Papers by Dimitar Nikolov
Otorinolaryngologie a Foniatrie
Neurofibromas of the larynx are extremely rare. The clinical symptoms of laryngeal neurofibroma a... more Neurofibromas of the larynx are extremely rare. The clinical symptoms of laryngeal neurofibroma are similar to other types of laryngeal tumors and are depending on the size and localization of the tumor. An association with diffuse neurofibromatosis up to 50 % of patients has been described. In our case, we present an isolated occurrence and treatment of multiple submucosal neurofibromas of the larynx in 24-year-old woman with minimal clinical symptoms. The clinical findings, diagnostic and therapy are discussed.
Low-grade myofibroblastic sarcoma (LGMS) is a very rare, atypical myofibroblastic tumor with fibr... more Low-grade myofibroblastic sarcoma (LGMS) is a very rare, atypical myofibroblastic tumor with fibromatosis-like features with predilection mostly in head and neck region. LGMS occurs primarily in adult patients with a slight male predominance. Only few cases of LGMS affecting the larynx have been reported in literature to this date. We describe a case of low-grade myofibroblastic sarcoma of the larynx in a 40-year-old male patient. The clinicopathological characteristics, immunohistochemical findings and treatment are discussed.
Interactive cardiovascular and thoracic surgery, 2011
Coarctation of thoracic aorta is an uncommon diagnosis in adults. Catheter-based intervention con... more Coarctation of thoracic aorta is an uncommon diagnosis in adults. Catheter-based intervention consisting of primary ballooning and stenting is becoming one of the methods of choice for the treatment of native coarctation. We describe the case of a young adult with coarctation of the aorta treated unsuccessfully with percutaneous transluminal angioplasty and stent implantation that resulted in stent migration into the aortic arch and led to an urgent operative intervention. In one step, we performed the evacuation of the foreign body from the aortic arch as well as the treatment of the aortic coarctation through an extra-anatomical vascular graft interposition between the ascending and descending thoracic aorta. In this article, we discuss the need for emergency surgical intervention in this case.
The Berlin Heart INCOR system (Berlin Heart AG, Berlin, Germany) is a left ventricular assist dev... more The Berlin Heart INCOR system (Berlin Heart AG, Berlin, Germany) is a left ventricular assist device that generates a laminar blood flow. One of our INCOR-implanted patients was admitted to the hospital with clinical data indicating device thrombosis. The flow through the pump was assessed by contrast injection into the inflow canula. Lack of flow through the pump was found. A decision was made to perform fibrinolysis, which was performed by a reteplase injection into the device's inflow canula. After the manipulation, a restoration of the flow through the pump was observed. The patient was discharged 9 days after the procedure with no complications.
GBM Annual Fall meeting M�nster 2004, 2004
Cell Adhesion & Migration, 2014
The Eph receptor tyrosine kinases and their ephrin ligands direct axon pathfinding and neuronal c... more The Eph receptor tyrosine kinases and their ephrin ligands direct axon pathfinding and neuronal cell migration, and mediate many other cell-cell communication events. The Ephs and ephrins both localize to the plasma membrane and, upon cell-cell contact, form extensive signaling assemblies at the contact sites. Recent structural, biochemical and cell-biological studies revealed that these assemblies are generated not only via Eph-ephrin interactions, but also via homotypic interactions between neighboring receptor molecules. In addition, Eph-Eph interactions mediate receptor pre-clustering, which ensures fast and efficient activation once ligands come into contact range. Here we summarize the current knowledge about the homotypic Eph-Eph interactions and discuss how they could modulate the initiation of Eph/ephrin signaling.
Videosurgery and Other Miniinvasive Techniques, 2014
Introduction: Currently, the predominant question is whether a laparoscopic approach is comparati... more Introduction: Currently, the predominant question is whether a laparoscopic approach is comparatively radical in comparison with an open access approach, especially in the circumferential resection margin and quality of the completeness of total mesorectal excision. These factors are important in determining the quality of surgical care as well as long-term results of the treatment.
Neuron, 2003
The semaphorins are a large group of extracellular proteins involved in a variety of processes du... more The semaphorins are a large group of extracellular proteins involved in a variety of processes during development, including neuronal migration and axon guidance. Their distinctive feature is a conserved 500 amino acid semaphorin domain, a ligand-receptor interaction module also present in plexins and scatter-factor receptors. We report the crystal structure of a secreted 65 kDa form of Semaphorin-3A (Sema3A), containing the full semaphorin domain. Unexpectedly, the semaphorin fold is a variation of the beta propeller topology. Analysis of the Sema3A structure and structure-based mutagenesis data identify the neuropilin binding site and suggest a potential plexin interaction site. Based on the structure, we present a model for the initiation of semaphorin signaling and discuss potential similarities with the signaling mechanisms of other beta propeller cell surface receptors, such as integrins and the LDL receptor.
Science (New York, N.Y.), Jan 13, 2014
Netrins are secreted proteins that regulate axon guidance and neuronal migration. Deleted in colo... more Netrins are secreted proteins that regulate axon guidance and neuronal migration. Deleted in colorectal cancer (DCC) is a well-established netrin-1 receptor mediating attractive responses. We provide evidence that its close relative neogenin is also a functional netrin-1 receptor that acts with DCC to mediate guidance in vivo. We determined the structures of a functional netrin-1 region, alone and in complexes with neogenin or DCC. Netrin-1 has a rigid elongated structure containing two receptor-binding sites at opposite ends through which it brings together receptor molecules. The ligand/receptor complexes reveal two distinct architectures: a 2:2 heterotetramer and a continuous ligand/receptor assembly. The differences result from different lengths of the linker connecting receptor domains fibronectin type III domain 4 (FN4) and FN5, which differs among DCC and neogenin splice variants, providing a basis for diverse signaling outcomes.
Sensors and Actuators A: Physical, 2005
... observed. We have found that when the offset is initially adjusted to be V B1,2 (B = 0) = 0 a... more ... observed. We have found that when the offset is initially adjusted to be V B1,2 (B = 0) = 0 at T = 0°C, its average temperature drift β per °C in the range 0 ≤ T ≤ 80 °C is less than β = 0.03 % per °C. As it can be seen on Fig. 4 ...
Protein Science, 2007
Eph receptors and ephrins play important roles in regulating cell migration and positioning durin... more Eph receptors and ephrins play important roles in regulating cell migration and positioning during both normal and oncogenic tissue development. Using a surface plasma resonance (SPR) biosensor, we examined the binding kinetics of representative monomeric and dimeric ephrins to their corresponding Eph receptors and correlated the apparent binding affinity with their functional activity in a neuronal growth cone collapse assay. Our results indicate that the Eph receptor binding of dimeric ephrins, formed through fusion with disulfide-linked Fc fragments, is best described using a bivalent analyte model as a two-step process involving an initial monovalent 2:1 binding followed by a second bivalent 2:2 binding. The bivalent binding dramatically decreases the apparent dissociation rate constants with little effect on the initial association rate constants, resulting in a 30- to 6000-fold decrease in apparent equilibrium dissociation constants for the binding of dimeric ephrins to Eph receptors relative to their monomeric counterparts. Interestingly, the change was more prominent in the A-class ephrin/Eph interactions than in the B-class of ephrins to Eph receptors. The increase in apparent binding affinities correlated well with increased activation of Eph receptors and the resulting growth cone collapse. Our kinetic analysis and correlation of binding affinity with function helped us better understand the interactions between ephrins and Eph receptors and should be useful in the design of inhibitors that interfere with the interactions.
Protein Science, 2007
The Eph receptors, the largest subfamily of receptor tyrosine kinases, and their ephrin ligands a... more The Eph receptors, the largest subfamily of receptor tyrosine kinases, and their ephrin ligands are important mediators of cell-cell communication regulating cell attachment, pathfinding, and mobility in the nervous and cardiovascular systems. Recent structural studies have revealed unique molecular features that explain many of the biochemical and signaling properties of Ephs and ephrins. Nevertheless, open questions remain, including understanding the precise molecular mechanism underlining their binding-partner preferences and subclass specificity. In this study, we have determined and present the crystal structure of the extracellular domain of ephrin-A5-the first structure of an unbound A-class ephrin. The structure, determined at 2.1 A resolution, is a variation of the Greek key beta-barrel folding topology, containing eight beta-strands, and stabilized by two disulphide bonds. Overall, ephrin-A5 is structurally very similar to ephrin-B1 and ephrin-B2 but, unlike ephrin-B2, it does not show dimerization either in solution or in the crystals. Comparing free ephrin-A5 to the previously published structure of EphB2-bound ephrin-A5 reveals that significant conformational changes occur only around the G-H ephrin loop that upon binding bends toward the receptor. Interestingly, the G-H loop undergoes a very similar conformational rearrangement in ephrin-B2 upon receptor binding. The results of this study further emphasize the importance of the G-H loop for receptor recognition and selectivity, and could serve as a starting point for the development of structure-based Eph antagonists.
Protein Expression and Purification, 2013
Eph receptors are the largest family of Receptor Tyrosine Kinases containing a single membrane-sp... more Eph receptors are the largest family of Receptor Tyrosine Kinases containing a single membrane-spanning segment. They are involved in a various developmental and cell-cell communication events. Although there is extensive structural information available on both the extra-and intracellular regions of Eph's in isolation, no structures are available for the entire receptor. To facilitate structural studies on functionally relevant Eph/ephrin complexes, we have developed an expression system for producing the fulllength human EphA2 receptor. We successfully expressed milligram amounts of the receptor using baculovirus-based vector and insect cells. We were also able to extract the protein from the cell membranes and purify it to near homogeneity in two simple steps. The purified receptor was shown to retain its biological activity in terms of both binding to its functional ligands and being able to auto-phosphorylate the key tyrosine residues of the cytoplasmic kinase domain.
Proceedings of the National Academy of Sciences, 1996
The TATA box-binding protein (TBP) is required by all three eukaryotic RNA polymerases for correc... more The TATA box-binding protein (TBP) is required by all three eukaryotic RNA polymerases for correct initiation of transcription of ribosomal, messenger, small nuclear, and transfer RNAs. The cocrystal structure of the C-terminal/core region of human TBP complexed with the TATA element of the adenovirus major late promoter has been determined at 1.9 angstroms resolution. Structural and functional analyses of the protein-DNA complex are presented, with a detailed comparison to our 1.9-angstroms resolution structure of Arabidopsis thaliana TBP2 bound to the same TATA box.
Proceedings of the National Academy of Sciences, 2010
Eph receptor tyrosine kinases and their ephrin ligands regulate cell navigation during normal and... more Eph receptor tyrosine kinases and their ephrin ligands regulate cell navigation during normal and oncogenic development. Signaling of Ephs is initiated in a multistep process leading to the assembly of higher-order signaling clusters that set off bidirectional signaling in interacting cells. However, the structural and mechanistic details of this assembly remained undefined. Here we present high-resolution structures of the complete EphA2 ectodomain and complexes with ephrin-A1 and A5 as the base unit of an Eph cluster. The structures reveal an elongated architecture with novel Eph/Eph interactions, both within and outside of the Eph ligand-binding domain, that suggest the molecular mechanism underlying Eph/ephrin clustering. Structure-function analysis, by using site-directed mutagenesis and cell-based signaling assays, confirms the importance of the identified oligomerization interfaces for Eph clustering.
Organic Letters, 2003
[reaction: see text] In an effort to expand the scope of natural product in vitro glycorandomizat... more [reaction: see text] In an effort to expand the scope of natural product in vitro glycorandomization (IVG), the substrate specificity of NovM was investigated. A test of four aglycon analogues and over 40 nucleotide sugars revealed NovM has a surprisingly stringent substrate specificity and provided only three new "unnatural" natural products. On the basis of the determined substrate specificity, an alternative to the sugar nucleotide biosynthetic dogma and a cautionary note for the general applicability of IVG are introduced.
Nature Neuroscience, 2004
The interactions between Eph receptor tyrosine kinases and their ephrin ligands regulate cell mig... more The interactions between Eph receptor tyrosine kinases and their ephrin ligands regulate cell migration and axon pathfinding. The EphA receptors are generally thought to become activated by ephrin-A ligands, whereas the EphB receptors interact with ephrin-B ligands. Here we show that two of the most widely studied of these molecules, EphB2 and ephrin-A5, which have never been described to interact with each other, do in fact bind one another with high affinity. Exposure of EphB2-expressing cells to ephrin-A5 leads to receptor clustering, autophosphorylation and initiation of downstream signaling. Ephrin-A5 induces EphB2mediated growth cone collapse and neurite retraction in a model system. We further show, using X-ray crystallography, that the ephrin-A5-EphB2 complex is a heterodimer and is architecturally distinct from the tetrameric EphB2-ephrin-B2 structure. The structural data reveal the molecular basis for EphB2-ephrin-A5 signaling and provide a framework for understanding the complexities of functional interactions and crosstalk between A-and B-subclass Eph receptors and ephrins.
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Papers by Dimitar Nikolov