20 %.
Maps are also compared with Version 6 data from the Measurements Of Pollution In The Troposphere (MOPITT) satellite instrument. While agreement is good in the lowermost troposphere, the MOPITT CO profile shows negative biases of ∼ 20 % between 500 and 300 hPa. These upper troposphere biases are not related to the
mapping procedure, as almost identical differences are found with the original in situ MOZAIC-IAGOS data. The total CO trajectory-mapped MOZAIC-IAGOS climatology column agrees with the MOPITT CO total column within ±5 %, which is consistent with previous reports.
The maps clearly show major regional CO sources such as biomass burning in the central and southern Africa and anthropogenic emissions in eastern China. The dataset shows the seasonal CO cycle over different latitude bands and altitude ranges that are representative of the regions as well as long-term trends over latitude bands. We observe a decline in CO over the Northern Hemisphere extratropics and the tropics consistent with that reported by previous studies.
Similar maps have been made using the concurrent O3 measurements by MOZAICIAGOS, as the global variation of O3–CO correlations can be a useful tool for the evaluation of ozone sources and transport in chemical transport models. We anticipate use of the trajectory-mapped MOZAIC-IAGOS CO dataset as an a priori climatology for satellite retrieval, and for air quality model validation and initialization.
The first step in methanol metabolism in methylotrophic yeasts, the oxidation of methanol and higher alcohols with molecular oxygen to formaldehyde and hydrogen peroxide, is catalysed by alcohol oxidase (AOX), a 600-kDa homo-octamer containing eight FAD cofactors. When these yeasts are grown with methanol as the carbon source, AOX forms large crystalline arrays in peroxisomes. We determined the structure of AOX by cryo-electron microscopy at a resolution of 3.4 Å. All residues of the 662-amino acid polypeptide as well as the FAD are well resolved. AOX shows high structural homology to other members of the GMC family of oxidoreductases, which share a conserved FAD binding domain, but have different substrate specificities. The preference of AOX for small alcohols is explained by the presence of conserved bulky aromatic residues near the active site. Compared to the other GMC enzymes, AOX contains a large number of amino acid inserts, the longest being 75 residues. These segments are found at the periphery of the monomer and make extensive inter-subunit contacts which are responsible for the very stable octamer. A short surface helix forms contacts between two octamers, explaining the tendency of AOX to form crystals in the peroxisomes.
Advantageous fragmentation? : reimagining metropolitan governance and spatial planning in Rhine-Main
(2006)
This paper traces the latest round of debates about appropriate scales and scopes of government and governance in Rhine-Main - an economically highly integrated but politically, territorially and emotionally divided region. We identify a downscaling of political power from the regional to the municipal level, and an upscaling of informal networking and image building to an extended regional scale. These countertrends are signs of a more complex geographical rearrangement in municipal and institutional relations. The inherent contradictions in the rescaling and reimagining of Rhine-Main are evident in the Strategic Vision for Frankfurt/Rhein-Main 2020. Its new conceptualization of Rhine-Main postulates complementary polycentricity as a competitive asset but remains firmly grounded in an institutional territorial logic that contravenes its own economically-driven agenda.
Unter der Signatur VI/273 befinden sich in der Stiftsbibliothek Kremsmünster acht Pergamentstreifen unterschiedlicher Breite (...) und unregelmäßiger Länge (...). Es handelt sich um die Reste von zwei Pergamentdoppelblättern (...). Die Schrift gehört wohl noch dem 12. Jahrhundert an, sie macht jedenfalls einen altertümlicheren Eindruck als die der Göttinger Bruchstücke, der bisher ältesten Überlieferung des Lucidarius (...). Inhaltlich erweist sich die vorliegende Textpartie zugehörig zum 3. Buch des Lucidarius (...).
Die Annahme, Fuß sei ein Minnesänger gewesen, beruht auf der Zuordnung zu drei Personen, die auf diesem Gebiet hervorgetreten sind, und auf der Interpretation der Bezeichnung ‚puler’. Trifft nun schon die Angabe „Minnesänger“ bei Wolfram nur für ein dem späten Mittelalter kaum mehr gegenwärtiges Nebengebiet seines dichterischen Schaffens zu, so bedeutet ‚puler’ in den (...) [Volker Mertens] bekannten Belegen soviel wie „Minner, Liebhaber“, in einem Fall auch „Sachverständiger in Liebesdingen“ (...), aber niemals „Minnesänger“.
Die Papier-Hs. B II, 1 der Fürstlich Fürstenbergischen Bibliothek Donaueschingen enthält die Postille des Hartung/Heinrich von Erfurt (…). Sie wurde laut Schreiberkolophon f. 320v i.J. 1451 geschrieben. (…) Abschließend (…) [gibt Volker Mertens] eine Konkordanz der Überlieferung der Postille. Sie enthält den liturgischen Ort, bzw. das Textwort und für die Hss. Z, F, D, K und R die laufende Nummer und die jeweilige Seitenangabe, ausgerichtet an Z, weil diese Hs. in der Anordnung am zuverlässigsten ist.
Groß ist die Spannweite der Interpretationen, die die ersten Verse von Hartmanns 'Iwein' erfahren haben. (…) Das reicht vom „Inbegriff der güete..., bei dem caritas, misericordia und summum bonum mitgedacht werden müssen“ (…) bis zum „recht verstandenen Rittertum“ (…), die als „leitstern“ (…) des Gedichts fungieren; kürzlich hat D.G. MOWATT den Prolog sogar ironisch verstehen wollen (…), wobei beweiskräftige sprachliche Signale für uneigentliches Sprechen jedoch kaum auffindbar sein dürften (…) und die Annahme einer nachträglichen Ironisierung des Beginns durch das (einseitig interpretierte) Ende des Roman nur aus der vergleichenden Lektüre des modernen Interpreten, nicht aber aus einer kontinuierlich-linearen zuhörenden Aufnahme durch Hartmanns Publikum abgeleitet werden kann.
„Unter unsern Altdeutschen Gedichten wenigstens wüßte ich kein Paar zu nennen, das uns mit einer solchen Familienähnlichkeit überraschte wie der Iwein und Wigalois“, schreibt G. F. Benecke in der Einleitung seiner Wigalois-Ausgabe (S. XV). (…) Als vermittelnde Kategorie zwischen der literarischen Gestaltung der historischen Realität (sowohl auf der Produktions- wie der Rezeptionsseite) (…) [benutzt Volker Mertens] im Folgenden die Konzeption der „Lebensform“ (…): der erzählerisch mit wichtigen Signalen angedeuteten Lebenssituationen, des Handlungsrahmens und der Vorstellungen der Personen können die Zuhörer Selbst- oder Fremdidentifikationen entnehmen und so die erzählte Geschichte als Antwort auf die Aussage zu einer bestimmten historischen Situation verstehen.
Alte Themen, auch unter neuen Vorzeichen nachspielbar [Volker Mertens fragt] nach ihrer Realisierbarkeit im höfischen Tristanroman des späten 12. und frühen 13. Jahrhundert, wie er von den beiden unvollständigen Werken des Thomas von Britannien und Gottfrieds von Straßburg repräsentiert wird. (…) Drei Szenen (…) [greift er heraus]: Tristans Pygmalion-Situation im Bildersaal, die allegorische Liebesapotheose der Minnegrotte und den mythischen liebebegründenden Trank.
New Philology: Das ist zunächst ein Schlagwort gegenwärtiger mediävistischer Methodendiskussion, und fast möchte man meinen, es hätte noch prägnanter formuliert werden können, wenn man etwas auf eine Bildung in Analogie zu anderen kurrenten ‚New-isms’ – New Medievalism (…) oder New Historicism (…) etwa – verfallen wäre: ‚New Philologism’. (…) Als Interdependenz (…) [einer] relativ situationsabstrakten ‚Formiertheit’ der poetischen Rede und der spezifischen situationellen variance des Textes (…) müsste man die soziale, also kommunikative Logik des mittelalterlichen Textes rekonstruieren können. Dabei dürfte dann auch sichtbar werden, daß die ‚Schließung’ des Textes nicht nur eine Generalisierung und Anonymisierung von poetischen Kommunikationssituationen voraussetzt (…) Sondern es könnte sich dann auch zeigen, daß an die stabile soziale Institution des Autors sowie an generalisierte und anonymisierte Kommunikationsverhältnisse gebundene und daher weitgehend invariante Text fortschreitend verzichten kann (…) auf jene Formierungen der literarischen Rede, welche unter den Voraussetzungen okkasioneller poetischer Kommunikation die Bedingung ihrer Möglichkeit waren. Der Text und seine Textualität sind dann etwas ganz anderes, weil seine Situationalität sich grundsätzlich verändert hat.
Die Geschichte der mediävistischen Literaturgeschichtsschreibung im 20. Jahrhundert ist die Geschichte einer zunehmenden Verunsicherung. Diese Verunsicherung ergibt sich weniger aus dem Problem, daß das Zusammentragen und Darstellen der beständig gewachsenen Menge an Fakten und Daten dem einzelnen kaum mehr möglich ist. [...] In dieser Situation scheint es [...] [Jans Haustein] vernünftig zu sein, wenn man das einer Literaturgeschichte zugrunde gelegte Material zunächst radikal begrenzt. [...] [Er möchte] für eine - erneute - Hinwendung der Literaturgeschichtsschreibung zur Region plädieren. Nur so, auf begrenztem Terrain und an einem überschaubarem Material, lassen sich Interpretationen und Überlieferungen sachgerecht aufeinander beziehen [...]. Für die thüringische Literaturgeschichte wären etwa die 'Losse-Sammlung' [...] mit Blick auf spätmittelalterliche Sammlungen von Minnereden oder die Pommersfeldener Handschrift im Kontext der Märenhandschriften einschlägig.
(...) [Jens Hausteins] folgende(n) Überlegungen haben ihre spezifische Gestalt durch die Beschäftigung mit Grundannahmen der New Philology gefunden, in erster Linie der Forderung nach einer Historisierung philologischer Grundkategorien (...) wie auch der , den Literaturbegriff deutlicher an der Tatsache zu orientieren, daß die Literatur des Mittelalters in einer manuscript culture entstanden. [Die Jens Haustein] beschäftigende Frage ist, welche Bedeutung das Insistieren auf dieser Tatsache für die Literaturgeschichtsschreibung haben könnte. Wie jede auf eine Handschriftenkultur bezogene Geschichtsschreibung diachron, d.h. sie abstrahiert aus dem in aller Regel später Überlieferten einen Geschichtsverlauf, ordnet das Überlieferte früheren Phasen zu, dem Zeitpunkt der mutmaßlichen oder tatsächlichen Entstehung. Ein solches 'methodisches Konzept' ist notwendig, wenn das Überlieferte in eine Ordnung gebracht sein soll, in der es Nachfolgendem präduliert oder Vorangegangenes fortentwickelt, wenn überhaupt das Prozeßhafte in der Literatur deutlich werden soll.
An einem Beispiel aus der Boppe-Überlieferung wird die Frage nach literarischer Kohärenz und Leistung meisterlicher Liebesdichtung behandelt. Die fünf Strophen des Liedes RSM Bop/1/500a sind sämtlich in andere, ebenfalls in der Kolmarer Liederhandschrift überlieferte Lieder integriert. Dieser Integrationsprozess zeigt ganz verschiedene Formen und einen je anderen Zuschnitt: Neben der fast unmotiviert erscheinenden Zusammenstellung unterschiedlicher Strophengruppen und der thematisch orientierten Verbindung älterer Einzelstrophen gibt es das aus einem übernommenen Motivkomplex entwickelte Meisterlied, dessen zeitliche Schichtung in der gelungenen produktiven Anverwandlung kaum mehr erkennbar ist.
Wachingers Ergebnisse zu den ‚Sängerkriegen’ des 13. Jh.s warnen davor, den künstlerisch-literarischen Wettstreit als Erscheinungsform materieller Rivalität zu deuten. Auch die Reimar- und Walthertexte geben in diesem Punkt keine unmittelbare Rechtfertigung für eine solche Interpretation. Ob Reimar überhaupt einen ökonomischen Wettbewerb zu fürchten hatte, bleibt dahingestellt (...). Aus seiner Position des adligen Dilettanten heraus wehrte er sich dann gegen die Erweiterung des dichtungs- und minnetheoretischen Geltungsanspruchs des höfischen Liebesliedes, wie Walther sie in deinen ‚Mädchenliedern’ und (...) im ‚Lindenlied’ betreibt. Dem Berufsdichter, der seine Kenntnisse der mittellateinischen Lyrik (...) systematisch zur Expansion der vorgegebenen sängerischen Möglichkeiten nutzt, setzt Reinmar die Tradition des adligen Sanges als ausdrücklich fiktionales Sprechen über Eros und Sexus entgegen.
Die deutschsprachigen Predigttexte sind schon von ihren ältesten Zeugnissen her nicht auf eine Funktion festlegbar: das Predigtmuster, die Anleitung zum Kanzelvortrag ist wohl die älteste. (...) Die angestrebte Unterscheidung von Predigt und Traktat scheint (...) [Volker Mertens] von der intentionalen virtuellen Mündlichkeit her am ehesten faßbar, sei sie post- oder anteskriptiv: als Predigten sollen daher Texte gelten, die textinterne oder –externe Markierungen dieser Mündlichkeit aufweisen. Zu unterscheiden von dieser intentionalen Mündlichkeit ist die occasionelle, die für viele Texttypen gilt: vom Traktat über Legende, Exempel, Fabel, usw.
Drei Tagweisen schreibt die Kolmarer Liederhandschrift einem sonst nicht weiter bekannten ‚Graff peter von arberg’ zu, darunter befindet sich die bekannte ‚Große Tagweise’ mit dem Text ‚Ach starcker got’. (...) Originale Texte von Peter von Aarberg kennen wir nicht (...). Wahrscheinlich standen seine Lieder auch ganz in den traditionellen literarischen und gesellschaftlichen Formen, so daß nur seine Töne lebendig blieben: mit neuen Texten, die in ihrer religiösen Thematik eher als die an ein bestimmtes soziales Ideal gebundene Minnelyrik das trafen, was auch nach der Mitte des 14. Jh.s bis weit in das 15. Jh. hinein zeitgemäß war.
Parzivals doppelte Probe
(1979)
Als Parzival zum erstenmal nach Munsalvaesche kommt, verlangt er, wie Gurnemanz ihm geraten hatte, gleich nach Wasser, um 'îsers râme' abzuwaschen. Er erhält den Mantel der Repanse de Schoye geliehen, und der kameraere ist sicher, ihn 'rehte geprüevet' zu haben (...) Da tritt ein 'redespaeher man' zu ihm und bittet ihn 'vrävellîche', zum Gastgeber zu kommen. Parzival reagiert mit äußerster Erregung, fast geht es dem kühnen Frager ans Leben, aber die Ritter greifen rechtzeitig ein. (...) [Volker Mertens möchte die Stelle] parallel zur versäumten Gralsfrage sehen und daher den Versuch Wolframs herauslesen, einer möglichen Fehlinterpretation von Parzivals Versagen vorzubeugen. (...)
Vergänglichkeitsmetapher oder Bild für den Aussatz – um diese Interpretationen der Stelle E 73 (bzw. B 143) "ze hewe wart sîn grüenez gras" im neuaufgefundenen Benediktbeurer Fragment des "Armen Heinrich" ist ein Streit zwischen L. Wolff und Gesa Bonath einerseits und H. Rosenfeld andererseits entbrannt (....). Die strittigen Verse im "Armen Heinrich" aber sind in ihrer, das "ûzen" (Vergehen der Schönheit) ebenso wie das innen (Krankheit als Prüfung) erfassen Mehrschichtigkeit doch eher das Werk eines theologische Anregungen verwertenden Dichter, und damit (...) [nimmt Volker Mertens an], Hartmann selbst.
In seinen Ausgaben der Altdeutschen Predigten (...) hatte A.E. Schönbach mehrmals (...) einen Untersuchungsband angekündigt; obwohl er bei Edition des 3. Bandes als für die vorliegenden Texte fertig bezeichnet wird, ist er nie erschienen.(...) Die folgenden Studien (...) wollen aus dem umfangreichen Programm Schönbachs (...) zur Hauptsache nur Fragen der Überlieferung behandeln und eine weitergehende Aufschlüsselung der Vorgeschichte der Leipziger Sammlung bieten, als sie A. Linsenmayer in seiner ‚Geschichte der Predigt in Deutschland’ (...) gegeben hat.
Im Stil stellt sich die Predigt in die Nachbarschaft der Predigtsammlungen des 12. Jahrhunderts. Der ausgesprochen hypokratische Satzbau findet seine Entsprechung in den längeren Stücken des deutschen Speculum ecclesiae, in denen der Bearbeiter wie in dieser Predigt sich nicht allzu weit vom lateinischen Text entfernte, und in Schönbach III, dem Predigtbuch des Priesers Konrad, der ebenfalls die hypotaktisch gegliederte Periode vorzieht. (...) Im Vergleich zum Priester Konrad wird diese Figur sehr zurückhaltend verwendet, wie überhaupt dieser Text im Vergleich zu der Weitschweifigkeit und Redseligkeit jenes Predigtbuches die lateinische Vorlage nur geringfügig erweitert und rhetorisch verbreitert.