IFT88 transports Gucy2d, a guanylyl cyclase, to maintain sensory cilia function in Drosophila

Cilia are involved in a plethora of motility and sensory-related functions. Ciliary defects cause several ciliopathies, some of which with late-onset, suggesting cilia are actively maintained. While much is known about cilia assembly, little is understood about the mechanisms of their maintenance. Given that intraflagellar transport (IFT) is essential for cilium assembly, we investigated the role of one of its main players, IFT88, in ciliary maintenance. We show that DmIFT88, the Drosophila melanogaster orthologue of IFT88, continues to move along fully formed sensory cilia, and that its acute knockdown in the ciliated neurons of the adult affects sensory behaviour. We further identify DmGucy2d, the Drosophila guanylyl cyclase 2d, as a DmIFT88 cargo, whose loss also leads to defects in sensory behaviour maintenance. DmIFT88 binds to the intracellular part of DmGucy2d, a highly, evolutionarily conserved and mutated in several degenerative retina diseases, taking the cyclase into the cilia. Our results offer a novel mechanism for the maintenance of sensory cilia function and its potential role in human diseases

Toll-like receptor 2/6-dependent stimulation of mesenchymal stem cells promotes angiogenesis by paracrine factors

Reconstruction of critical size bone defects represents a major challenge in orthopaedic surgery. Insufficient angiogenesis is a limiting factor for engraftment of large-scale tissue transplants. Transplantation or stimulation of local mesenchymal stem cells (MSCs) represents a potential solution to enhance angiogenesis. We recently identified angiogenic properties for the Toll-like receptor (TLR) 2/6 agonist MALP-2 and now investigated if MALP-2 could be used to stimulate MSCs in order to promote angiogenesis in vitro and in vivo.Human MSCs from the bone marrow of healthy subjects were isolated, cultured and expanded in vitro and were shown to be positive for mesenchymal stem cells markers as well as for the MALP-2 receptors TLR2 and TLR6. MALP-2 directly enhanced migration but not proliferation of human MSCs. Conditioned medium from MALP-2 stimulated MSCs significantly increased proliferation, migration and tube formation of endothelial cells. Analysis of the conditioned medium from MSCs revealed that MALP-2 stimulation enhanced the secretion of several chemokines and growth factors including vascular endothelial growth factors (VEGF) and granulocyte-macrophage colony-stimulating factor (GM-CSF). Finally, we studied MALP-2 effects on MSCs in a sheep model of tissue engineering in vivo. Therefore, MSCs were isolated from the iliac crest of black head sheep and co-cultivated with MALP-2 ex vivo. Implantation of autologous MSCs within a scaffold cylinder into the M. latissimus dorsi significantly enhanced vessel density of these constructs after 6 months.We here present the first evidence that TLR2/6-dependent stimulation of MSCs promotes angiogenesis in vitro and in vivo offering a novel strategy for therapeutic angiogenesis, e.g., for tissue engineering of bone

Hard Tissue Engineering

Peer reviewe

Localized direction selective responses in the dendrites of visual interneurons of the fly

<p>Abstract</p> <p>Background</p> <p>The various tasks of visual systems, including course control, collision avoidance and the detection of small objects, require at the neuronal level the dendritic integration and subsequent processing of many spatially distributed visual motion inputs. While much is known about the pooled output in these systems, as in the medial superior temporal cortex of monkeys or in the lobula plate of the insect visual system, the motion tuning of the elements that provide the input has yet received little attention. In order to visualize the motion tuning of these inputs we examined the dendritic activation patterns of neurons that are selective for the characteristic patterns of wide-field motion, the lobula-plate tangential cells (LPTCs) of the blowfly. These neurons are known to sample direction-selective motion information from large parts of the visual field and combine these signals into axonal and dendro-dendritic outputs.</p> <p>Results</p> <p>Fluorescence imaging of intracellular calcium concentration allowed us to take a direct look at the local dendritic activity and the resulting local preferred directions in LPTC dendrites during activation by wide-field motion in different directions. These 'calcium response fields' resembled a retinotopic dendritic map of local preferred directions in the receptive field, the layout of which is a distinguishing feature of different LPTCs.</p> <p>Conclusions</p> <p>Our study reveals how neurons acquire selectivity for distinct visual motion patterns by dendritic integration of the local inputs with different preferred directions. With their spatial layout of directional responses, the dendrites of the LPTCs we investigated thus served as matched filters for wide-field motion patterns.</p

Insect Bio-inspired Neural Network Provides New Evidence on How Simple Feature Detectors Can Enable Complex Visual Generalization and Stimulus Location Invariance in the Miniature Brain of Honeybees

This work was supported by a Human Frontier Science Program Grant RGP0022/2014 to LC and Queen Mary University of London Scholarship to MR. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

SimBench: Open source time series of power load, storage and generation for the simulation of electrical distribution grids

In operation and planning of electrical grids, it is essential to account for temporal fluctuation of produced and consumed electric energy. Time series based studies often use standardized load profiles for this, which, however, cannot accurately represent the individual peak patterns in load and demand and their random combinations. As part of the SimBench project, we developed a dataset of energy time series to be assigned as individual profiles to grid nodes in high voltage (HV), medium voltage (MV) and low voltage (LV) grids to calculate local power flows in a more realistic way. Load profiles are classified and assigned to categories on the basis of similarity to standard load profiles to represent a broad range of energy users and generation profiles were created using weather data and an agent-based simulation tool. The subset presented in this paper comprises different 77 one-year-profiles with a 15 minute resolution, containing commercial consumers, household consumers, storage, and production units based on real measurements from Germany with a focus on MV and LV levels

Soziodemografische Aspekte und therapiebezogene Faktoren von Patienten mit Mundhöhlenkarzinomen bei der Teilnahme an einer Rehabilitation

Objectives: After resection of an oral carcinoma, patients are faced with physical, psychological, and socioeconomic challenges. Rehabilitation plays an essential role in patients' reintegration into their social and professional environment. This study evaluated whether socioeconomic aspects affect oral cancer patients' participation in rehabilitation treatment. Materials and methods: A retrospective analysis was conducted with 1,532 patients following surgical treatment of oral cancer during an international multicenter rehabilitation study of the German-Swiss-Austrian Cooperative Working Group on Maxillofacial Tumors using a questionnaire comprising disease-related and psychosocial items postoperatively and at least 6 months after surgery.Results: Only 35.4% of patients participated in rehabilitation. Age (p<0.001), sex (p<0.001), and marital status (p<0.05) significantly influenced participation in rehabilitation. Postoperative impairment (p<0.05) as well as quality of life (p<0.01) were significantly worse in patients who participated in rehabilitation. Nevertheless, this group of patients returned to work significantly more often, although later, than those who did not participate in rehabilitation (p<0.05). Conclusions: The findings show social inequalities and suggest a general undersupply of rehabilitative follow-up treatment in patients with oral cancer. More patients, especially older people and women should be referred to rehabilitation.Ziele: Nach Resektion eines Mundhöhlenkarzinoms stehen Patienten vor körperlichen, psychischen und sozioökonomischen Herausforderungen. Die Rehabilitation spielt eine wesentliche Rolle bei der Wiedereingliederung der Patienten in ihr soziales und berufliches Umfeld. In dieser Studie wurde untersucht, ob sozioökonomische Aspekte die Teilnahme von Mundkrebspatienten an einer Rehabilitationsbehandlung beeinflussen.Material und Methoden: Im Rahmen der internationalen multizentrischen Rehabilitationsstudie des Deutsch-Österreichisch-Schweizerischen Arbeitskreises für Tumoren des Kiefer-Gesichtsbereichs wurde mittels eines Fragebogens eine retrospektive Analyse von 1.532 Patienten mindestens 6 Monate nach operativer Behandlung eines Mundhöhlenkarzinoms durchgeführt.Ergebnisse: Nur 35,4% der Patienten nahmen an einer Rehabilitation teil. Alter (p<0,001), Geschlecht (p<0,001) und Familienstand (p<0,05) beeinflussten die Teilnahme an der Rehabilitation signifikant. Die postoperative Beeinträchtigung (p<0,05) sowie die Lebensqualität (p<0,01) waren bei Patienten, die an der Rehabilitation teilnahmen, signifikant schlechter. Dennoch kehrte diese Patientengruppe signifikant häufiger, wenn auch später, in den Beruf zurück als diejenigen, die nicht an der Rehabilitation teilnahmen (p<0,05).Schlussfolgerungen: Die Ergebnisse zeigen soziale Ungleichheiten und deuten auf eine generelle Unterversorgung bei der rehabilitativen Nachbehandlung von Patienten mit Mundhöhlenkarzinomen hin. Mehr Patienten, insbesondere ältere Menschen und Frauen, sollten zu Rehabilitationsmaßnahmen angeleitet werden

IFT88 maintains sensory function by localising signalling proteins along Drosophila cilia

Ciliary defects cause several ciliopathies, some of which have late onset, suggesting cilia are actively maintained. Still, we have a poor understanding of the mechanisms underlying their maintenance. Here, we show Drosophila melanogaster IFT88 (DmIFT88/nompB) continues to move along fully formed sensory cilia. We further identify Inactive, a TRPV channel subunit involved in Drosophila hearing and negative-gravitaxis behaviour, and a yet uncharacterised Drosophila Guanylyl Cyclase 2d (DmGucy2d/CG34357) as DmIFT88 cargoes. We also show DmIFT88 binding to the cyclase´s intracellular part, which is evolutionarily conserved and mutated in several degenerative retinal diseases, is important for the ciliary localisation of DmGucy2d. Finally, acute knockdown of both DmIFT88 and DmGucy2d in ciliated neurons of adult flies caused defects in the maintenance of cilium function, impairing hearing and negative-gravitaxis behaviour, but did not significantly affect ciliary ultrastructure. We conclude that the sensory ciliary function underlying hearing in the adult fly requires an active maintenance program which involves DmIFT88 and at least two of its signalling transmembrane cargoes, DmGucy2d and Inactive

En bloc prefabrication of vascularized bioartificial bone grafts in sheep and complete workflow for custom-made transplants

The aim of this pilot study was to determine, in a new experimental model, whether complex bioartificial monoblocs of relevant size and stability can be prefabricated in a defined three-dimensional design, in which the latissimus dorsi muscle serves as a natural bioreactor and the thoracodorsal vessel tree is prepared for axial construct perfusion. Eighteen sheep were included in the study, with six animals in each of three experimental groups. Vitalization of the β-tricalcium phosphate-based constructs was performed by direct application of unmodified osteogenic material from the iliac crest (group A), in vivo application of nucleated cell concentrate (NCC) from bone marrow aspirate (group B), and in vitro cultivation of bone marrow stromal cells (BMSC) in a perfusion bioreactor system (group C). The contours of the constructs were designed digitally and transferred onto the bioartificial bone grafts using a titanium cage, which was bent over a stereolithographic model of the defined subvolume intraoperatively. At the end of the prefabrication process, only the axial vascularized constructs of group A demonstrated vital bone formation with considerable stability. In groups B and C, the applied techniques were not able to induce ectopic bone formation. The presented computer-assisted workflow allows the prefabrication of custom-made bioartificial transplants