Assembly Maps and Pseudoisotopy Functors

In this thesis we show the existence of a stable, smooth pseudoisotopyfunctor and construct in the topological, piecewise linear, and smooth category a zig-zag of natural weak equivalences between the stable pseudoisotopyfunctor and the corresponding functor of Whitehead spectra. To achieve the former, we use the language of quasicategories to enhance the definition of a pseudoisotopy homotopy functor by Burghelea and Lashof to a functor of infinity categories. There are two main steps: First, we observe that most of the constructions by Burghelea and Lashof are unique in a homotopy coherent sense. Then, we give an explicit geometric construction to resolve coherence issues related to corners (of manifolds with corners) of arbitrary degree. This concludes the definition of a stable, smooth pseudoisotopyfunctor. For the latter, we extend the definition of the Whitehead spectrum to a functor of infinity categories to reduce the problem to a natural transformation of infinity functors. At the center of the natural transformation lies yet again an explicit geometric construction. We define families of retraction maps curtailed to the category of choices, which is used in Enkelmann's PhD thesis to define the topological and piecewise linear pseudoisotopyfunctors, and show these families to be unique up to coherence via the Alexander trick. The results of this thesis clarify the relation between the functor structures of pseudoisotopies, interesting due to their relations to automorphism spaces of manifolds, and the computationally accessible Whitehead spectrum. In conjunction with work on the Farrell-Jones conjecture for A-theory this resolves all questions concerning the original Farrell-Jones conjecture for pseudoisotopy. As an aside, we hope for eventual applications in the search of explicit nontrivial elements of homotopy groups of automorphism spaces of manifolds.Assembly Abbildungen und Pseudoisotopie Funktoren Wir konstruieren einen stabilen, glatten Pseudoisotopiefunktor und, in der topologischen, PL-, und glatten Kategorie, einen Zig-Zag von natürlichen schwachen Äquivalenzen zwischen dem stabilen Pseudoisotopiefunktor und dem entsprechenden Funktor von Whitehead Spektren. Für unser erstes Ziel nutzen wir die Sprache von Quasikategorien, um die Definition eines Pseudoisotopiehomotopiefunktors nach Burghelea und Lashof zu einem Funktor von Unendlichkategorien zu erweitern. Es gibt zwei wesentliche Schritte: Zunächst zeigen wir, dass die Konstruktionen von Burghela und Lashof in einem homotopiekohärenten Sinne eindeutig sind. Dann geben wir eine explizite geometrische Konstruktion, um Kohärenzprobleme mit Mannigfaltigkeiten mit Ecken beliebiger Dimension zu lösen. Dies schließt die Definition des stabilen, glatten Pseudoisotopiefunktors ab. Im zweiten Teil verallgemeinern wir die Definition des Whitehead Spektrums zu einem Funktor von Unendlichkategorien, um unser Problem auf die Frage nach einer natürlichen Transformation zwischen Unendlichfunktoren zurückzuführen. Der zentrale Punkt in der Konstruktion der natürlichen Transformation ist erneut ein explizites geometrisches Argument. Wir geben Familien von Retraktionsabbildungen an, die mit der Kategorie von Wahlen zur Konstruktion des topologischen und PL-Pseudoisotopiefunktors aus Enkelmanns Doktorarbeit verträglich sind, und zeigen mittels des Alexandertricks, dass diese Familien in einem homotopiekohärenten Sinne zusammenziehbar sind. Die Ergebnisse dieser Arbeit klären den Zusammenhang zwischen den Funktorstrukturen von Pseudoisotopien, die aufgrund ihres Bezugs zu Automorphismenräumen von Mannigfaltigkeiten betrachtet werden, und den für Berechnungen zugänglicheren Whitehead Spektren. Zusammen mit Resultaten zur Farrell-Jones Vermutung für A-Theorie beweist dies die ursprüngliche Farrell-Jones Vermutung für Pseudoisotopien. Daneben hoffen wir langfristig auf Anwendungen bei der Konstruktion expliziter nichttrivialer Elemente in Homotopiegruppen von Automorphismenräumen von Mannigfaltigkeiten

Dynamic contrast in scanning microscopic OCT

While optical coherence tomography (OCT) provides a resolution down to 1 micrometer it has difficulties to visualize cellular structures due to a lack of scattering contrast. By evaluating signal fluctuations, a significant contrast enhancement was demonstrated using time-domain full-field OCT (FF-OCT), which makes cellular and subcellular structures visible. The putative cause of the dynamic OCT signal is ATP-dependent motion of cellular structures in a sub-micrometer range, which provides histology-like contrast. Here we demonstrate dynamic contrast with a scanning frequency-domain OCT (FD-OCT). Given the inherent sectional imaging geometry, scanning FD-OCT provides depth-resolved images across tissue layers, a perspective known from histopathology, much faster and more efficiently than FF-OCT. Both, shorter acquisition times and tomographic depth-sectioning reduce the sensitivity of dynamic contrast for bulk tissue motion artifacts and simplify their correction in post-processing. The implementation of dynamic contrast makes microscopic FD-OCT a promising tool for histological analysis of unstained tissues.Comment: 7 pages, 3 figures, 1 Video available on reques

Bitter taste signaling in tracheal epithelial brush cells elicits innate immune responses to bacterial infection

Constant exposure of the airways to inhaled pathogens requires efficient early immune responses protecting against infections. How bacteria on the epithelial surface are detected and first-line protective mechanisms are initiated are not well understood. We have recently shown that tracheal brush cells (BCs) express functional taste receptors. Here we report that bitter taste signaling in murine BCs induces neurogenic inflammation. We demonstrate that BC signaling stimulates adjacent sensory nerve endings in the trachea to release the neuropeptides CGRP and substance P that mediate plasma extravasation, neutrophil recruitment, and diapedesis. Moreover, we show that bitter tasting quorum-sensing molecules from Pseudomonas aeruginosa activate tracheal BCs. BC signaling depends on the key taste transduction gene Trpm5, triggers secretion of immune mediators, among them the most abundant member of the complement system, and is needed to combat P. aeruginosa infections. Our data provide functional insight into firstline defense mechanisms against bacterial infections of the lung

Bitter taste signaling in tracheal epithelial brush cells elicits innate immune responses to bacterial infection.

peer reviewedConstant exposure of the airways to inhaled pathogens requires efficient early immune responses protecting against infections. How bacteria on the epithelial surface are detected and first-line protective mechanisms are initiated are not well understood. We have recently shown that tracheal brush cells (BCs) express functional taste receptors. Here we report that bitter taste signaling in murine BCs induces neurogenic inflammation. We demonstrate that BC signaling stimulates adjacent sensory nerve endings in the trachea to release the neuropeptides CGRP and substance P that mediate plasma extravasation, neutrophil recruitment, and diapedesis. Moreover, we show that bitter tasting quorum-sensing molecules from Pseudomonas aeruginosa activate tracheal BCs. BC signaling depends on the key taste transduction gene Trpm5, triggers secretion of immune mediators, among them the most abundant member of the complement system, and is needed to combat P. aeruginosa infections. Our data provide functional insight into first-line defense mechanisms against bacterial infections of the lung

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Process Development for Synthesizing the Cephalosporin Antibiotic Cefotaxime in Batch and Flow Mode

Pieper M, Kumpert M, König B, Schleich H, Bayer T, Gröger H. Process Development for Synthesizing the Cephalosporin Antibiotic Cefotaxime in Batch and Flow Mode. Organic Process Research & Development. 2018;22(8):947-954.The pharmaceutically active substance cefotaxime, a commercial cephalosporin-type antibiotic, is accessible in an amide-bond-forming reaction from 7-aminocephalosporanic acid as the amine donor and nonactivated (Z)-(2-aminothiazol-4-yl)-methoxyiminoacetic acid as the acid component with 4-toluenesulfonyl chloride as a coupling reagent, leading to only toluenesulfonic acid as an easy-to-separate byproduct. In this work, optimization of a batch process for this reaction is described as well as the extension toward a continuous process in a tube reactor with a diameter in the millimeter range. An opportunity to avoid the utilization of a chlorinated solvent system has been identified, thus contributing to the development of an ecologically friendly process. It was further shown that a higher reaction temperature of up to -10 degrees C is possible for the reaction when the process is conducted in a continuously operating fashion, which is an advantage from the perspective of energy demand. Thus, compared with the batch process, the continuous process turned out to be superior with respect to energy consumption and in terms of safety issues because of better heat dissipation for exothermic reactions. It also provides an opportunity to work in different process operating windows. A higher space-time yield represents a further advantage of the continuous process

Microvascular Decompression and MRI Findings in Trigeminal Neuralgia and Hemifacial Spasm. A Single Center Experience.

OBJECTIVE: For patients with medically unresponsive trigeminal neuralgia (TIC) and hemifacial spasm (HS), surgical microvascular decompression (MVD) is the procedure of choice. The authors of this report sought to review their outcomes with MVD in patients with TIC and HS, and the success of preoperative magnetic resonance imaging (MRI) in identifying the offending vascular compression. METHODS: Since 2004, there were a total of 51 patients with TIC and 12 with HS with available MRI scans. All patients underwent preoperative MRI to rule out non-surgical etiologies for facial pain and facial spasm, and confirm vascular compression. Follow-up after surgery was 13 ± 22 months for the patients with TIC and 33 ± 27 months for the patients with HS. RESULTS: There were 45 responders to MVD in the TIC cohort (88%), with a Visual Analog Score (VAS) of 1 ± 3. All patients with HS responded to MVD between 25 and 100%, with a mean of 75 ± 22%. Wound complications occurred in 10% of patients with MVD for TIC, and 1 patient reported hearing loss after MVD for HS, documented by audiogram. The congruence rate between the preoperative MRI and operative findings of vascular compression was 84% in TIC and 75% in HS. CONCLUSION: MVD is an effective and safe modality of treatment for TIC and HS. In addition to ruling out structural lesions, MRI can offer additional information by highlighting vascular loops associated with compressions. On conventional scans as obtained here, the resolution of MRI was congruent with operative findings in 84% in TIC and 75% in HS. This review emphasizes that the decision to undertake MVD in TIC or HS should be based on clinical diagnosis and not visualization of a compressing vessel by MRI. Conversely, the presence of a compressing vessel by MRI demands perseverance by the surgeon until the nerve is decompressed

Recommended guidelines for pain management programmes

Originally published in Optics Express on 07 September 2015 (oe-23-18-23217

Papain Degrades Tight Junction Proteins of Human Keratinocytes In Vitro and Sensitizes C57BL/6 Mice via the Skin Independent of its Enzymatic Activity or TLR4 Activation

Papain is commonly used in food, pharmaceutical, textile, and cosmetic industries and is known to induce occupational allergic asthma. We have previously shown that the papain-like cysteine protease Dermatophagoides pteronyssinus 1 from house dust mite exhibits percutaneous sensitization potential. We aimed here to investigate the potential of papain itself in epicutaneous sensitization. The effects of papain on tight junction (TJ) proteins were tested in vitro in human primary keratinocytes. Using C57BL/6 wild-type and Toll-like receptor 4 (TLR4)-deficient mice, we analyzed the sensitization potential of papain, its effects on the skin barrier, and immune cell recruitment. Our results show that papain affects the skin barrier by increasing transepidermal water loss, degrading TJ proteins and inducing vasodilation. When topically applied, papain exhibited a high epicutaneous inflammatory potential by recruiting neutrophils, mast cells, and CD3-positive cells and by induction of a TH2-biased antibody response. However, its high potency for specific sensitization via the skin was TLR4 independent and, in spite of its capacity to degrade epidermal TJ proteins, does not rely on its enzymatic function. From our data, we conclude that papain has all features to act as a strong allergen via the skin

High-resolution rectoscopy using MHz optical coherence tomography: a step towards real time 3D endoscopy

Abstract Colonoscopy and endoscopic ultrasound play pivotal roles in the assessment of rectal diseases, especially rectal cancer and inflammatory bowel diseases. Optical coherence tomography (OCT) offers a superior depth resolution, which is a critical factor for individualizing the therapeutic concept and evaluating the therapy response. We developed two distinct rectoscope prototypes, which were integrated into a 1300 nm MHz-OCT system constructed at our facility. The rapid rotation of the distal scanning probe at 40,000 revolutions per minute facilitates a 667 Hz OCT frame rate, enabling real-time endoscopic imaging of large areas. The performance of these OCT-rectoscopes was assessed in an ex vivo porcine colon and a post mortem human in-situ colon. The OCT-rectoscope consistently distinguished various layers of the intestinal wall, identified gut-associated lymphatic tissue, and visualized a rectal polyp during the imaging procedure with 3D-reconstruction in real time. Subsequent histological examination confirmed these findings. The body donor was preserved using an ethanol-glycerol-lysoformin-based technique for true-to-life tissue consistency. We could demonstrate that the novel MHZ-OCT-rectoscope effectively discriminates rectal wall layers and crucial tissue characteristics in a post mortem human colon in-situ. This real-time-3D-OCT holds promise as a valuable future diagnostic tool for assessing disease state and therapy response on-site in rectal diseases