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Berlin Brandenburg

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  • 1
    Language: English
    In: Genetics, May 2018, Vol.209(1), pp.173-193
    Description: Covalent attachment of ubiquitin to substrate proteins changes their function or marks them for proteolysis, and the specificity of ubiquitin attachment is mediated by the numerous E3 ligases encoded by animals. Mind Bomb is an essential E3 ligase during Notch pathway signaling in insects and vertebrates. While encodes a Mind Bomb homolog (), it has never been recovered in the extensive Notch suppressor/enhancer screens that have identified numerous pathway components. Here, we show that null mutants have a spermatogenesis-defective phenotype that results in a heterogeneous mixture of arrested spermatocytes, defective spermatids, and motility-impaired spermatozoa. mutants also have chromosome segregation defects during meiosis, molecular null mutants are intrinsically temperature-sensitive, and many spermatids contain large amounts of tubulin. These phenotypic features are similar to the endogenous RNA intereference (RNAi) mutants, but mutants do not affect RNAi. MIB-1 protein is expressed throughout the germ line with peak expression in spermatocytes followed by segregation into the residual body during spermatid formation. expression, while upregulated during spermatogenesis, also occurs somatically, including in vulva precursor cells. Here, we show that mutants suppress both and ( Notch) gain-of-function mutants, restoring anchor cell formation and a functional vulva to the former and partly restoring oocyte production to the latter. However, suppressed hermaphrodites are only observed when grown at 25°, and they are self-sterile. This probably explains why was not previously recovered as a Notch pathway component in suppressor/enhancer selection experiments.
    Keywords: C. Elegans ; Mind Bomb ; Notch Signaling ; Spermatogenesis ; Ubiquitin E3 Ligase ; Caenorhabditis Elegans -- Genetics ; Caenorhabditis Elegans Proteins -- Metabolism ; Glucagon-Like Peptide 1 -- Metabolism ; Ki-67 Antigen -- Genetics ; Receptors, Notch -- Metabolism ; Spermatogenesis -- Genetics
    ISSN: 00166731
    E-ISSN: 1943-2631
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  • 2
    Language: English
    In: Cancer Research, 07/01/2017, Vol.77(13 Supplement), pp.1803-1803
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
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  • 3
    Language: German
    In: neuroreha, 2014, Vol.06(03), pp.113-116
    Description: Das Schädel-Hirn-Trauma ist die häufigste Ursache für Mortalität und dauerhafte Morbidität in der Bevölkerung der Industrienationen bis zum 45. Lebensjahr. Die primäre Schädigung des Gehirns entsteht durch das Trauma selbst. Therapieziel ist die Vermeidung sekundärer Hirnschädigungen durch Ischämie. Daher muss der intrakranielle Druck innerhalb physiologischer Grenzen gehalten und müssen Hypotonie, Hypoxie und Hypovolämie im Rahmen der Akuttherapie medikamentös verhindert werden. Nach Stabilisierung der Vitalparameter werden Patienten mit einem schweren Schädel-Hirn-Trauma in ein Traumazentrum gebracht, das die Diagnostik, eine potenziell operative Therapie und eine spezifische intensivmedizinische Betreuung gewährleistet.
    ISSN: 1611-6496
    E-ISSN: 1611-7654
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  • 4
    Language: English
    In: Nature, 03 December 2015, Vol.528(7580), pp.93-8
    Description: Astrocytic brain tumours, including glioblastomas, are incurable neoplasms characterized by diffusely infiltrative growth. Here we show that many tumour cells in astrocytomas extend ultra-long membrane protrusions, and use these distinct tumour microtubes as routes for brain invasion, proliferation, and to interconnect over long distances. The resulting network allows multicellular communication through microtube-associated gap junctions. When damage to the network occurred, tumour microtubes were used for repair. Moreover, the microtube-connected astrocytoma cells, but not those remaining unconnected throughout tumour progression, were protected from cell death inflicted by radiotherapy. The neuronal growth-associated protein 43 was important for microtube formation and function, and drove microtube-dependent tumour cell invasion, proliferation, interconnection, and radioresistance. Oligodendroglial brain tumours were deficient in this mechanism. In summary, astrocytomas can develop functional multicellular network structures. Disconnection of astrocytoma cells by targeting their tumour microtubes emerges as a new principle to reduce the treatment resistance of this disease.
    Keywords: Astrocytoma -- Pathology ; Brain Neoplasms -- Pathology ; Gap Junctions -- Metabolism
    ISSN: 00280836
    E-ISSN: 1476-4687
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  • 5
    Language: English
    In: Journal of neurosurgery. Pediatrics, March 2016, Vol.17(3), pp.285-8
    Description: The authors present the unusual case of a 4-year-old boy who had a complex history of posthemorrhagic hydrocephalus and who underwent more than 40 surgeries related to this condition. In the course of trying to treat his condition, ventriculoperitoneal, ventriculoatrial, and ventriculopleural shunts were inserted and failed. The child presented with a dysfunction of his shunt system. A ventriculopleural shunt was inserted, but within days the patient developed dyspnea as a clinical symptom of pleural effusion that required repeated thoracentesis. A bipleural drainage system was inserted, and no relevant pleural effusions developed during the follow-up period. Although the authors' experience is based on a single case, they do suggest bipleural drainage in patients with clinically relevant pleural effusions when the more common alternatives are not a good choice. Bipleural drainage might particularly be an option in children, who are prone to pleural effusion because of the smaller absorbing pleural surface. The authors reviewed the English-language literature on PubMed dating back to 1952. To their knowledge, this is the only published case in which a patient was treated with a ventriculo-bipleural shunt.
    Keywords: IVH = Intraventricular Hemorrhage ; VA = Ventriculoatrial ; VP = Ventriculoperitoneal ; Vpl = Ventriculopleural ; Hydrocephalus ; Pleural Effusion ; Ventriculopleural Shunt ; Cerebrospinal Fluid Shunts -- Adverse Effects ; Drainage -- Methods ; Hydrocephalus -- Surgery
    ISSN: 19330707
    E-ISSN: 1933-0715
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  • 6
    Language: English
    In: PLoS ONE, 2008, Vol.3(7), p.e2681
    Description: Functional and structural alterations of clustered postsynaptic ligand gated ion channels in neuronal cells are thought to contribute to synaptic plasticity and memory formation in the human brain. Here, we describe a novel molecular mechanism for structural alterations of NR1 subunits of the NMDA receptor. In cultured rat spinal cord neurons, chronic NMDA receptor stimulation induces disappearance of extracellular epitopes of NMDA receptor NR1 subunits, which was prevented by inhibiting matrix metalloproteinases (MMPs). Immunoblotting revealed the digestion of solubilized NR1 subunits by MMP-3 and identified a fragment of about 60 kDa as MMPs-activity-dependent cleavage product of the NR1 subunit in cultured neurons. The expression of MMP-3 in the spinal cord culture was shown by immunoblotting and immunofluorescence microscopy. Recombinant NR1 glycine binding protein was used to identify MMP-3 cleavage sites within the extracellular S1 and S2-domains. N -terminal sequencing and site-directed mutagenesis revealed S542 and L790 as two putative major MMP-3 cleavage sites of the NR1 subunit. In conclusion, our data indicate that MMPs, and in particular MMP-3, are involved in the activity dependent alteration of NMDA receptor structure at postsynaptic membrane specializations in the CNS.
    Keywords: Research Article ; Cell Biology ; Biochemistry -- Chemical Biology Of The Cell ; Cell Biology -- Neuronal Signaling Mechanisms
    E-ISSN: 1932-6203
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  • 7
    In: Neuro-Oncology, 2017, Vol. 19(10), pp.1316-1326
    Description: BackgroundPrimary and adaptive resistance against chemo- and radiotherapy and local recurrence after surgery limit the benefits from these standard treatments in glioma patients. Recently we found that glioma cells can extend ultra-long membrane protrusions, "tumor microtubes" (TMs), for brain invasion, proliferation, and interconnection of single cells to a syncytium that is resistant to radiotherapy. We wondered whether TMs also convey resistance to the other 2 standard treatment modalities. MethodsPatient-derived glioblastoma stemlike cell (GBMSC) lines were implanted under a cranial window in mice. Longitudinal in vivo two-photon laser scanning microscopy was used to follow tumor growth, including the fate of single glioma cells over months. ResultsAfter a cylindrical surgical lesion, GBMSCs increasingly extended TMs toward the lesion area, which contributed to the repopulation of this area over many weeks. In fact, an excessive "healing response" was observed in which tumor cell densities significantly exceeded those of unlesioned brain regions over time. Inhibition of TM formation and function by genetic targeting of growth associated protein-43 robustly suppressed this surgery-induced tumor growth reaction, in contrast to standard postsurgical anti-inflammatory treatment with dexamethasone. After one cycle of temozolomide chemotherapy, intra- and intertumoral heterogeneity of TM formation and interconnection was strongly associated with therapy response: when tumor cells were integrated in TM networks, they were more likely to resist chemotherapy. ConclusionTMs can contribute to the resistance against standard treatment modalities in gliomas. Specific inhibition of TMs is a promising approach to reduce local recurrence after surgery and lower resistance to chemotherapy.
    Keywords: Chemotherapy ; Glioma ; Resistance ; Surgery ; Tumor Microtubes
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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  • 8
    Language: English
    In: Nature medicine, August 2018, Vol.24(8), pp.1192-1203
    Description: The oncometabolite (R)-2-hydroxyglutarate (R-2-HG) produced by isocitrate dehydrogenase (IDH) mutations promotes gliomagenesis via DNA and histone methylation. Here, we identify an additional activity of R-2-HG: tumor cell-derived R-2-HG is taken up by T cells where it induces a perturbation of nuclear factor of activated T cells transcriptional activity and polyamine biosynthesis, resulting in suppression of T cell activity. IDH1-mutant gliomas display reduced T cell abundance and altered calcium signaling. Antitumor immunity to experimental syngeneic IDH1-mutant tumors induced by IDH1-specific vaccine or checkpoint inhibition is improved by inhibition of the neomorphic enzymatic function of mutant IDH1. These data attribute a novel, non-tumor cell-autonomous role to an oncometabolite in shaping the tumor immune microenvironment.
    Keywords: Immunity ; Glutarates -- Metabolism ; T-Lymphocytes -- Immunology
    ISSN: 10788956
    E-ISSN: 1546-170X
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  • 9
    In: Experimental and Clinical Endocrinology & Diabetes, 2018
    Description: OBJECTIVEPituitary apoplexy is a serious medical complication of a pre-existing pituitary adenoma characterized by a variety of clinical symptoms ranging from mild headache to neurologically impaired and finally comatose patients. Management options are surgery or conservative treatment (e. g., with dexamethasone). Surgery is commonly performed in case of severe acute neurological and visual symptoms. However, prospective studies demonstrating a benefit of surgery over conservative treatment in terms of visual, neurological and even endocrine outcomes are lacking. Decision making is still controversial, and recommendations for surgery are based on low evidence grades and focus on visual impairment. Endocrine function and especially markers identifying patients with potential for pituitary recovery after surgery are not well described in the literature. PATIENTS AND DESIGNWe analysed data from 24 patients (m:f/16:8) with a median age of 64 yrs (38 to 83yrs) that underwent surgery for pituitary apoplexy regardless of time from symptom onset. Apoplexies were necrotic in 14 cases and haemorrhagic in 10 cases. RESULTSPreoperatively, 7 patients (29.2%) showed complete anterior pituitary insufficiency, 16 patients (66.6%) had partial anterior pituitary insufficiency and one patient (4.17%) had normal pituitary functions. Persistent panhypopituitarism was found in 7 patients (29.2%), whereas an overall improvement of pituitary function was noted in 13 (57.1%) patients. Preoperative prolactin (PRL) levels were significantly associated with recovery of endocrine functions, whereas specifically all patients with preoperative PRL levels of at least 8.8 ng/ml recovered partially or fully. Time to surgery (0-7 days vs. 1-4 weeks vs.〉4 weeks) was not significantly associated with outcome. CONCLUSIONSOur data emphasize that normal and high preoperative PRL levels are associated with better endocrine outcome after surgery. We conclude that patients benefit from surgical intervention even after delayed diagnosis with the serum PRL levels is being a valid biomarker for clinical decision making.
    Keywords: Hypopituitarism ; Prolactin ; Hypocortisolism
    ISSN: 0947-7349
    E-ISSN: 1439-3646
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  • 10
    Language: English
    In: Biology of Reproduction, 07/01/2007, Vol.77(Suppl_1), pp.65-65
    ISSN: 0006-3363
    E-ISSN: 1529-7268
    Source: Oxford University Press (via CrossRef)
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