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Precise tune determination and split beam emittance reconstruction at the CERN PS synchrotron
(2023)
In accelerator physics, the need to improve the performance and better control the operating point of an accelerator has become, year after year, an increasingly important need in order to achieve higher energies and brightness, as well as point-like particle beams. If this involves increasingly advanced technological developments (in terms, for example, of materials for more intense superconducting magnets), it can not take place in the absence of targeted studies of linear and non-linear beam dynamics. In the context of this Ph.D. thesis in physics, linear and non-linear dynamics of charged particles in circular accelerators is the topic that will be discussed and treated in detail. In particular, the presentation and discussion of the results will be divided in two main topics: the need to know the physical properties of a proton beam; and the development of innovative methods to determine and study the accelerator’s working point. With regard to the first topic, an innovative procedure will be presented to determine the transverse size of the PS beam in the beam extraction phase. Among the different ways the extraction occurs at the PS, the analysed one is based on the transverse splitting of the beam by means of non-linear fields. Thus, the knowledge of the transverse beam size is not trivial since resonant linear and non-linear beam structures (namely, core and islands) arise and, for each of them, the beam size has to be quantified. This parameter is crucial for two main reasons: the accelerator that will receive the beam exiting the upstream accelerator may have restrictions (physical or magnetic) that involve a partial or total loss of the incoming beam; and any experiments located downstream of the considered accelerator may need a beam with a transversal size as constant as possible; consequently, its monitoring and control are essential. The second topic concerns the accurate determination of the working point of an accelerator, defined as the number of transverse oscillations the particle beam travels per unit of accelerator circumference, both horizontally and vertically. This quantity is called horizontal and vertical tune, respectively. Their knowledge is also crucial to understand whether the beam will be stable or unstable. In fact, not all tune values are acceptable, as there are particular values that bring the beam into resonance. In this configuration, the amplitude of the transverse oscillations of the particles increases in an uncontrolled manner and leads to the loss of all or part of the beam. Note that, in particular operating conditions, the resonant conditions are sought and desired to model, in a suitable way, the transversal shape of the beam, such as the above mentioned PS extraction scheme. It is even clearer how much the determination of the machine working point is essential to determine the operating conditions of an accelerator. In this context, several methods (also taken from the field of applied mathematics) to calculate the tune will be demonstrated and tested numerically on different types of synthetic signals. At the end of this description, the use of experimental data will allow to obtain the benchmark of a new method for the direct calculation of some characteristic quantities of non-linear beam dynamics (namely, the amplitude detuning, i.e. the variation of tune as a function of intensity of the perturbation provided to the beam.
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.
Cancer cells, including leukemic cells, can react to therapeutic treatment by altering their metabolic phenotype (“metabolic reprogramming”) to keep their accelerated proliferative state, eventually becoming resistant to the treatment. There is an increasing amount of evidence indicating that metabolic reprogramming is one of the key mechanisms of acquisition of drug resistance by cancer cells. In agreement, several metabolic studies targeting leukaemia and specifically acute myeloid leukaemia (AML) and chronic myeloid leukaemia (CML), have been conducted over the last decades. However, there is still a lack of understanding the metabolic features of both AML and CML leukaemia specially in the acquisition of drug resistance, that is needed for unveiling novel and effective treatments for resistant and non-resistant patients. Therefore, the main objective of this thesis was to investigate the rewiring of cell metabolism occurring in the process of acquisition of resistance to conventional therapeutic treatments in AML and CML malignancies. Next, by revealing this metabolic rewiring, we intended to highlight potential metabolic and non-metabolic targets that could be exploited to overcome resistance to treatments. To this end, we have performed a comprehensive and comparative multi-OMIC study to analyse the links between the metabolic reprogramming and the resistance acquisition of THP-1 and HL-60 AML cell models sensitive or resistant to cytarabine (AraC) and doxorubicin (Dox), and of KU812 CML cell model sensitive or resistant to imatinib, all under normoxic (21% O2) and hypoxic (1% O2) conditions. The results of this thesis are divided into two chapters. On the one hand, in Chapter 1, the multi-OMIC study performed in AML parental and resistant cells unveiled that the acquisition of AraC resistance causes the reprogramming of the glucose metabolism of THP-1 and HL-60 cells by increasing the glycolytic flux whereas it is not associated with an alteration in the mitochondrial respiration. Moreover, our results also exhibited a possible disfunction of ETC complex I as well as alterations in glutamine and serine-glycine-1C metabolism in AML cells that display a more active mitochondrial metabolism. Moreover, we have also identified that the acquisition of Dox resistance causes alterations in the glucose and amino acid metabolism. Importantly, we have observed an important loss of mitochondrial respiration capacity of AML cells resistant to Dox chemotherapeutic drug, which constitutes a potential metabolic vulnerability that can be exploited for the treatment of AML patients resistant to Dox. On the other hand, in Chapter 2 is shown that the acquisition of imatinib resistance causes the reprogramming of glucose metabolism by enhancing the glycolytic flux, PPP, and glycogen metabolism, thus highlighting these metabolic pathways as potential metabolic weaknesses of KU812 cells resistant to imatinib. Moreover, we have observed a high metabolic plasticity of KU812 cells resistant to imatinib which includes the orchestration of many metabolic routes associated with the amino acid metabolism. Importantly, the CML multi-OMIC study has also unveiled an enhanced mitochondrial respiration capacity, which constitutes another potential vulnerability that can be exploited to overcome imatinib resistance. Finally, both AML and CML multi-OMIC studies have allowed us to propose and/or validate different metabolic and non-metabolic targets. In this regard, in this thesis we have identified and validated a battery of single-hit inhibitions that were able to reduce the cell viability of both parental and resistant AML and CML cells. Finally, we have confirmed that the repurposing of Dox chemotherapeutic drug counteracts the imatinib resistance in the KU812 cells resistant to imatinib.
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.
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 1983, Brian Henderson published an article that examined various types of narrative structure in film, including flashbacks and flashforwards. After analyzing a whole spectrum of techniques capable of effecting a transition between past and present – blurs, fades, dissolves, and so on – he concluded: "Our discussions indicate that cinema has not (yet) developed the complexity of tense structures found in literary works". His "yet" (in parentheses) was an instance of laudable caution, as very soon – in some ten–fifteen years – the situation would change drastically, and temporal twists would become a trademark of a new genre that has not (yet) acquired a standardized name: "modular narratives", "puzzle films", and "complex films" are among the labels used.
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.
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.
The early acquisition of Greek compounds by two monolingual Greek girls aged between 1;8 and 3;0 years is studied in a usage-based theoretical framework. Special importance is attached to the morphological structure of Greek compound types occurring in child speech and child-directed speech. Greek nominal compound formation does not consist in the mere juxtaposition of words or roots, but involves stems as well as a compound marker. Major questions addressed are the transparency of compounds and productive nominal compound formation. Evidence for productivity of nominal compound formation has been found with only one of the two girls. In contrast to other languages, neoclassical nominal compounds by far exceed endocentric subordinative ones tokenwise in Greek child speech and child-directed speech providing evidence of entrenchment rather than productivity.
In a cross-linguistic comparison it is shown that, in spite of the fact that both Standard Modern Greek and German are rich in nominal compounds, their number is much more limited in Greek than in German child speech. An explanation for this apparent paradox is provided by an onomasiological approach to lexical typology based on a sample list of nominal compounds occurring in German child language and their Greek translational equivalents. It has been found that while use of nominal compounds is common in colloquial German including child-centered situations, it is more typical of Greek formal than colloquial registers.
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.
This study of the conditions, character and consequences of the conversion of dollar currency into Palestine Pounds, with special reference to the utilisation of these dollars for purchase of American capital goods and raw materials, is addressed particularly to our friends in the United States. ...
Fair play for the Jews
(1939)
The bringing together of the two realms, that of Tristan and Isolde and that of Arthur, thus has a mutually corrosive effect. However, in the further course of the action Tristan and Isolde’s love regains some of its absoluteness: for instance Heinrich refrains from taking over the quarrel of lovers from Eilhart. He plays a double game, on the one hand reducing the absoluteness and self-sufficiency of love, on the other hand building it up again and thus preventing the establishment of a firm doctrine in the course of the narrative (…), as neither the Arthurian court nor the love of Tristan and Isolde provides an absolute norm. Heinrich wrote his romance for the Bohemian noble Raimund von Lichtenburg, and the account of the foundation of the Round Table and the self-directed activities of the knights have belonged (…). The initial Arthurian ideal has become a confirmatory ritual for an exclusive body of noblemen – that matches the spirit of the knightly societies.
Four new species of the genus Sokoloviana (Pterolichoidea; Ptiloxenidae) from waders suborder Charadrii (Charadriiformes) are described: Sokoloviana cornuta sp. nov. from the Banded Stilt, Cladorhynchus leucocephalus; Sokoloviana ibidorhynchae sp. nov. from the Ibis-bill, Ibidorhyncha strutersi; Sokoloviana chilensis sp. nov. from the Southern Lapwing, Vanellus chilensis and Sokoloviana vanelli sp. nov. from the Red-wattled Lapwing, Vanellus indicus atronuchalis. A key to all described species is given.
Based on his studies of the genus Rubus in the Czech Republic, the author describes classification of brambles from Rubus subgen. Rubus in Europe, its recent history, present state, and current problems. In general, the author follows the adherents of "Weberian batology" which in the last 25 years has assumed European responsibility for attempting to ciassify that particular genus. The thesis that not every bramble plant can be inciuded in the ciassification is accepted. The objective reasons for taxonomic difficulties within Rubus subgen. Rubus are connected with special features of taxogenesis of its members, especially with incomplete apomixis, frequent hybridization, splitting of the progeny into different morphotypes, resexualization, transitory existence of segregants, etc. The progress of the evolution of a new taxon in the given taxonomic group can be ranked: individual bush - local type - regional species - species with an extensive distribution area. When classifying a taxon, alongside sufficient morphological characteristics,
great emphasis should be put on the distribution area; its extent can render possible the taxon to be accepted into the classification scheme. On the basis of experience gained from the Czech Republic, the author has accepted some modifications of the scale for acceptance of plants as species. The basic difference is in lowering the low limit of the extent of the distribution area for regional species, to be acceptable for their lnclusion to the classification, i.e. to 20 km in diameter. In contrast to taxa of other plant groups, species of apomictic brambles with more extensive distribution areas are phytogeographically more important than those with small distribution areas. In spite of the use of stricter requirements for the description of new species in Rubus, it appears that many (distinct) species have been neglected until now, and that the number of species in Rubus subgen. Rubus is continuously increasing. The author stresses the necessity of studying the group ser. Glandulosi in Central Europe and points out the usefulness of cooperation with population ecologists to describe the quantitative representation of taxonomically unclassified bramble plants in the field.
Meadowbird populations in The Netherlands are under great pressure. Recently, predation is named increasingly
often as one of the key factors in contributing to the declines. A four-year research project (2001-2005) aimed to
collect (as yet mostly nonexisting) data to provide a factual basis for this discussion. A country-wide inventory based
on data for wader nests found by volunteers who mark nests for their protection from grazing/mowing indicated that
above-average predation losses are found predominantly in the half-open landscapes of northern and eastern Netherlands,
but also locally in the low-lying open grasslands which are the key areas for meadowbirds. Nest predation has increased in recent years, but the same is true for agricultural losses, at least in areas where no nest-protection takes
place. At a local scale, predation losses vary greatly from area to area and from year to year. Temperature loggers in nest showed that diurnal and nocturnal predators contribute equally in total predation losses up to 50%, but higher predation losses are mainly caused by nocturnal predators. As many as 10 animal species were identified as nest predators
on nests under surveillance with video cameras. Chick survival, investigated using radiotelemetry, was very low. About 60-80% were lost by predation, 5-15% by agricultural activities and 10-15% to all kind of other losses. At least 15
predator species were implied, with an apparently larger share taken by birds (notably Buzzard (16%) and Grey Heron
(7-18%)) than mammals, with one exception: stoat (16%). Of the most-discussed predator species, Carrion Crows were
W. Teunissen et al. Osnabrücker Naturwiss. Mitt. 32 2006
138 remarkably rarely involved in both nest and chick predation, while Red Foxes take a large toll of clutches in some areas, but not in others. Of all losses during the reproductive cycle about 75% and 60% was due to predation in Lapwing and Black-tailed Godwit respectively. Predation on chicks by birds had the largest effect on total breeding success, but at the same time elimination of this loss factor (if at all possible) alone would not be sufficient to establish a self-sustaining population. Predation seems to have become a factor of importance in some areas, in combination with already existing other losses. Our findings suggest that solutions to predation problems probably have to be found in locally/regionally targeted, specific action on multiple fronts rather than countrywide measures.
The diplopod orders Callipodida and Polydesmida, and their respective families Abacionidae and
Xystodesmidae, are initially recorded from South Dakota as is Polydesmidae from North Dakota. Other new records of
indigenous taxa include Abacion Rafinesque, 1820/A. texense (Loomis, 1937) and Pleuroloma/P. flavipes, both by
Rafinesque, 1820, from South Dakota, and Pseudopolydesmus Attems, 1898/P. serratus (Say, 1821) from Alabama,
Connecticut, Delaware, New Hampshire, North Dakota, South Carolina, and the District of Columbia. New records of
Aniulus garius Chamberlin, 1912, A. (Hakiulus) d. diversifrons (Wood, 1867), and Oriulus venustus (Wood, 1864)
(Julida: Parajulidae) are provided for western Minnesota and/or eastern North Dakota. Published records from these
states are summarized, and the introduced taxa, Julidae/Cylindroiulus Verhoeff, 1894/C. caeruleocinctus (Wood, 1864)
and Paradoxosomatidae/Oxidus Cook, 1911/O. gracilis (C. L. Koch, 1847), are newly recorded from the Dakotas. The
distribution of P. serratus, which extends from Maine to South Carolina and the Florida panhandle, west to Texas, and
north to Fargo, North Dakota is described and discussed. This distribution exhibits a prominent southeastern lacuna
which we hypothesize suggests replacement by younger, more successful species, as postulated for a similar distributional
gap in Scytonotus granulatus (Say, 1821).
Snoqualmia, new genus, is described for two species of polydesmid millipeds from the northwestern
United States: Snoqualmia snoqualmie, new species, from Washington State, and S. idaho, new species,
from Idaho. Males of S. idaho possess unusually complex gonopods, perhaps the most complex to be found in the Order
Polydesmida. Snoqualmia is placed in context with other polydesmid genera known from North America. The
polydesmid fauna of North America is discussed, as well as characters of the gonopods of the family.
Recent fieldwork on North Andros Island by the authors resulted in the collection of six species of Pterophoridae
(Lepidoptera), five of which were previously unrecorded for the Bahamas in published accounts. Three
additional species are noted for the Bahamian fauna based on specimens collected in the 1980s on other islands.
Representative specimens are illustrated from North Andros along with genitalic images for species where these
are not readily available in other publications. In addition, images of the larva and pupa are provided for a reared
species for which the life history was previously unknown.
With the discovery of Mitocybe auriportae Cook and Loomis, 1928 (Platydesmida: Andrognathidae) in Alameda County (Co.), east of San Francisco Bay, a potential overall distribution in coastal California is projected based on those of partly congruent diplopods. The area extends from northern Mendocino to central Monterey cos. and inland to central Lake, Yolo, and Santa Clara cos.
Currently, the genus Chimarra Stephens (Trichoptera: Philopotamidae) is represented in the Oriental Region by 259 species. Of these, 61 species have been described or recorded from Vietnam. In this paper, 9 new species from Vietnam are described and illustrated (Chimarra aculeata, C. carinata, C. corneola, C. insolita, C. mina, C. prominens, C. rostrata, C. undulata, and C. ungula). In addition, 3 new country records are noted (Chimarra areli Malicky and Mey, Chimarra pipake Malicky and Chantaramongkol, and Chimarra suthepensis Chantaramongkol and Malicky), and 1 new species group (minuta Group) is proposed and populated. An additional species group (georgensis “Group”), with 1 new species from Vietnam, but otherwise only known from Africa, is discussed, but not formally defined. A table listing all known Vietnamese species of Chimarra is included, along with discussion of variability in the anal veins of the forewing found within this genus, and its relevance for defining subgenera and species groups.
A taxonomic review of the ancora species group of Graphipterus Latreille (Coleoptera: Carabidae)
(2012)
The taxonomy of the ancora species group of Graphipterus Latreille (Coleoptera: Carabidae) is reviewed and seven species are recognized, all from southern Africa: Graphipterus ancora Dejean, Graphipterus cordiger Dejean, Graphipterus distinctus Péringuey (new status), Graphipterus fasciatus Chaudoir, Graphipterus fritschi Chaudoir, Graphipterus wahlbergi Boheman (new status), and Graphipterus westwoodi Brême (new status).
Diagnostic features are provided for each species and adult specimens of each species are illustrated.
Two new species of the genus Pahamunaya Schmid (Trichoptera: Polycentropodidae), P. talon sp. n. and P. spinifera sp. n., from Vietnam are described and illustrated. Examination of the holotype male of P. khoii Oláh and Johanson, in combination with an additional specimen of the same species, revealed new characters. New illustrations for this species are provided.
Two species of the genus Sisyra Burmeister (Neuroptera: Sisyridae), S. cameroonensis, n. sp., and S. gruwelli, n. sp., are described from the African Republic of Cameroon. Sisyra pallida Meinander is synonymized with Sisyra delicata Smithers, new synonymy, after comparison of the types of the former with topotypic paratypes of the latter. Type material of Sisyra nilotica Tjeder appears to be lost. Examples of Sisyra are recorded from Nigeria, Ethiopia and Uganda. A second species of the endemic African genus, Sisyborina, Monserrat, S. scitula, n. sp., is described from Cameroon, Guinea, and Zambia.