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Background: Obesity is a global problem leading to reduced life expectancy, cardiovascular diseases, diabetes and many types of cancer. Even people willing to accept treatment only achieve a mean weight loss of about 5 kg using commercial weight loss programs. Surgical interventions, e.g. sleeve gastrectomy or gastric bypass are effective but accompanied by risk of serious complications and side effects. Less invasive endoscopic procedures mainly comprise the intragastric balloon (IB) and the duodenal-jejunal bypass liner (DJBL). To date, a randomized comparison between these devices has not been undertaken or shown to be superior to a sham procedure.
Methods: We designed a multi-center, randomized, patient and assessor-blinded, controlled trial comparing weight loss in endoscopically implanted IB vs. DJBL vs. a sham procedure. A total of 150 patients with a BMI > 35 kg/m2 or > 30 with obesity-related comorbidities and indication for proton pump inhibitors are randomized to receive either IB, DJBL or a sham gastroscopy (2:2:1 ratio). All participants undergo regular dietary consultation. The IB will be removed after 6 months, whereas the DJBL will be explanted after 12 months. All patients will receive gastroscopies at implantation and explantation of the devices or sedation without gastroscopy to maintain blinding. Main exclusion criteria are malignant diseases, peptic ulcer or previous bariatric intervention. Weight loss 12 months after explantation of the devices, changes in comorbidities, quality of life, complication rates and safety will be evaluated.
Discussion: This trial could help to identify the most effective and safest endoscopic device, thus determining the new standard procedure for endoscopic bariatric treatment.
Trial registration: 16th January 2017. DRKS00011036. Funded by the German Research Foundation (DFG).
Different response of Ptch mutant and Ptch wildtype Rhabdomyosarcoma toward SMO and PI3K inhibitors
(2018)
Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma with poor prognosis. RMS frequently show Hedgehog (HH) pathway activity, which is predominantly seen in the embryonal subtype (ERMS). They also show activation of Phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) signaling. Here we compared the therapeutic effectiveness and the impact on HH target gene expression of Smoothened (SMO) antagonists with those of the PI3K inhibitor pictilisib in ERMS with and without mutations in the HH receptor Patched1 (PTCH). Our data demonstrate that growth of ERMS showing canonical Hh signaling activity due to Ptch germline mutations is efficiently reduced by SMO antagonists. This goes along with strong downregulation of the Hh target Gli1. Likewise Ptch mutant tumors are highly responsive toward the PI3K inhibitor pictilisib, which involves modulation of AKT and caspase activity. Pictilisib also modulates Hh target gene expression, which, however, is rather not correlated with its antitumoral effects. In contrast, sporadic ERMS, which usually express HH target genes without having PTCH mutation, apparently lack canonical HH signaling activity. Thus, stimulation by Sonic HE (SHH) or SAG (Smoothened agonist) or inhibition by SMO antagonists do not modulate HH target gene expression. In addition, SMO antagonists do not provoke efficient anticancer effects and rather exert off-target effects. In contrast, pictilisib and other PI3K/AKT/mTOR inhibitors potently inhibit cellular growth. They also efficiently inhibit HH target gene expression. However, of whether this is correlated with their antitumoral effects it is not clear. Together, these data suggest that PI3K inhibitors are a good and reliable therapeutic option for all ERMS, whereas SMO inhibitors might only be beneficial for ERMS driven by PTCH mutations.
The opportunistic pathogen Acinetobacter baumannii is able to grow on carnitine. The genes encoding the pathway for carnitine degradation to the intermediate malic acid are known but the transporter mediating carnitine uptake remained to be identified. The open reading frame HMPREF0010_01347 (aci01347) of Acinetobacter baumannii is annotated as a gene encoding a potential transporter of the betaine/choline/carnitine transporter (BCCT) family. To study the physiological function of Aci01347, the gene was deleted from A. baumannii ATCC 19606. The mutant was no longer able to grow on carnitine as sole carbon and energy source demonstrating the importance of this transporter for carnitine metabolism. Aci01347 was produced in Escherichia coli MKH13, a strain devoid of any compatible solute transporter, and the recombinant E. coli MKH13 strain was found to take up carnitine in an energy‐dependent fashion. Aci01347 also transported choline, a compound known to be accumulated under osmotic stress. Choline transport was osmolarity‐independent which is consistent with the absence of an extended C‐terminus found in osmo‐activated BCCT. We propose that the Aci01347 is the carnitine transporter mediating the first step in the growth of A. baumannii on carnitine.
Danger signals in trauma
(2018)
This review summarizes a short list of currently discussed trauma-induced danger-associated molecular patterns (DAMP). Due to the bivalent character and often pleiotropic effects of a DAMP, it is difficult to describe its “friend or foe” role in post-traumatic inflammation and regeneration, both systemically as well locally in tissues. DAMP can be used as biomarkers to indicate or monitor disease or injury severity, but also may serve as clinically applicable parameters for better indication and timing of surgery. Due to the inflammatory processes at the local tissue level or the systemic level, the precise role of DAMP is not always clear to define. While in vitro and experimental studies allow for the detection of these biomarkers at the different levels of an organism—cellular, tissue, circulation—this is not always easily transferable to the human setting. Increased knowledge exploring the dual role of DAMP after trauma, and concentrating on their nuclear functions, transcriptional targets, release mechanisms, cellular sources, multiple functions, their interactions and potential therapeutic targeting is warranted.
Oncogenic rearrangements leading to targetable gene fusions are well-established cancer driver events in lung adenocarcinoma. Accurate and reliable detection of these gene fusions is crucial to select the appropriate targeted therapy for each patient. We compared the targeted next-generation-sequencing Oncomine Focus Assay (OFA; Thermo Fisher Scientific) with conventional ALK FISH and anti-Alk immunohistochemistry in a cohort of 52 lung adenocarcinomas (10 ALK rearranged, 18 non-ALK rearranged, and 24 untested cases). We found a sensitivity and specificity of 100% for detection of ALK rearrangements using the OFA panel. In addition, targeted next generation sequencing allowed us to analyze a set of 23 driver genes in a single assay. Besides EML4-ALK (11/52 cases), we detected EZR-ROS1 (1/52 cases), KIF5B-RET (1/52 cases) and MET-MET (4/52 cases) fusions. All EML4-ALK, EZR-ROS1 and KIF5B-RET fusions were confirmed by multiplexed targeted next generation sequencing assay (Oncomine Solid Tumor Fusion Transcript Kit, Thermo Fisher Scientific). All cases with EML4-ALK rearrangement were confirmed by Alk immunohistochemistry and all but one by ALK FISH. In our experience, targeted next-generation sequencing is a reliable and timesaving tool for multiplexed detection of targetable rearrangements. Therefore, targeted next-generation sequencing represents an efficient alternative to time-consuming single target assays currently used in molecular pathology.
The p300/CBP‐associated factor (PCAF) and related GCN5 bromodomain‐containing lysine acetyl transferases are members of subfamily I of the bromodomain phylogenetic tree. Iterative cycles of rational inhibitor design and biophysical characterization led to the discovery of the triazolopthalazine‐based L‐45 (dubbed L‐Moses) as the first potent, selective, and cell‐active PCAF bromodomain (Brd) inhibitor. Synthesis from readily available (1R,2S)‐(−)‐norephedrine furnished L‐45 in enantiopure form. L‐45 was shown to disrupt PCAF‐Brd histone H3.3 interaction in cells using a nanoBRET assay, and a co‐crystal structure of L‐45 with the homologous Brd PfGCN5 from Plasmodium falciparum rationalizes the high selectivity for PCAF and GCN5 bromodomains. Compound L‐45 shows no observable cytotoxicity in peripheral blood mononuclear cells (PBMC), good cell‐permeability, and metabolic stability in human and mouse liver microsomes, supporting its potential for in vivo use.
Objective. Traumatic injury or severe surgery leads to a profound immune response with a diminished functionality of monocytes and subsequently their IL-1β release. IL-1β plays an important role in host immunity and protection against infections. Its biological activation via IL-1β-precursor processing requires the transcription of inflammasome components and their activation. Deregulated activity of NOD-like receptor inflammasomes (NLR) like NLRP3 that leads to the maturation of IL-1β has been described in various diseases. While the role of other inflammasomes has been studied in monocytes, nothing is known about NLRP3 inflammasome after a traumatic injury. Here, the role of the NLRP3 inflammasome in impaired monocyte functionality after a traumatic injury was analyzed.
Measurements and Main Results. Ex vivo-in vitro stimulation of isolated CD14+ monocytes with lipopolysaccharide (LPS) showed a significantly higher IL-1β secretion in healthy volunteers (HV) compared to trauma patients (TP) after admission. Reduced IL-1β secretion was paralleled by significantly lowered gene expression of NLRP3 in monocytes from TP compared to those of HV. Transfection of monocytes with NLRP3-encoding plasmid recovered the functionality of monocytes from TP regarding the IL-1β secretion.
Conclusions. This study demonstrates that CD14+ monocytes from TP are significantly diminished in their function and that the presence of NLRP3 components is necessary in recovering the ability of monocytes to produce active IL-1β. This recovery of the NLRP3 inflammasome in monocytes may imply a new target for treatment and therapy of immune suppression after severe injury.
Species identification of adult African blowflies (Diptera: Calliphoridae) of forensic importance
(2017)
Necrophagous blowflies can provide an excellent source of evidence for forensic entomologists and are also relevant to problems in public health, medicine, and animal health. However, access to useful information about these blowflies is constrained by the need to correctly identify the flies, and the poor availability of reliable, accessible identification tools is a serious obstacle to the development of forensic entomology in the majority of African countries. In response to this need, a high-quality key to the adults of all species of forensically relevant blowflies of Africa has been prepared, drawing on high-quality entomological materials and modern focus-stacking photomicroscopy. This new key can be easily applied by investigators inexperienced in the taxonomy of blowflies and is made available through a highly accessible online platform. Problematic diagnostic characters used in previous keys are discussed.
2010 yılında Polonya'nın Varşova kentinde "Vielheit und Einheit der Germanistik" teması ile gerçekleştirilen 12. Uluslararası Germanistik Kongresi’nin ardından 13. Uluslararası Germanistik Kongresi 2015 yılında "Germanistik zwischen Tradition und Innovation" teması ile Çin Halk Cumhuriyeti Şanghay Tongji Üniversitesi'nde 23-30 Ağustos 2015 tarihlerinde düzenlendi. Türkiye'nin de aralarında bulunduğu 96 ülkeden kongreye katılan 1200'ün üzerinde değerli akademisyen ve araştırmacı kongrede bildirilerini sundular.
Der 13. Weltkongress der Internationalen Vereinigung für Germanistik (IVG) fand vom 23.08.2015 bis zum 30.08.2015 unter dem Motto "Germanistik zwischen Tradition und Innovation" in Shanghai/China statt. Gastgeber dieses vielfältigen und reichhaltigen internationalen Kongresses war die Tongji-Universität. Mehr als 1200 Teilnehmerinnen und Teilnehmer aus 69 Ländern haben an diesem Kongress, der alle fünf Jahre organisiert wird, teilgenommen. Auch die Türkei beteiligte sich mit ca. 30 Wissenschaftlerinnen und Wissenschaftlern aus Edirne bis Van an diesem Kongress.
Das wissenschaftliche Interesse auf dem Feld der Germanistik ist in den letzten Jahren in Rumänien, auch dank Herta Müller, die 2009 den Nobelpreis für Literatur bekommen hat, stark gestiegen. Nach dem letzten Kongress der Germanisten Rumäniens 2012 in Bukarest wurde der 10. Kongress der Germanisten Rumäniens vom 01. bis 04. Juni 2015 in der Aula an der Universität Transilvania in Braşov/Kronstadt veranstaltet. Die Tagung wird alle drei Jahre an jeweils wechselnden Hochschulen vom dortigen Germanistik-Fachbereich veranstaltet, was zeigt, dass die Germanistik in Rumänien an vielen Orten durch zum Teil kleine, aber aktive Lehrstühle vertreten ist.
Considering the misunderstanding of the particles used as an adverb by itself in closely related languages, we will try to provide the comprehension of sense of language about this area, which is missing in German. For this purpose, opposite language pairs seeming logical and etimological proofs about language variation will be presented. Firstly, we will try to explain what the sense of language is. We believe that it is more appropriate to say 'language acquisition' which can be acquired and developed by means of activities in foreign language classes. Examples verify this. In the conclusion, some other clarifying questions follow.
Sowohl international als auch national ist erkennbar, dass Länder in Bereichen Wirtschaft, kommunikative und informative Technologien, Politik, Bildung und Gesellschaft in unterschiedlicher Art und Weise mit kulturellen bzw. interkulturellen Tendenzen konfrontiert sind. Diese Tatsachen reflektieren somit, dass Gesellschaften immer mehr mit interkulturellen Herausforderungen in Kontakt kommen. Interkulturelles Lernen, Interkulturalität und interkulturelle Kompetenz enthalten gleichfalls im gegenwärtigen und modernen Fremdsprachenunterricht eine bedeutende Rolle und ein wichtiges Aufgabenfeld.
Present conditions are affecting the educational process and as a result of these changes restructuring these processes is essential. There is no doubt that in teaching foreign languages in general and in particular German as a foreign language, one of the prerequisites to gain for providing a qualified German language teaching is the training of qualified and well equipped German teachers. In this context one of the substantial competences in the training process is the linguistic competence. It is aimed that at the end of their study period, German language teacher candidates should have the ability of using the German language in written and spoken area and creating models for their prospective students.
Despite the new technological developments writing has not lost its importance; on the contrary, ist importance has been increasing day by day. German teacher candidates should be trained to be able to express themself written as well as verbally to respond to their students' writing needs. For this reason students who graduated from the German Language Teaching Department of Hasan Ali Yücel Faculty of Education of Istanbul University in 2013-2014 academic year were asked to evaluate their writing competence.
The self assessments results of the candidate teachers are going to be compared with the results of the writing competence part of the Goethe Zertifikat C1 examination. The aim is to determine proficiency in the duration of 4 years. The results also constitute the scientific basis of curricular discussions in the field of writing courses of the German Language Teaching Department.
In den letzten Jahren ist eine kaum überschaubare Anzahl von Büchern zum Thema Körpermodifikationen erschienen, was aber bisher fehlt, ist ein klares Verständnis und eine kurze überblicksartige Dаrstellung der gängigen Formen der Fachausdrücke im Bereich der ästhetischen Chirurgie, die dem linguistisch-medizinisch Interessierten einen prägnanten Einblick in die Herkunft, die Wоrtbildung und die Häufigkeit und vergleichende Analyse der medizinischen Termini liefert. Deshalb soll in diesem Artikel versucht werden, einen kleinen Beitrag zur Bildung und Entwicklung ästhetisch-medizinischer Terminologie zu leisten. Bei dem vorliegenden Artikel handelt es sich um eine deskriptive Terminоlоgiearbeit, deren Ziel es ist, die verwendete Terminologie eines Fachgebietes zu beschreiben und aufzuzeichnen
This article focuses primarily on three areas: First the article deals with Alfred Döblin's concept of the novel and the function of the montage technique from his perspective. Secondly, the article draws attention to the fact that Alfred Döblin, a neurologist by profession, who later dedicated himself exclusively to his writing, used the montage technique intensively in his great city novel Berlin Alexanderplatz. The technique, which operates at different levels of language, narrative technique and plot, is demonstrated by selected examples from the novel. In each case the intention of the novelist is discussed. The article considers whether individual accumulating elements accord with the wholeness of the novel, and if so, how this interesting synthesis occurs. The final focus is on his efforts to use the montage technique to portray the big city. In the case of Berlin Alexanderplatz, this effort ultimately ends with a big city epic. In this study, we consider how Döblin used the montage technique in Berlin Alexanderplatz, which was central, and new for German literature at that time. Additionally, narrative styles and techniques as parables, paraboles, sound associations, word and rhyme repetition and relevant passages are supported by quotations from the novel.
Else LaskerSchüler (1869-1945), among the significant expressionist woman writers, did not only suffer from being both a woman and author, but also had to struggle under difficulties of being a hebrew. In this paper, especially the letter novel titled "Der Malik : Eine Kaisergeschichte" has been handled in the light of Homi K. Bhabha's 'Third Space Theory'. In regard to this, the "Third Space", which is defined by postcolonial theoretician Homi K. Bhabha as an extra place where minorities and outcast groups can express themselves in his work "The Location of Culture", is adapted to the literary "Orient" and defined once again in Else Lasker-Schüler's novel as it was never approached and interpreted before. In this sense, this supports the relevance to analyze her mentioned works in terms of the "Third Space Theory". Else Lasker-Schüler constructed a new world for herself through literature; her works were her life and her life was her works.
Black Humor, Brimstone Grotesque and A Terrifying Scenery in the work of Thomas Bernhard named "The Painter". Thomas Bernhard (1931-1989) is one of the most important writers of the Austrian postwar literature. All of his works reflect the characteristics of that period. "Bernhardesque" literature (just as the "Kafkaesque") always shapes the language and brings it out forcing the maximum limits of the semantics and stylistics expression facilities of the language. Bernhard generally figures out the inner world of the modern people psychologically disturbed and represents their wholly technological, noncommunicative and hostile environment in his works, especially features ironic, absurd, and grotesque and a little bit comic elements. Thomas Bernhard, a worldwide famous writer, poet and playwright, wrote a prose novel entitled "Ereignisse" (Events) that includes thirty-one extraordinary stories in 1957. These are the stories can be read both independently from each other and also in coherence. This study is aimed to analyses one of these works, the twelfth one in the light of eclectical way, mostly involves 'black humor' which is named "Der Anstreicher" (The Painter). The term Black Humor is generally defined for the works characterized by a desperate, sardonic humor intended to induce laughter as the appropriate response to the apparent meaninglessness and absurdity of existence. This short story of Bernhard tells about an "Event" derived its theme from the daily life and can be thought as a simple work accident but it brings a death to his main character. Narrator narrates this fatal and ordinary event with a horrific, grotesque and agonizing absurdity and as we try to figure out in this study; The Painter includes 'Black Humor' in this context.
Biological invasions are frequently studied topics in ecological research. Unfortunately, within invasion ecology parasite-associated aspects such as parasite impacts on new environments and on local host populations are less well-studied. Round gobies migrating from the Ponto-Caspian region into the Rhine River system are heavily infested with the Ponto-Caspian acanthocephalan parasite Pomphorhynchus laevis. As shown by experimental infestations the acanthocephalans occur as pre-adults in host-encapsulated cysts within the internal organs of the migrating gobies, but remain infective for their definitive host chub. Recently, we described the occurrence of larvae of another parasite, the invasive eel swim bladder nematode Anguillicola crassus, in these Pomphorhynchus cysts. In the present study, we could prove the infectivity of the nematode larvae for European eels for the first time. After experimental inoculation of Pomphorhynchus cysts occasionally infested with A. crassus larvae, the nematodes grow to maturity and reproduce whereas all P. laevis were unviable. We therefore postulate that the nematode larvae behave like immunological hitchhikers that follow a “Trojan horse strategy” in order to avoid the paratenic host’s immune response. Accordingly, the interaction between both invasive parasites gives first evidence that the invasional meltdown hypothesis may also apply to parasites.
New technologies and therapies designed to facilitate development of personalized treatments are rapidly emerging in the field of biomedicine. Strikingly, the goal of personalized medicine refined the concept of therapy by developing cell-based therapies, the so-called “living drugs”. Breakthrough advancements were achieved in this regard in the fields of gene therapy, cell therapy, tissue-engineered products and advanced therapeutic techniques. The Advanced Therapies in Healthcare symposium, organized by the Clinical Research Center Department of Sidra Medicine, in Doha, Qatar (October 2017), brought together world-renowned experts from the fields of oncology, hematology, immunology, inflammation, autoimmune disorders, and stem cells to offer a comprehensive picture of the status of worldwide advanced therapies in both pre-clinical and clinical development, providing insights to the research phase, clinical data and regulatory aspects of these therapies. Highlights of the meeting are provided in this meeting report.