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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.
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 (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.
Testing for liver-related autoantibodies should be included in the workup of patients with hepatitis or cholestasis of unknown origin. Although most of these autoantibodies are not disease specific, their determination is a prerequisite to diagnose autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC), and they are components of the diagnostic scoring system in these diseases. In primary sclerosing cholangitis (PSC), on the other hand, autoantibodies are frequently present but play a minor role in establishing the diagnosis. In PSC, however, data on antibodies suggest a link between disease pathogenesis and the intestinal microbiota. This review will focus on practical aspects of antibody testing in the three major autoimmune liver diseases AIH, PBC, and PSC.
In AD 79 the town of Herculaneum was suddenly hit and overwhelmed by volcanic ash-avalanches that killed all its remaining residents, as also occurred in Pompeii and other settlements as far as 20 kilometers from Vesuvius. New investigations on the victims' skeletons unearthed from the ash deposit filling 12 waterfront chambers have now revealed widespread preservation of atypical red and black mineral residues encrusting the bones, which also impregnate the ash filling the intracranial cavity and the ash-bed encasing the skeletons. Here we show the unique detection of large amounts of iron and iron oxides from such residues, as revealed by inductively coupled plasma mass spectrometry and Raman microspectroscopy, thought to be the final products of heme iron upon thermal decomposition. The extraordinarily rare preservation of significant putative evidence of hemoprotein thermal degradation from the eruption victims strongly suggests the rapid vaporization of body fluids and soft tissues of people at death due to exposure to extreme heat.
Background: Bacterial meningitis is associated with high mortality and long-term neurological sequelae. Increasing the phagocytic activity of microglia could improve the resistance of the CNS against infections. We studied the influence of activin A, a member of the TGF-β family with known immunoregulatory and neuroprotective effects, on the functions of microglial cells in vitro.
Methods: Primary murine microglial cells were treated with activin A (0.13 ng/ml–13 μg/ml) alone or in combination with agonists of TLR2, 4, and 9. Phagocytosis of Escherichia coli K1 as well as release of TNF-α, IL-6, CXCL1, and NO was assessed.
Results: Activin A dose-dependently enhanced the phagocytosis of Escherichia coli K1 by microglial cells activated by agonists of TLR2, 4, and 9 without further increasing NO and proinflammatory cytokine release. Cell viability of microglial cells was not affected by activin A.
Conclusions: Priming of microglial cells with activin A could increase the elimination of bacteria in bacterial CNS infections. This preventive strategy could improve the resistance of the brain to infections, particularly in elderly and immunocompromised patients.
Lymphangioleiomyomatosis (LAM) is a rare disease that generally affects young women and involves the abnormal proliferation of smooth muscle-like cells (LAM cells) in the lungs (pulmonary LAM) and extrapulmonary sites (extrapulmonary LAM). This disease is rare in males. It is hard to distinguish between lung cancer and pulmonary LAM, especially during early stages. Herein, we present a case of a 66-year-old man with a small nodule in the right upper lobe that was first diagnosed as a lung malignancy using a chest CT scan. After a wedge dissection, a pathologist performed a histologic and immunohistochemical examination, and a diagnosis of pulmonary LAM was made. We further performed a 518-gene panel analysis using next-generation sequencing, and only three genes, BARD1, BLM, and BRCA2, were found to have mutations. We also provide a summary of the diagnosis and treatment of this disease.
Die Bewertung der Nitrataustragsgefährdung (NAG) landwirtschaftlich genutzter Flächen in Wasserschutzgebieten (WSG) erfolgte bislang auf Basis bodenkundlicher Kartierungen und wurde seit 1996 nach einem im Staatsanzeiger für das Land Hessen veröffentlichten Merkblatt des ehemaligen Hessischen Landesamtes für Bodenforschung im Rahmen der Muster-Wasserschutzgebietsverordnung geregelt (HLfB 1996, HMUJFG 1996). Infolge der Verfügbarkeit hochauflösender Bodendaten in Form der „Bodenflächendaten 1: 5.000, landwirtschaftliche Nutzfläche“ (BFD5L) wird die Ermittlung der Nitrataustragsgefährdung landwirtschaftlich genutzter Flächen neu geregelt. Die BFD5L liefert Auswertungen der Bodenschätzungsdaten zur Feldkapazität des Wurzelraums sowie weiterer relevanter Parameter, die zur Bewertung der Nitrataustragsgefährdung herangezogen werden können.
Um die Eignung der BFD5L-Daten zur Ermittlung der Nitrataustragsgefährdung zu überprüfen, wurden in den Jahren 2009 bis 2012 bodenkundliche Vergleichskartierungen im Rahmen eines Pilotvorhabens im Wasserschutzgebiet Eschollbrücken/Pfungstadt in Südhessen, im Wassereinzugsgebiet der Quelle Meineringhausen bei Korbach, im Wasserschutzgebiet des Tiefbrunnens Spieß der Gemeinde Bad Emstal sowie im WSG Quelle Ohmes der Stadt Kirtorf durchgeführt. Ziel war es, die Umsetzungsmöglichkeiten bei der Nutzung der BFD5LDaten in organisatorischer und technischer Hinsicht zu erproben und das bisherige Verfahren zu überarbeiten (PETER & MILLER 2009, PETER & MILLER 2010a und 2010b, PETER & MILLER 2012).
Die Ergebnisse der Vergleichskartierungen zeigen, dass sich die Daten der BFD5L grundsätzlich für die Ermittlung der Nitrataustragsgefährdung in Wasserschutzgebieten eignen. Lediglich für Flächen, für die nach den bislang im System BFD5L enthaltenen Methoden keine Kennwerte abgeleitet werden können sowie für Sonderstandorte, muss die Nitrataustragsgefährdung durch bodenkundliche Geländearbeiten ermittelt werden.
Ḥoveret taḳtsirim : kenes ha-Ḥevrah ha-Geologit 2018 : Yiśraʿel-Ḳafrisin 25.03.2018 - 29.03.2018
(2018)
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.
"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. ...
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.
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.
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.