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This article presents an immersive virtual reality (VR) system for training classroom management skills, with a specific focus on learning to manage disruptive student behavior in face-to-face, one-to-many teaching scenarios. The core of the system is a real-time 3D virtual simulation of a classroom populated by twenty-four semi-autonomous virtual students. The system has been designed as a companion tool for classroom management seminars in a syllabus for primary and secondary school teachers. This will allow lecturers to link theory with practice using the medium of VR. The system is therefore designed for two users: a trainee teacher and an instructor supervising the training session. The teacher is immersed in a real-time 3D simulation of a classroom by means of a head-mounted display and headphone. The instructor operates a graphical desktop console, which renders a view of the class and the teacher whose avatar movements are captured by a marker less tracking system. This console includes a 2D graphics menu with convenient behavior and feedback control mechanisms to provide human-guided training sessions. The system is built using low-cost consumer hardware and software. Its architecture and technical design are described in detail. A first evaluation confirms its conformance to critical usability requirements (i.e., safety and comfort, believability, simplicity, acceptability, extensibility, affordability, and mobility). Our initial results are promising and constitute the necessary first step toward a possible investigation of the efficiency and effectiveness of such a system in terms of learning outcomes and experience.
Honeybees learn color information of rewarding flowers and recall these memories in future decisions. For fine color discrimination, bees require differential conditioning with a concurrent presentation of target and distractor stimuli to form a long-term memory. Here we investigated whether the long-term storage of color information shapes the neural network of microglomeruli in the mushroom body calyces and if this depends on the type of conditioning. Free-flying honeybees were individually trained to a pair of perceptually similar colors in either absolute conditioning towards one of the colors or in differential conditioning with both colors. Subsequently, bees of either conditioning groups were tested in non-rewarded discrimination tests with the two colors. Only bees trained with differential conditioning preferred the previously learned color, whereas bees of the absolute conditioning group, and a stimuli-naïve group, chose randomly among color stimuli. All bees were then kept individually for three days in the dark to allow for complete long-term memory formation. Whole-mount immunostaining was subsequently used to quantify variation of microglomeruli number and density in the mushroom-body lip and collar. We found no significant differences among groups in neuropil volumes and total microglomeruli numbers, but learning performance was negatively correlated with microglomeruli density in the absolute conditioning group. Based on these findings we aim to promote future research approaches combining behaviorally relevant color learning tests in honeybees under free-flight conditions with neuroimaging analysis; we also discuss possible limitations of this approach.q
People with post-stroke motor aphasia know what they would like to say but cannot express it through motor pathways due to disruption of cortical circuits. We present a theoretical background for our hypothesized connection between attention and aphasia rehabilitation and suggest why in this context, Brain-Computer Interface (BCI) use might be beneficial for patients diagnosed with aphasia. Not only could BCI technology provide a communication tool, it might support neuronal plasticity by activating language circuits and thereby boost aphasia recovery. However, stroke may lead to heterogeneous symptoms that might hinder BCI use, which is why the feasibility of this approach needs to be investigated first. In this pilot study, we included five participants diagnosed with post-stroke aphasia. Four participants were initially unable to use the visual P300 speller paradigm. By adjusting the paradigm to their needs, participants could successfully learn to use the speller for communication with accuracies up to 100%. We describe necessary adjustments to the paradigm and present future steps to investigate further this approach.
B cells and DCs are suspected to play an important role in the pathogenesis of cGvHD, which is a serious complication of HSCT with high morbidity. It is characterized by immune responses of donor immune cells against recipient-derived antigens. athogenesis is not yet fully understood, however reconstitution of B cells after HSCT has similarities to physiologic ontogeny. Immunophenotyping and co-cultivation-experiments of B cells and DCs from pediatric patients with cGvHD as well as healthy donors were conducted. Significant differences between patients and healthy donors were observed with increased memory, transitional, CD69+ and CD86+ phenotype and lower levels of naïve B cells due to apoptosis. Co-cultivation revealed this to be primarily B cell-dependent without major effects of and with DCs. There was a decreased CD11c- phenotype in patients and less apoptosis of DCs. Our data suggest a disturbed homeostasis in B cells with increased memory phenotype in patients, whereas DCs could not influence these differences, therefore DCs are not imposing as promising targets. B cell-dependent approaches should be further investigated.
Natural genetic variation makes it possible to discover evolutionary changes that have been maintained in a population because they are advantageous. To understand genotype–phenotype relationships and to investigate trait architecture, the existence of both high-resolution genotypic and phenotypic data is necessary. Arabidopsis thaliana is a prime model for these purposes. This herb naturally occurs across much of the Eurasian continent and North America. Thus, it is exposed to a wide range of environmental factors and has been subject to natural selection under distinct conditions. Full genome sequencing data for more than 1000 different natural inbred lines are available, and this has encouraged the distributed generation of many types of phenotypic data. To leverage these data for meta analyses, AraPheno (https://arapheno.1001genomes.org) provide a central repository of population-scale phenotypes for A. thaliana inbred lines. AraPheno includes various features to easily access, download and visualize the phenotypic data. This will facilitate a comparative analysis of the many different types of phenotypic data, which is the base to further enhance our understanding of the genotype–phenotype map.
Background
The impact of sex on cardiac morphology and function in chronic volume overload has been described in detail. However, the relation between sex and contractile properties at the actin-myosin level has not been well defined. Therefore, we evaluated the influence of sex on the contractile capacities of patients with chronic volume overload.
Methods
In 36 patients (18 males, 65 ± 9 years; 18 females, 65 ± 13 years) scheduled for elective mitral valve surgery due to severe mitral regurgitation (MR) with preserved left ventricular function, right auricle samples were obtained prior to extracorporal circulation. The fibers were prepared and skinned and exposed to a gradual increase in the calcium concentration (from pCa of 6.5–4.0) for calcium-induced force-developing measurements. Calcium sensitivity was also measured and recorded.
Results
The pCa-force relationship of the fibers obtained from males and females was significantly different, with the force values of the female fibers greater than those of male fibers at maximum calcium concentrations (pCa of 4.0: 3.6 ± 0.3 mN versus 3.2 ± 0.4 mN, p 0.02) and pCa of 4.5 2.6 ± 0.6 versus 2.0 ± 0.5, p 0.002). In contrast, the force values of female fibers were lower at mean calcium concentrations compared to those of male fibers (at 5.5 and pCa of 6.0: 1.0 ± 0.3 mN versus 1.2 ± 0.5 mN, p 0.04; 0.61 ± 0.05 versus 0.88 ± 0.09, p 0.04).
Calcium sensitivity was observed at pCa of 5.0 in females and pCa of 4.5 in males.
Conclusion
This study demonstrated that female fibers from patients exposed to chronic volume overload developed higher force values at a given calcium concentration compared to fibers from male patients. We assume that female patients might tap the full force potential, which is required when exposed to the highest calcium concentrations in our experimental cycle. The calcium sensitivity among genders was significantly different, with the results suggesting that males have higher calcium sensitivity and might compensate for lower force values at maximal calcium concentrations by a higher affinity for calcium. Hence, female patients with MR seem to work more “energy efficient”.
Background
Anastomotic leakage (AL) is one of the most common and serious complications following visceral surgery. In recent years, endoluminal vacuum therapy has dramatically changed therapeutic options for AL, but its use has been limited to areas easily accessible by endoscope.
Case presentation
We describe the first use of endoluminal vacuum therapy in the small intestine employing a combined surgical and endoscopic “rendezvous technique” in which the surgeon assists the endoscopic placement of an endoluminal vacuum therapy sponge in the jejunum by means of a pullback string. This technique led to a completely closed AL after 27 days and 7 changes of the endosponge.
Conclusion
The combined surgical and endoscopic rendezvous technique can be useful in cases of otherwise difficult endosponge placement.
This study investigates a two component decomposition technique for HH/VV-polarized PolSAR (Polarimetric Synthetic Aperture Radar) data. The approach is a straight forward adaption of the Yamaguchi decomposition and decomposes the data into two scattering contributions: surface and double bounce under the assumption of a negligible vegetation scattering component in Tundra environments. The dependencies between the features of this two and the classical three component Yamaguchi decomposition were investigated for Radarsat-2 (quad) and TerraSAR-X (HH/VV) data for the Mackenzie Delta Region, Canada. In situ data on land cover were used to derive the scattering characteristics and to analyze the correlation among the PolSAR features. The double bounce and surface scattering features of the two and three component scattering model (derived from pseudo-HH/VV- and quad-polarized data) showed similar scattering characteristics and positively correlated-R2 values of 0.60 (double bounce) and 0.88 (surface scattering) were observed. The presence of volume scattering led to differences between the features and these were minimized for land cover classes of low vegetation height that showed little volume scattering contribution. In terms of separability, the quad-polarized Radarsat-2 data offered the best separation of the examined tundra land cover types and will be best suited for the classification. This is anticipated as it represents the largest feature space of all tested ones. However; the classes “wetland” and “bare ground” showed clear positions in the feature spaces of the C- and X-Band HH/VV-polarized data and an accurate classification of these land cover types is promising. Among the possible dual-polarization modes of Radarsat-2 the HH/VV was found to be the favorable mode for the characterization of the aforementioned tundra land cover classes due to the coherent acquisition and the preserved co-pol. phase. Contrary, HH/HV-polarized and VV/VH-polarized data were found to be best suited for the characterization of mixed and shrub dominated tundra.
The Sentinel-1 Satellite (S-1) of ESA's Copernicus Mission delivers freely available C-Band Synthetic Aperture Radar (SAR) data that are suited for interferometric applications (InSAR). The high geometric resolution of less than fifteen meter and the large coverage offered by the Interferometric Wide Swath mode (IW) point to new perspectives on the comprehension and understanding of surface changes, the quantification and monitoring of dynamic processes, especially in arid regions. The contribution shows the application of S-1 intensities and InSAR coherences in time series analysis for the delineation of changes related to fluvial morphodynamics in Damghan, Iran. The investigations were carried out for the period from April to October 2015 and exhibit the potential of the S-1 data for the identification of surface disturbances, mass movements and fluvial channel activity in the surroundings of the Damghan Playa. The Amplitude Change Detection highlighted extensive material movement and accumulation - up to sizes of more than 4,000 m in width - in the east of the Playa via changes in intensity. Further, the Coherence Change Detection technique was capable to indicate small-scale channel activity of the drainage system that was neither recognizable in the S-1 intensity nor the multispectral Landsat-8 data. The run off caused a decorrelation of the SAR signals and a drop in coherence. Seen from a morphodynamic point of view, the results indicated a highly dynamic system and complex tempo-spatial patterns were observed that will be subject of future analysis. Additionally, the study revealed the necessity to collect independent reference data on fluvial activity in order to train and adjust the change detector.
Polypeptoids are an old but recently rediscovered polymer class with interesting synthetic, physico-chemical and biological characteristics. Here, we introduce new aromatic monomers, N-benzyl glycine N-carboxyanhydride and N-phenethyl glycine N-carboxyanhydride and their block copolymers with the hydrophilic polysarcosine. We compare their self-assembly in water and aqueous buffer with the self-assembly of amphiphilic block copolypeptoids with aliphatic side chains. The aggregates in water were investigated by dynamic light scattering and electron microscopy. We found a variety of morphologies, which were influenced by the polymer structure as well as by the preparation method. Overall, we found polymersomes, worm-like micelles and oligo-lamellar morphologies as well as some less defined aggregates of interconnected worms and vesicles. Such, this contribution may serve as a starting point for a more detailed investigation of the self-assembly behavior of the rich class of polypeptoids and for a better understanding between the differences in the aggregation behavior of non-uniform polypeptoids and uniform peptoids.
In vertebrates, one of the first recognizable sex differences in embryos is the onset of meiosis, known to be regulated by retinoic acid (RA) in mammals. We investigated in medaka a possible meiotic function of RA during the embryonic sex determination (SD) period and in mature gonads. We found RA mediated transcriptional activation in germ cells of both sexes much earlier than the SD stage, however, no such activity during the critical stages of SD. In adults, expression of the RA metabolizing enzymes indicates sexually dimorphic RA levels. In testis, RA acts directly in Sertoli, Leydig and pre-meiotic germ cells. In ovaries, RA transcriptional activity is highest in meiotic oocytes. Our results show that RA plays an important role in meiosis induction and gametogenesis in adult medaka but contrary to common expectations, not for initiating the first meiosis in female germ cells at the SD stage.
Isolated generalized dystonia is a central motor network disorder characterized by twisted movements or postures. The most frequent genetic cause is a GAG deletion in the Tor1a (DYT1) gene encoding torsinA with a reduced penetrance of 30-40 % suggesting additional genetic or environmental modifiers. Development of dystonia-like movements after a standardized peripheral nerve crush lesion in wild type (wt) and Tor1a+/- mice, that express 50 % torsinA only, was assessed by scoring of hindlimb movements during tail suspension, by rotarod testing and by computer-assisted gait analysis. Western blot analysis was performed for dopamine transporter (DAT), D1 and D2 receptors from striatal and quantitative RT-PCR analysis for DAT from midbrain dissections. Autoradiography was used to assess the functional DAT binding in striatum. Striatal dopamine and its metabolites were analyzed by high performance liquid chromatography. After nerve crush injury, we found abnormal posturing in the lesioned hindlimb of both mutant and wt mice indicating the profound influence of the nerve lesion (15x vs. 12x relative to control) resembling human peripheral pseudodystonia. In mutant mice the phenotypic abnormalities were increased by about 40 % (p < 0.05). This was accompanied by complex alterations of striatal dopamine homeostasis. Pharmacological blockade of dopamine synthesis reduced severity of dystonia-like movements, whereas treatment with L-Dopa aggravated these but only in mutant mice suggesting a DYT1 related central component relevant to the development of abnormal involuntary movements. Our findings suggest that upon peripheral nerve injury reduced torsinA concentration and environmental stressors may act in concert in causing the central motor network dysfunction of DYT1 dystonia.
A framework for the optimal sparse-control of the probability density function of a jump-diffusion process is presented. This framework is based on the partial integro-differential Fokker-Planck (FP) equation that governs the time evolution of the probability density function of this process. In the stochastic process and, correspondingly, in the FP model the control function enters as a time-dependent coefficient. The objectives of the control are to minimize a discrete-in-time, resp. continuous-in-time, tracking functionals and its L2- and L1-costs, where the latter is considered to promote control sparsity. An efficient proximal scheme for solving these optimal control problems is considered. Results of numerical experiments are presented to validate the theoretical results and the computational effectiveness of the proposed control framework.
We report a giant thermal shift of 2.1 MHz/K related to the excited-state zero-field splitting in the silicon vacancy centers in 4H silicon carbide. It is obtained from the indirect observation of the optically detected magnetic resonance in the excited state using the ground state as an ancilla. Alternatively, relative variations of the zero-field splitting for small temperature differences can be detected without application of radiofrequency fields, by simply monitoring the photoluminescence intensity in the vicinity of the level anticrossing. This effect results in an all-optical thermometry technique with temperature sensitivity of 100 mK/Hz\(^{1/2}\) for a detection volume of approximately 10\(^{−6}\) mm\(^3\). In contrast, the zero-field splitting in the ground state does not reveal detectable temperature shift. Using these properties, an integrated magnetic field and temperature sensor can be implemented on the same center.
Background
Salvage radiotherapy (SRT) is clinically established in prostate cancer (PC) patients with PSA persistence or biochemical relapse (BCR) after prior radical surgery. PET/CT imaging prior to SRT may be performed to localize disease recurrence. The recently introduced \(^{68}\)Ga-PSMA outperforms other PET tracers for detection of recurrence and is therefore expected also to impact radiation planning.
Forty-five patients with PSA persistence (16 pts) or BCR (29 pts) after prior prostatectomy, scheduled to undergo SRT of the prostate bed, underwent \(^{68}\)Ga-PSMA PET/CT. The median PSA level was 0.67 ng/ml. The impact of \(^{68}\)Ga-PSMA PET/CT on the treatment decision was assessed. Patients with oligometastatic (≤5 lesions) PC underwent radiotherapy (RT), with the extent of the RT area and dose escalation being based on PET positivity.
Results
Suspicious lesions were detected in 24/45 (53.3 %) patients. In 62.5 % of patients, lesions were only detected by 68Ga-PSMA PET. Treatment was changed in 19/45 (42.2 %) patients, e.g., extending SRT to metastases (9/19), administering dose escalation in patients with morphological local recurrence (6/19), or replacing SRT by systemic therapy (2/19). 38/45 (84.4 %) followed the treatment recommendation, with data on clinical follow-up being available in 21 patients treated with SRT. All but one showed biochemical response (mean PSA decline 78 ± 19 %) within a mean follow-up of 8.12 ± 5.23 months.
Conclusions
\(^{68}\)Ga-PSMA PET/CT impacts treatment planning in more than 40 % of patients scheduled to undergo SRT. Future prospective studies are needed to confirm this significant therapeutic impact on patients prior to SRT.
Background
The Goutallier Classification is a semi quantitative classification system to determine the amount of fatty degeneration in rotator cuff muscles. Although initially proposed for axial computer tomography scans it is currently applied to magnet-resonance-imaging-scans. The role for its clinical use is controversial, as the reliability of the classification has been shown to be inconsistent. The purpose of this study was to compare the semi quantitative MRI-based Goutallier Classification applied by 5 different raters to experimental MR spectroscopic quantitative fat measurement in order to determine the correlation between this classification system and the true extent of fatty degeneration shown by spectroscopy.
Methods
MRI-scans of 42 patients with rotator cuff tears were examined by 5 shoulder surgeons and were graduated according to the MRI-based Goutallier Classification proposed by Fuchs et al. Additionally the fat/water ratio was measured with MR spectroscopy using the experimental SPLASH technique. The semi quantitative grading according to the Goutallier Classification was statistically correlated with the quantitative measured fat/water ratio using Spearman’s rank correlation.
Results
Statistical analysis of the data revealed only fair correlation of the Goutallier Classification system and the quantitative fat/water ratio with R = 0.35 (p < 0.05). By dichotomizing the scale the correlation was 0.72. The interobserver and intraobserver reliabilities were substantial with R = 0.62 and R = 0.74 (p < 0.01).
Conclusion
The correlation between the semi quantitative MRI based Goutallier Classification system and MR spectroscopic fat measurement is weak. As an adequate estimation of fatty degeneration based on standard MRI may not be possible, quantitative methods need to be considered in order to increase diagnostic safety and thus provide patients with ideal care in regard to the amount of fatty degeneration. Spectroscopic MR measurement may increase the accuracy of the Goutallier classification and thus improve the prediction of clinical results after rotator cuff repair. However, these techniques are currently only available in an experimental setting.
Background
The vascular type represents a very rare, yet the clinically most fatal entity of Ehlers-Danlos syndrome (EDS). Patients are often admitted due to arterial bleedings and the friable tissue and the altered coagulation contribute to the challenge in treatment strategies. Until now there is little information about clotting characteristics that might influence hemostasis decisively and eventually worsen emergency situations.
Results
22 vascular type EDS patients were studied for hemoglobin, platelet volume and count, Quick and activated partial thromboplastin time, fibrinogen, factor XIII, von Willebrand disease, vitamin D and platelet aggregation by modern standard laboratory methods. Results show a high prevalence of over 50 % for platelet aggregation disorders in vascular type EDS patients, especially for collagen and epinephrine induced tests, whereas the plasmatic cascade did not show any alterations. Additionally, more than half of the tested subjects showed low vitamin D serum levels, which might additionally affect vascular wall integrity.
Conclusion
The presented data underline the importance of detailed laboratory screening methods in vascular type EDS patients in order to allow for targeted application of platelet-interacting substances that might be of decisive benefit in the emergency setting.
Background
Multimodal treatment strategies – perioperative chemotherapy (CTx) and radical surgery – are currently accepted as treatment standard for locally advanced gastric cancer. However, the role of adjuvant postoperative CTx (postCTx) in addition to neoadjuvant preoperative CTx (preCTx) in this setting remains controversial.
Methods
Between 4/2006 and 12/2013, 116 patients with locally advanced gastric cancer were treated with preCTx. 72 patients (62 %), in whom complete tumor resection (R0, subtotal/total gastrectomy with D2-lymphadenectomy) was achieved, were divided into two groups, one of which receiving adjuvant therapy (n = 52) and one without (n = 20). These groups were analyzed with regard to survival and exclusion criteria for adjuvant therapy.
Results
Postoperative complications, as well as their severity grade, did not correlate with fewer postCTx cycles administered (p = n.s.). Long-term survival was shorter in patients receiving postCTx in comparison to patients without postCTx, but did not show statistical significance. In per protocol analysis by excluding two patients with perioperative death, a shorter 3-year survival rate was observed in patients receiving postCTx compared to patients without postCTx (3-year survival: 71.2 % postCTx group vs. 90.0 % non-postCTx group; p = 0.038).
Conclusion
These results appear contradicting to the anticipated outcome. While speculative, they question the value of post-CTx. Prospectively randomized studies are needed to elucidate the role of postCTx.
Out of the corner of the driver's eye: Peripheral processing of hazards in static traffic scenes
(2016)
Effective gaze control in traffic, based on peripheral visual information, is important to avoid hazards. Whereas previous hazard perception research mainly focused on skill-component development (e.g., orientation and hazard processing), little is known about the role and dynamics of peripheral vision in hazard perception. We analyzed eye movement data from a study in which participants scanned static traffic scenes including medium-level versus dangerous hazards and focused on characteristics of fixations prior to entering the hazard region. We found that initial saccade amplitudes into the hazard region were substantially longer for dangerous (vs. medium-level) hazards, irrespective of participants' driving expertise. An analysis of the temporal dynamics of this hazard-level dependent saccade targeting distance effect revealed that peripheral hazard-level processing occurred around 200–400 ms during the course of the fixation prior to entering the hazard region. An additional psychophysical hazard detection experiment, in which hazard eccentricity was manipulated, revealed better detection for dangerous (vs. medium-level) hazards in both central and peripheral vision. Furthermore, we observed a significant perceptual decline from center to periphery for medium (but not for highly) dangerous hazards. Overall, the results suggest that hazard processing is remarkably effective in peripheral vision and utilized to guide the eyes toward potential hazards.
Cropping Intensity in the Aral Sea Basin and Its Dependency from the Runoff Formation 2000–2012
(2016)
This study is aimed at a better understanding of how upstream runoff formation affected the cropping intensity (CI: number of harvests) in the Aral Sea Basin (ASB) between 2000 and 2012. MODIS 250 m NDVI time series and knowledge-based pixel masking that included settlement layers and topography features enabled to map the irrigated cropland extent (iCE). Random forest models supported the classification of cropland vegetation phenology (CVP: winter/summer crops, double cropping, etc.). CI and the percentage of fallow cropland (PF) were derived from CVP. Spearman’s rho was selected for assessing the statistical relation of CI and PF to runoff formation in the Amu Darya and Syr Darya catchments per hydrological year. Validation in 12 reference sites using multi-annual Landsat-7 ETM+ images revealed an average overall accuracy of 0.85 for the iCE maps. MODIS maps overestimated that based on Landsat by an average factor of ~1.15 (MODIS iCE/Landsat iCE). Exceptional overestimations occurred in case of inaccurate settlement layers. The CVP and CI maps achieved overall accuracies of 0.91 and 0.96, respectively. The Amu Darya catchment disclosed significant positive (negative) relations between upstream runoff with CI (PF) and a high pressure on the river water resources in 2000–2012. Along the Syr Darya, reduced dependencies could be observed, which is potentially linked to the high number of water constructions in that catchment. Intensified double cropping after drought years occurred in Uzbekistan. However, a 10 km × 10 km grid of Spearman’s rho (CI and PF vs. upstream runoff) emphasized locations at different CI levels that are directly affected by runoff fluctuations in both river systems. The resulting maps may thus be supportive on the way to achieve long-term sustainability of crop production and to simultaneously protect the severely threatened environment in the ASB. The gained knowledge can be further used for investigating climatic impacts of irrigation in the region.
B cell aggregates in the central nervous system (CNS) have been associated with rapid disease progression in patients with multiple sclerosis (MS). Here we demonstrate a key role of carcinoembryogenic antigen-related cell adhesion molecule1 (CEACAM1) in B cell aggregate formation in MS patients and a B cell-dependent mouse model of MS. CEACAM1 expression was increased on peripheral blood B cells and CEACAM1\(^+\) B cells were present in brain infiltrates of MS patients. Administration of the anti-CEACAM1 antibody T84.1 was efficient in blocking aggregation of B cells derived from MS patients. Along these lines, application of the monoclonal anti-CEACAM1 antibody mCC1 was able to inhibit CNS B cell aggregate formation and significantly attenuated established MS-like disease in mice in the absence of any adverse effects. CEACAM1 was co-expressed with the regulator molecule T cell immunoglobulin and mucin domain −3 (TIM-3) on B cells, a novel molecule that has recently been described to induce anergy in T cells. Interestingly, elevated coexpression on B cells coincided with an autoreactive T helper cell phenotype in MS patients. Overall, these data identify CEACAM1 as a clinically highly interesting target in MS pathogenesis and open new therapeutic avenues for the treatment of the disease.
We uncover the fine structure of a silicon vacancy in isotopically purified silicon carbide (4H-\(^{28}\)SiC) and reveal not yet considered terms in the spin Hamiltonian, originated from the trigonal pyramidal symmetry of this spin-3/2 color center. These terms give rise to additional spin transitions, which would be otherwise forbidden, and lead to a level anticrossing in an external magnetic field. We observe a sharp variation of the photoluminescence intensity in the vicinity of this level anticrossing, which can be used for a purely all-optical sensing of the magnetic field. We achieve dc magnetic field sensitivity better than 100 nT/√Hz within a volume of 3×10\(^{−7}\)mm\(^3\) at room temperature and demonstrate that this contactless method is robust at high temperatures up to at least 500 K. As our approach does not require application of radio-frequency fields, it is scalable to much larger volumes. For an optimized light-trapping waveguide of 3 mm\(^3\), the projection noise limit is below 100 fT/√Hz.
Evaluation of set up error detection by a transperineal ultrasound in comparison with a cone beam CT (CBCT) based system in external beam radiation therapy (EBRT) of prostate cancer.
Methods: Setup verification was performed with transperineal ultrasound (TPUS) and CBCT for 10 patients treated with EBRT for prostate cancer. In total, 150 ultrasound and CBCT scans were acquired in rapid succession and analyzed for setup errors. The deviation between setup errors of the two modalities was evaluated separately for each dimension.
Results: A moderate correlation in lateral, vertical and longitudinal direction was observed comparing the setup errors. Mean differences between TPUS and CBCT were (−2.7 ± 2.3) mm, (3.0 ± 2.4) mm and (3.2 ± 2.7) mm in lateral, vertical and longitudinal direction, respectively. The mean Euclidean difference between TPUS and CBCT was (6.0 ± 3.1) mm. Differences up to 19.2 mm were observed between the two imaging modalities. Discrepancies between TPUS and CBCT of at least 5 mm occurred in 58 % of monitored treatment sessions.
Conclusion: Setup differences between TPUS and CBCT are 6 mm on average. Although the correlation of the setup errors determined by the two different image modalities is rather week, the combination of setup verification by CBCT and intrafraction motion monitoring by TPUS imaging can use the benefits of both imaging modalities.
Calcification of the medial collateral ligament (MCL) of the knee is a very rare disease. We report on a case of a patient with a calcifying lesion within the MCL and simultaneous calcifying tendinitis of the rotator cuff in both shoulders. Case presentation: Calcification of the MCL was diagnosed both via x-ray and magnetic resonance imaging (MRI) and was successfully treated surgically. Calcifying tendinitis of the rotator cuff was successfully treated applying conservative methods. Conclusion: This is the first case report of a patient suffering from both a calcifying lesion within the medial collateral ligament and calcifying tendinitis of the rotator cuff in both shoulders. Clinical symptoms, radio-morphological characteristics and macroscopic features were very similar and therefore it can be postulated that the underlying pathophysiology is the same in both diseases. Our experience suggests that magnetic resonance imaging and x-ray are invaluable tools for the diagnosis of this inflammatory calcifying disease of the ligament, and that surgical repair provides a good outcome if conservative treatment fails. It seems that calcification of the MCL is more likely to require surgery than calcifying tendinitis of the rotator cuff. However, the exact reason for this remains unclear to date.
Background:
Attention deficit/hyperactivity disorder has been shown to affect working memory, and fMRI studies in children and adolescents with attention deficit/hyperactivity disorder report hypoactivation in task-related attentional networks. However, studies with adult attention deficit/hyperactivity disorder patients addressing this issue as well as the effects of clinically valid methylphenidate treatment are scarce. This study contributes to closing this gap.
Methods:
Thirty-five adult patients were randomized to 6 weeks of double-blind placebo or methylphenidate treatment. Patients completed an fMRI n-back working memory task both before and after the assigned treatment, and matched healthy controls were tested and compared to the untreated patients.
Results:
There were no whole-brain differences between any of the groups. However, when specified regions of interest were investigated, the patient group showed enhanced BOLD responses in dorsal and ventral areas before treatment. This increase was correlated with performance across all participants and with attention deficit/hyperactivity disorder symptoms in the patient group. Furthermore, we found an effect of treatment in the right superior frontal gyrus, with methylphenidate-treated patients exhibiting increased activation, which was absent in the placebo-treated patients.
Conclusions:
Our results indicate distinct activation differences between untreated adult attention deficit/hyperactivity disorder patients and matched healthy controls during a working memory task. These differences might reflect compensatory efforts by the patients, who are performing at the same level as the healthy controls. We furthermore found a positive effect of methylphenidate on the activation of a frontal region of interest. These observations contribute to a more thorough understanding of adult attention deficit/hyperactivity disorder and provide impulses for the evaluation of therapy-related changes.
Tyrosine kinase inhibitors (TKI) have shown clinical effectiveness in iodine-refractory differentiated thyroid cancer (DTC). The corresponding role of serum thyroglobulin (Tg) in iodine-refractory DTC has not been investigated yet. 9 patients (3 female, 61 ± 8y) with progressive iodine-refractory DTC starting on lenvatinib were considered. Tumor restaging was performed every 2–3 months including contrast-enhanced computed tomography (CT, RECIST 1.1). Serum Tg was measured and compared to imaging findings. After treatment initiation, serum Tg levels dropped in all patients with a median reduction of 86.2%. During long-term follow-up (median, 25.2 months), fluctuations in Tg could be observed in 8/9 subjects. According to RECIST, 6/9 subjects achieved a partial response or stable disease with the remaining 3/9 experiencing progressive disease (2/3 with Tg levels rising above baseline). All of the patients with disease progression presented with a preceding continuous rise in serum Tg, whereas tumor marker oscillations in the subjects with controlled disease were only intermittent. Initiation of lenvatinib in iodine-refractory DTC patients is associated with a significant reduction in serum Tg levels as a marker of treatment response. In the course of treatment, transient Tg oscillations are a frequent phenomenon that may not necessarily reflect morphologic tumor progression.
New antimycotic drugs are challenging to find, as potential target proteins may have close human orthologs. We here focus on identifying metabolic targets that are critical for fungal growth and have minimal similarity to targets among human proteins. We compare and combine here: (I) direct metabolic network modeling using elementary mode analysis and flux estimates approximations using expression data, (II) targeting metabolic genes by transcriptome analysis of condition-specific highly expressed enzymes, and (III) analysis of enzyme structure, enzyme interconnectedness (“hubs”), and identification of pathogen-specific enzymes using orthology relations. We have identified 64 targets including metabolic enzymes involved in vitamin synthesis, lipid, and amino acid biosynthesis including 18 targets validated from the literature, two validated and five currently examined in own genetic experiments, and 38 further promising novel target proteins which are non-orthologous to human proteins, involved in metabolism and are highly ranked drug targets from these pipelines.
The present study investigates how different emotions can alter social bargaining behavior. An important paradigm to study social bargaining is the Ultimatum Game. There, a proposer gets a pot of money and has to offer part of it to a responder. If the responder accepts, both players get the money as proposed by the proposer. If he rejects, none of the players gets anything. Rational choice models would predict that responders accept all offers above 0. However, evidence shows that responders typically reject a large proportion of all unfair offers. We analyzed participants’ behavior when they played the Ultimatum Game as responders and simultaneously collected electroencephalogram data in order to quantify the feedback-related negativity and P3b components. We induced state affect (momentarily emotions unrelated to the task) via short movie clips and measured trait affect (longer-lasting emotional dispositions) via questionnaires. State happiness led to increased acceptance rates of very unfair offers. Regarding neurophysiology, we found that unfair offers elicited larger feedback-related negativity amplitudes than fair offers. Additionally, an interaction of state and trait affect occurred: high trait negative affect (subsuming a variety of aversive mood states) led to increased feedback-related negativity amplitudes when participants were in an angry mood, but not if they currently experienced fear or happiness. We discuss that increased rumination might be responsible for this result, which might not occur, however, when people experience happiness or fear. Apart from that, we found that fair offers elicited larger P3b components than unfair offers, which might reflect increased pleasure in response to fair offers. Moreover, high trait negative affect was associated with decreased P3b amplitudes, potentially reflecting decreased motivation to engage in activities. We discuss implications of our results in the light of theories and research on depression and anxiety.
While deficient brain plasticity is a well-established pathophysiologic feature of depression, little is known about disorder-associated enhanced cognitive processing. Here, we studied a novel mouse paradigm that potentially models augmented learning of adverse memories during development of a depressive-like state. We used a modification of the classic two-day protocol of a mouse Porsolt test with an additional session occurring on Day 5 following the initial exposure. Unexpectedly, floating behaviour and brain glycogen synthase kinase-3 beta (GSK-3beta) mRNA levels, a factor of synaptic plasticity as well as a marker of distress and depression, were increased during the additional swimming session that was prevented by imipramine. Observed increases of GSK-3beta mRNA in prefrontal cortex during delayed testing session correlated with individual parameters of behavioural despair that was not found in the classic Porsolt test. Repeated swim exposure was accompanied by a lower pGSK-3beta/GSK-3beta ratio. A replacement of the second or the final swim sessions with exposure to the context of testing resulted in increased GSK-3beta mRNA level similar to the effects of swimming, while exclusion of the second testing prevented these changes. Together, our findings implicate the activation of brain GSK-3beta expression in enhanced contextual conditioning of adverse memories, which is associated with an individual susceptibility to a depressive syndrome.
The drug-minded protein interaction database (DrumPID) has been designed to provide fast, tailored information on drugs and their protein networks including indications, protein targets and side-targets. Starting queries include compound, target and protein interactions and organism-specific protein families. Furthermore, drug name, chemical structures and their SMILES notation, affected proteins (potential drug targets), organisms as well as diseases can be queried including various combinations and refinement of searches. Drugs and protein interactions are analyzed in detail with reference to protein structures and catalytic domains, related compound structures as well as potential targets in other organisms. DrumPID considers drug functionality, compound similarity, target structure, interactome analysis and organismic range for a compound, useful for drug development, predicting drug side-effects and structure–activity relationships.
Age‐dependent transcriptional and epigenomic responses to light exposure in the honey bee brain
(2016)
Light is a powerful environmental stimulus of special importance in social honey bees that undergo a behavioral transition from in-hive to outdoor foraging duties. Our previous work has shown that light exposure induces structural neuronal plasticity in the mushroom bodies (MBs), a brain center implicated in processing inputs from sensory modalities. Here, we extended these analyses to the molecular level to unravel light-induced transcriptomic and epigenomic changes in the honey bee brain. We have compared gene expression in brain compartments of 1- and 7-day-old light-exposed honey bees with age-matched dark-kept individuals. We have found a number of differentially expressed genes (DEGs), both novel and conserved, including several genes with reported roles in neuronal plasticity. Most of the DEGs show age-related changes in the amplitude of light-induced expression and are likely to be both developmentally and environmentally regulated. Some of the DEGs are either known to be methylated or are implicated in epigenetic processes suggesting that responses to light exposure are at least partly regulated at the epigenome level. Consistent with this idea light alters the DNA methylation pattern of bgm, one of the DEGs affected by light exposure, and the expression of microRNA miR-932. This confirms the usefulness of our approach to identify candidate genes for neuronal plasticity and provides evidence for the role of epigenetic processes in driving the molecular responses to visual stimulation.
Whole Genome Duplications Shaped the Receptor Tyrosine Kinase Repertoire of Jawed Vertebrates
(2016)
The receptor tyrosine kinase (RTK) gene family, involved primarily in cell growth and differentiation, comprises proteins with a common enzymatic tyrosine kinase intracellular domain adjacent to a transmembrane region. The amino-terminal portion of RTKs is extracellular and made of different domains, the combination of which characterizes each of the 20 RTK subfamilies among mammals. We analyzed a total of 7,376 RTK sequences among 143 vertebrate species to provide here the first comprehensive census of the jawed vertebrate repertoire. We ascertained the 58 genes previously described in the human and mouse genomes and established their phylogenetic relationships. We also identified five additional RTKs amounting to a total of 63 genes in jawed vertebrates. We found that the vertebrate RTK gene family has been shaped by the two successive rounds of whole genome duplications (WGD) called 1R and 2R (1R/2R) that occurred at the base of the vertebrates. In addition, the Vegfr and Ephrin receptor subfamilies were expanded by single gene duplications. In teleost fish, 23 additional RTK genes have been retained after another expansion through the fish-specific third round (3R) of WGD. Several lineage-specific gene losses were observed. For instance, birds have lost three RTKs, and different genes are missing in several fish sublineages. The RTK gene family presents an unusual high gene retention rate from the vertebrate WGDs (58.75% after 1R/2R, 64.4% after 3R), resulting in an expansion that might be correlated with the evolution of complexity of vertebrate cellular communication and intracellular signaling.
Role of PTEN in Oxidative Stress and DNA Damage in the Liver of Whole-Body Pten Haplodeficient Mice
(2016)
Type 2 diabetes (T2DM) and obesity are frequently associated with non-alcoholic fatty liver disease (NAFLD) and with an elevated cancer incidence. The molecular mechanisms of carcinogenesis in this context are only partially understood. High blood insulin levels are typical in early T2DM and excessive insulin can cause elevated reactive oxygen species (ROS) production and genomic instability. ROS are important for various cellular functions in signaling and host defense. However, elevated ROS formation is thought to be involved in cancer induction. In the molecular events from insulin receptor binding to genomic damage, some signaling steps have been identified, pointing at the PI3K/AKT pathway. For further elucidation Phosphatase and Tensin homolog (Pten), a tumour suppressor phosphatase that plays a role in insulin signaling by negative regulation of PI3K/AKT and its downstream targets, was investigated here. Dihydroethidium (DHE) staining was used to detect ROS formation in immortalized human hepatocytes. Comet assay and micronucleus test were performed to investigate genomic damage in vitro. In liver samples, DHE staining and western blot detection of HSP70 and HO-1 were performed to evaluate oxidative stress response. DNA double strand breaks (DSBs) were detected by immunohistostaining. Inhibition of PTEN with the pharmacologic inhibitor VO-OHpic resulted in increased ROS production and genomic damage in a liver cell line. Knockdown of Pten in a mouse model yielded increased oxidative stress levels, detected by ROS levels and expression of the two stress-proteins HSP70 and HO-1 and elevated genomic damage in the liver, which was significant in mice fed with a high fat diet. We conclude that PTEN is involved in oxidative stress and genomic damage induction in vitro and that this may also explain the in vivo observations. This further supports the hypothesis that the PI3K/AKT pathway is responsible for damaging effects of high levels of insulin.
The KISS1 Receptor as an In Vivo Microenvironment Imaging Biomarker of Multiple Myeloma Bone Disease
(2016)
Multiple myeloma is one of the most common hematological diseases and is characterized by an aberrant proliferation of plasma cells within the bone marrow. As a result of crosstalk between cancer cells and the bone microenvironment, bone homeostasis is disrupted leading to osteolytic lesions and poor prognosis. Current diagnostic strategies for myeloma typically rely on detection of excess monoclonal immunoglobulins or light chains in the urine or serum. However, these strategies fail to localize the sites of malignancies. In this study we sought to identify novel biomarkers of myeloma bone disease which could target the malignant cells and/or the surrounding cells of the tumor microenvironment. From these studies, the KISS1 receptor (KISS1R), a G-protein-coupled receptor known to play a role in the regulation of endocrine functions, was identified as a target gene that was upregulated on mesenchymal stem cells (MSCs) and osteoprogenitor cells (OPCs) when co-cultured with myeloma cells. To determine the potential of this receptor as a biomarker, in vitro and in vivo studies were performed with the KISS1R ligand, kisspeptin, conjugated with a fluorescent dye. In vitro microscopy showed binding of fluorescently-labeled kisspeptin to both myeloma cells as well as MSCs under direct co-culture conditions. Next, conjugated kisspeptin was injected into immune-competent mice containing myeloma bone lesions. Tumor-burdened limbs showed increased peak fluorescence compared to contralateral controls. These data suggest the utility of the KISS1R as a novel biomarker for multiple myeloma, capable of targeting both tumor cells and host cells of the tumor microenvironment.
Fabry disease is an X-linked lysosomal storage disorder due to impaired activity of alpha-galactosidase A with intracellular accumulation of globotriaosylceramide. Associated small fiber pathology leads to characteristic pain in Fabry disease. We systematically assessed sensory system, physical activity, metabolic parameters, and morphology of male and female mice with alpha-galactosidase A deficiency (Fabry ko) from 2 to 27 months of age and compared results with those of age- and gender-matched wild-type littermates of C57Bl/6J background. Results From the age of two months, male and female Fabry mice showed mechanical hypersensitivity (p < 0.001 each) compared to wild-type littermates. Young Fabry ko mice of both genders were hypersensitive to heat stimulation (p < 0.01) and developed heat hyposensitivity with aging (p < 0.05), while cold hyposensitivity was present constantly in young (p < 0.01) and old (p < 0.05) Fabry ko mice compared to wild-type littermates. Stride angle increased only in male Fabry ko mice with aging (p < 0.01) in comparison to wild-type littermates. Except for young female mice, male (p < 0.05) and female (p < 0.01) Fabry ko mice had a higher body weight than wild-type littermates. Old male Fabry ko mice were physically less active than their wild-type littermates (p < 0.05), had lower chow intake (p < 0.001), and lost more weight (p < 0.001) in a one-week treadmill experiment than wild-type littermates. Also, Fabry ko mice showed spontaneous pain protective behavior and developed orofacial dysmorphism resembling patients with Fabry disease.
Conclusions. Mice with alpha-galactosidase A deficiency show age-dependent and distinct deficits of the sensory system. alpha-galactosidase A-deficient mice seem to model human Fabry disease and may be helpful when studying the pathophysiology of Fabry-associated pain.
Analysis of Triplet Exciton Loss Pathways in PTB7:PC\(_{71}\)BM Bulk Heterojunction Solar Cells
(2016)
A strategy for increasing the conversion efficiency of organic photovoltaics has been to increase the VOC by tuning the energy levels of donor and acceptor components. However, this opens up a new loss pathway from an interfacial charge transfer state to a triplet exciton (TE) state called electron back transfer (EBT), which is detrimental to device performance. To test this hypothesis, we study triplet formation in the high performing PTB7:PC\(_{71}\)BM blend system and determine the impact of the morphology-optimizing additive 1,8-diiodoctane (DIO). Using photoluminescence and spin-sensitive optically detected magnetic resonance (ODMR) measurements at low temperature, we find that TEs form on PC\(_{71}\)BM via intersystem crossing from singlet excitons and on PTB7 via EBT mechanism. For DIO blends with smaller fullerene domains, an increased density of PTB7 TEs is observed. The EBT process is found to be significant only at very low temperature. At 300 K, no triplets are detected via ODMR, and electrically detected magnetic resonance on optimized solar cells indicates that TEs are only present on the fullerenes. We conclude that in PTB7:PC\(_{71}\)BM devices, TE formation via EBT is impacted by fullerene domain size at low temperature, but at room temperature, EBT does not represent a dominant loss pathway.
Theta oscillations in the EEG have been shown to reflect ongoing cognitive processes related to mental effort. Here, we show that the pattern of theta oscillation in response to varying cognitive demands reflects stable individual differences in the personality trait epistemic motivation: Individuals with high levels of epistemic motivation recruit relatively more cognitive resources in response to situations possessing high, compared to low, cognitive demand; individuals with low levels do not show such a specific response. Our results provide direct evidence for the theory of the construct need for cognition and add to our understanding of the neural processes underlying theta oscillations. More generally, we provide an explanation how individual differences in personality traits might be represented on a neural level.
There is a largely divergent body of literature regarding the relationship between Epstein-Barr virus (EBV) infection and brain inflammation in multiple sclerosis (MS). Here, we tested MS patients during relapse (n = 11) and in remission (n = 19) in addition to n = 22 healthy controls to study the correlation between the EBV- and brain-specific B cell response in the blood by enzyme-linked immunospot (ELISPOT) and enzyme-linked immunosorbent assay (ELISA). Cytomegalovirus (CMV) was used as a control antigen tested in n = 16 MS patients during relapse and in n = 35 patients in remission. Over the course of the study, n = 16 patients were untreated, while n = 33 patients received immunomodulatory therapy. The data show that there was a moderate correlation between the frequencies of EBV- and brain-reactive B cells in MS patients in remission. In addition we could detect a correlation between the B cell response to EBV and disease activity. There was no evidence of an EBV reactivation. Interestingly, there was also a correlation between the frequencies of CMV- and brain-specific B cells in MS patients experiencing an acute relapse and an elevated B cell response to CMV was associated with higher disease activity. The trend remained when excluding seronegative subjects but was non-significant. These data underline that viral infections might impact the immunopathology of MS, but the exact link between the two entities remains subject of controversy.
Background. Medical rehabilitation increasingly considers occupational issues as determinants of health and work ability. Information on work-related rehabilitation concepts should therefore be made available to healthcare professionals. Objective. To revise a website providing healthcare professionals in medical rehabilitation facilities with information on work-related concepts in terms of updating existing information and including new topics, based on recommendations from implementation research.
Method. The modification process included a questionnaire survey of medical rehabilitation centers (n=28); two workshops with experts from rehabilitation centers, health payers, and research institutions (n=14); the selection of new topics and revision of existing text modules based on expert consensus; and an update of good practice descriptions of work-related measures.
Results. Health payers’ requirements, workplace descriptions, and practical implementation aids were added as new topics. The database of good practice examples was extended to 63 descriptions. Information on introductory concepts was rewritten and supplemented by current data. Diagnostic tools were updated by including additional assessments.
Conclusions. Recommendations from implementation research such as assessing user needs and including expert knowledge may serve as a useful starting point for the dissemination of information on work-related medical rehabilitation into practice. Web-based information tools such as the website presented here can be quickly adapted to current evidence and changes in medicolegal regulations.
Background
\(^{177}\)Lu is used in peptide receptor radionuclide therapies for the treatment of neuroendocrine tumors. Based on the recent literature, SST2 antagonists are superior to agonists in tumor uptake. The compound OPS201 is the novel somatostatin antagonist showing the highest SST2 affinity. The aim of this study was to measure the in vivo biodistribution and dosimetry of \(^{177}\)Lu-OPS201 in five anesthetized Danish Landrace pigs as an appropriate substitute for humans to quantitatively assess the absorbed doses for future clinical applications.
Results
\(^{177}\)Lu-OPS201 was obtained with a specific activity ranging from 10 to 17 MBq/μg. Prior to administration, the radiochemical purity was measured as s > 99.7 % in all cases. After injection, fast clearance of the compound from the blood stream was observed. Less than 5 % of the injected activity was presented in blood 10 min after injection. A series of SPECT/CT and whole-body scans conducted until 10 days after intravenous injection showed uptake mostly in the liver, spine, and kidneys. There was no visible uptake in the spleen. Blood samples were taken to determine the time-activity curve in the blood. Time-activity curves and time-integrated activity coefficients were calculated for the organs showing visible uptake. Based on these data, the absorbed organ dose coefficients for a 70-kg patient were calculated with OLINDA/EXM. For humans after an injection of 5 GBq \(^{177}\)Lu-OPS201, the highest predicted absorbed doses are obtained for the kidneys (13.7 Gy), the osteogenic cells (3.9 Gy), the urinary bladder wall (1.8 Gy), and the liver (1.0 Gy). No metabolites of 177Lu-OPS201 were found by radio HPLC analysis. None of the absorbed doses calculated will exceed organ toxicity levels.
Conclusions
The \(^{177}\)Lu-OPS201 was well tolerated and caused no abnormal physiological or behavioral signs. In vivo distributions and absorbed doses of pigs are comparable to those observed in other publications. According to the biodistribution data in pigs, presented in this work, the expected radiation exposure in humans will be within the acceptable range.
Background
Mandibular pseudocarcinomatous hyperplasia is a rare and generally benign pathology. We report on one of these rare cases.
Case presentation
The case history of a 73-year-old white man stated that he had a carcinoma of the oropharynx, which was primarily treated with radiotherapy and chemotherapy 4 years prior. As a result of radiotherapy he developed an osteoradionecrosis of his mandible and a consecutive pathological fracture of his left mandibular angle. Subsequent osteosynthesis was performed with a reconstruction plate. When we first saw him, his reconstruction plate was partially exposed with intraoral and extraoral fistulation. The resected bone of his defect-bordering jaw showed the typical pathohistological findings of an intraosseous mandibular pseudocarcinomatous hyperplasia. After a first reconstruction attempt with an iliac crest graft failed, definitive reconstruction of his mandible with a microvascular anastomosed fibula graft was achieved.
Conclusions
Intraosseous pseudocarcinomatous hyperplasia of the mandible is a rare differential diagnosis in maxillofacial surgery. Besides other benign epithelial neoplasms, such as calcifying epithelial odontogenic tumor, squamous odontogenic tumor, or different forms of ameloblastoma, the far more frequent invasive squamous cell carcinoma needs to be excluded. A misinterpretation of pseudocarcinomatous hyperplasia as squamous cell carcinoma must be avoided because it can lead to a massive overtreatment.
13-Lipoxygenase-derived oxylipins, such as jasmonates act as potent signaling molecules in plants. Although experimental evidence supports the impact of oxylipins generated by the 9-Lipoxygenase (9-LOX) pathway in root development and pathogen defense, their signaling function in plants remains largely elusive. Based on the root growth inhibiting properties of the 9-LOX-oxylipin 9-HOT (9-hydroxy-10,12,15-octadecatrienoic acid), we established a screening approach aiming at identifying transcription factors (TFs) involved in signaling and/or metabolism of this oxylipin. Making use of the AtTORF-Ex (Arabidopsis thaliana Transcription Factor Open Reading Frame Expression) collection of plant lines overexpressing TF genes, we screened for those TFs which restore root growth on 9-HOT. Out of 6,000 lines, eight TFs were recovered at least three times and were therefore selected for detailed analysis. Overexpression of the basic leucine Zipper (bZIP) TF TGA5 and its target, the monoxygenase CYP81D11 reduced the effect of added 9-HOT, presumably due to activation of a detoxification pathway. The highly related ETHYLENE RESPONSE FACTORs ERF106 and ERF107 induce a broad detoxification response towards 9-LOX-oxylipins and xenobiotic compounds. From a set of 18 related group S-bZIP factors isolated in the screen, bZIP11 is known to participate in auxin-mediated root growth and may connect oxylipins to root meristem function. The TF candidates isolated in this screen provide starting points for further attempts to dissect putative signaling pathways involving 9-LOX-derived oxylipins.
Social insects control brood development by using different thermoregulatory strategies. Camponotus mus ants expose their brood to daily temperature fluctuations by translocating them inside the nest following a circadian rhythm of thermal preferences. At the middle of the photophase brood is moved to locations at 30.8°C; 8 h later, during the night, the brood is transferred back to locations at 27.5°C. We investigated whether daily thermal fluctuations experienced by developing pupae affect the neuroarchitecture in the adult brain, in particular in sensory input regions of the mushroom bodies (MB calyces). The complexity of synaptic microcircuits was estimated by quantifying MB-calyx volumes together with densities of presynaptic boutons of microglomeruli (MG) in the olfactory lip and visual collar regions. We compared young adult workers that were reared either under controlled daily thermal fluctuations of different amplitudes, or at different constant temperatures. Thermal regimes significantly affected the large (non-dense) olfactory lip region of the adult MB calyx, while changes in the dense lip and the visual collar were less evident. Thermal fluctuations mimicking the amplitudes of natural temperature fluctuations via circadian rhythmic translocation of pupae by nurses (amplitude 3.3°C) lead to higher numbers of MG in the MB calyces compared to those in pupae reared at smaller or larger thermal amplitudes (0.0, 1.5, 9.6°C), or at constant temperatures (25.4, 35.0°C). We conclude that rhythmic control of brood temperature by nursing ants optimizes brain development by increasing MG densities and numbers in specific brain areas. Resulting differences in synaptic microcircuits are expected to affect sensory processing and learning abilities in adult ants, and may also promote interindividual behavioral variability within colonies.
An innovative framework has been developed for teamwork of two quadcopter formations, each having its specified formation geometry, assigned task, and matching control scheme. Position control for quadcopters in one of the formations has been implemented through a Linear Quadratic Regulator Proportional Integral (LQR PI) control scheme based on explicit model following scheme. Quadcopters in the other formation are controlled through LQR PI servomechanism control scheme. These two control schemes are compared in terms of their performance and control effort. Both formations are commanded by respective ground stations through virtual leaders. Quadcopters in formations are able to track desired trajectories as well as hovering at desired points for selected time duration. In case of communication loss between ground station and any of the quadcopters, the neighboring quadcopter provides the command data, received from the ground station, to the affected unit. Proposed control schemes have been validated through extensive simulations using MATLAB®/Simulink® that provided favorable results.
Background
Fabry disease is characterized by a progressive deposition of sphingolipids in different organ systems, whereby cardiac involvement leads to death. We hypothesize that lysosomal storage of sphingolipids in the heart as occurring in Fabry disease does not reflect in higher cardiac lipid concentrations detectable by \(^1\)H magnetic resonance spectroscopy (MRS) at 3 Tesla.
Methods
Myocardial lipid content was quantified in vivo by \(^1\)H-MRS in 30 patients (12 male, 18 female; 18 patients treated with enzyme replacement therapy) with genetically proven Fabry disease and in 30 healthy controls. The study protocol combined \(^1\)H-MRS with cardiac cine imaging and LGE MRI in a single examination.
Results
Myocardial lipid content was not significantly elevated in Fabry disease (p = 0.225). Left ventricular (LV) mass was significantly higher in patients suffering from Fabry disease compared to controls (p = 0.019). Comparison of patients without signs of myocardial fibrosis in MRI (LGE negative; n = 12) to patients with signs of fibrosis (LGE positive; n = 18) revealed similar myocardial lipid content in both groups (p > 0.05), while the latter showed a trend towards elevated LV mass (p = 0.076).
Conclusions
This study demonstrates the potential of lipid metabolic investigation embedded in a comprehensive examination of cardiac morphology and function in Fabry disease. There was no evidence that lysosomal storage of sphingolipids influences cardiac lipid content as measured by \(^1\)H-MRS. Finally, the authors share the opinion that a comprehensive cardiac examination including three subsections (LGE; \(^1\)H-MRS; T\(_1\) mapping), could hold the highest potential for the final assessment of early and late myocardial changes in Fabry disease.
Background
The aim of this study was to quantify the variability in spinal radiosurgery (SRS) planning practices between five international institutions, all member of the Elekta Spine Radiosurgery Research Consortium.
Methods
Four institutions provided one representative patient case each consisting of the medical history, CT and MR imaging. A step-wise planning approach was used where, after each planning step a consensus was generated that formed the basis for the next planning step. This allowed independent analysis of all planning steps of CT-MR image registration, GTV definition, CTV definition, PTV definition and SRS treatment planning. In addition, each institution generated one additional SRS plan for each case based on intra-institutional image registration and contouring, independent of consensus results.
Results
Averaged over the four cases, image registration variability ranged between translational 1.1 mm and 2.4 mm and rotational 1.1° and 2.0° in all three directions. GTV delineation variability was 1.5 mm in axial and 1.6 mm in longitudinal direction averaged for the four cases. CTV delineation variability was 0.8 mm in axial and 1.2 mm in longitudinal direction. CTV-to-PTV margins ranged between 0 mm and 2 mm according to institutional protocol. Delineation variability was 1 mm in axial directions for the spinal cord. Average PTV coverage for a single fraction18 Gy prescription was 87 ± 5 %; Dmin to the PTV was 7.5 ± 1.8 Gy averaged over all cases and institutions. Average Dmax to the PRV_SC (spinal cord + 1 mm) was 10.5 ± 1.6 Gy and the average Paddick conformity index was 0.69 ± 0.06.
Conclusions
Results of this study reflect the variability in current practice of spine radiosurgery in large and highly experienced academic centers. Despite close methodical agreement in the daily workflow, clinically significant variability in all steps of the treatment planning process was demonstrated. This may translate into differences in patient clinical outcome and highlights the need for consensus and established delineation and planning criteria.
High-resolution ultrasonography (HRUS) is an emerging new tool in the investigation of peripheral nerves. We set out to assess the utility of HRUS performed at lower extremity nerves in peripheral neuropathies. Nerves of 26 patients with polyneuropathies of different etiologies and 26 controls were investigated using HRUS. Patients underwent clinical, laboratory, electrophysiological assessment, and a diagnostic sural nerve biopsy as part of the routine work-up. HRUS was performed at the sural, tibial, and the common, superficial, and deep peroneal nerves. The superficial peroneal nerve longitudinal diameter (LD) distinguished best between the groups: patients with immune-mediated neuropathies (n = 13, including six with histology-proven vasculitic neuropathy) had larger LD compared to patients with non-immune-mediated neuropathies (p < 0.05) and to controls (p < 0.001). Among all subgroups, patients with vasculitic neuropathy showed the largest superficial peroneal nerve LD (p < 0.001) and had a larger sural nerve cross-sectional area when compared with disease controls (p < 0.001). Enlargement of the superficial peroneal and sural nerves as detected by HRUS may be a useful additional finding in the differential diagnosis of vasculitic and other immune-mediated neuropathies.
This study analyzed the spatiotemporal pattern of settlement expansion in Abuja, Nigeria, one of West Africa’s fastest developing cities, using geoinformation and ancillary datasets. Three epochs of Land-use Land-cover (LULC) maps for 1986, 2001 and 2014 were derived from Landsat images using support vector machines (SVM). Accuracy assessment (AA) of the LULC maps based on the pixel count resulted in overall accuracy of 82%, 92% and 92%, while the AA derived from the error adjusted area (EAA) method stood at 69%, 91% and 91% for 1986, 2001 and 2014, respectively. Two major techniques for detecting changes in the LULC epochs involved the use of binary maps as well as a post-classification comparison approach. Quantitative spatiotemporal analysis was conducted to detect LULC changes with specific focus on the settlement development pattern of Abuja, the federal capital city (FCC) of Nigeria. Logical transitions to the urban category were modelled for predicting future scenarios for the year 2050 using the embedded land change modeler (LCM) in the IDRISI package. Based on the EAA, the result showed that urban areas increased by more than 11% between 1986 and 2001. In contrast, this value rose to 17% between 2001 and 2014. The LCM model projected LULC changes that showed a growing trend in settlement expansion, which might take over allotted spaces for green areas and agricultural land if stringent development policies and enforcement measures are not implemented. In conclusion, integrating geospatial technologies with ancillary datasets offered improved understanding of how urbanization processes such as increased imperviousness of such a magnitude could influence the urban microclimate through the alteration of natural land surface temperature. Urban expansion could also lead to increased surface runoff as well as changes in drainage geography leading to urban floods.
Background
Ovarian cancer (OvCA) tissues show abundant expression of the ectonucleotidases CD39 and CD73 which generate immunomodulatory adenosine, thereby inhibiting cytotoxic lymphocytes. Little, however, is known about the effect of adenosine on myeloid cells. Considering that tumor associated macrophages (TAM) and myeloid-derived suppressor cells (MDSC) constitute up to 20 % of OvCA tissue, we investigated the effect of adenosine on myeloid cells and explored a possible contribution of myeloid cells to adenosine generation in vitro and ex vivo.
Methods
Monocytes were used as human blood-derived myeloid cells. After co-incubation with SK-OV-3 or OAW-42 OvCA cells, monocyte migration was determined in transwell assays. For conversion into M2-polarized “TAM-like” macrophages, monocytes were co-incubated with OAW-42 cells. Ex vivo TAMs were obtained from OvCA ascites. Macrophage phenotypes were investigated by intracellular staining for IL-10 and IL-12. CD39 and CD73 expression were assessed by FACS analysis both on in vitro-induced TAM-like macrophages and on ascites-derived ex situ-TAMs. Myeloid cells in solid tumor tissue were analyzed by immunohistochemistry. Generation of biologically active adenosine by TAM-like macrophages was measured in luciferase-based reporter assays. Functional effects of adenosine were investigated in proliferation-experiments with CD4+ T cells and specific inhibitors.
Results
When CD39 or CD73 activity on OvCA cells were blocked, the migration of monocytes towards OvCA cells was significantly decreased. In vivo, myeloid cells in solid ovarian cancer tissue were found to express CD39 whereas CD73 was mainly detected on stromal fibroblasts. Ex situ-TAMs and in vitro differentiated TAM-like cells, however, upregulated the expression of CD39 and CD73 compared to monocytes or M1 macrophages. Expression of ectonucleotidases also translated into increased levels of biologically active adenosine. Accordingly, co-incubation with these TAMs suppressed CD4+ T cell proliferation which could be rescued via blockade of CD39 or CD73.
Conclusion
Adenosine generated by OvCA cells likely contributes to the recruitment of TAMs which further amplify adenosine-dependent immunosuppression via additional ectonucleotidase activity. In solid ovarian cancer tissue, TAMs express CD39 while CD73 is found on stromal fibroblasts. Accordingly, small molecule inhibitors of CD39 or CD73 could improve immune responses in ovarian cancer.
Background
X-chromosomal inheritance patterns and generally rare occurrence of Fabry disease (FD) account for mono-mutational hemizygous male and heterozygous female patients. Female mutation carriers are usually clinically much less severely affected, which has been explained by a suggested mosaicism in cell phenotype due to random allele shutdown. However, clinical evidence is scarce and potential additional effects in female gene carriers, which might account for specific clinical characteristics such as less severe chronic kidney disease, are yet unknown.
Case presentation
This article reports on a 45 year old female patient carrying the two alpha-galactosidase A gene mutations c.416A > G, p.N139S in exon 3 and c.708G > C, p.W236C in exon 5, but still showing only mild organ manifestations.
Conclusion
This current case highlights the importance of careful clinical characterization in patients with Fabry disease, who may show additional rare constellations and, therefore, are in need of personalized medicine. The impact of potential additional protective effects exceeding the presence of a non-pathogenic GLA allele in female gene carriers requires further investigation.
Background
Traumatic brain injury (TBI) is a major cause of death and disability. Neuroinflammation contributes to acute damage after TBI and modulates long-term evolution of degenerative and regenerative responses to injury. The aim of the present study was to evaluate the relationship of microglia activation to trauma severity, brain energy metabolism, and cellular reactions to injury in a mouse closed head injury model using combined in vivo PET imaging, ex vivo autoradiography, and immunohistochemistry.
Methods
A weight-drop closed head injury model was used to produce a mixed diffuse and focal TBI or a purely diffuse mild TBI (mTBI) in C57BL6 mice. Lesion severity was determined by evaluating histological damage and functional outcome using a standardized neuroscore (NSS), gliosis, and axonal injury by immunohistochemistry. Repeated intra-individual in vivo μPET imaging with the specific 18-kDa translocator protein (TSPO) radioligand [\(^{18}\)F]DPA-714 was performed on day 1, 7, and 16 and [\(^{18}\)F]FDG-μPET imaging for energy metabolism on days 2–5 after trauma using freshly synthesized radiotracers. Immediately after [\(^{18}\)F]DPA-714-μPET imaging on days 7 and 16, cellular identity of the [\(^{18}\)F]DPA-714 uptake was confirmed by exposing freshly cut cryosections to film autoradiography and successive immunostaining with antibodies against the microglia/macrophage marker IBA-1.
Results
Functional outcome correlated with focal brain lesions, gliosis, and axonal injury. [\(^{18}\)F]DPA-714-μPET showed increased radiotracer uptake in focal brain lesions on days 7 and 16 after TBI and correlated with reduced cerebral [\(^{18}\)F]FDG uptake on days 2–5, with functional outcome and number of IBA-1 positive cells on day 7. In autoradiography, [\(^{18}\)F]DPA-714 uptake co-localized with areas of IBA1-positive staining and correlated strongly with both NSS and the number of IBA1-positive cells, gliosis, and axonal injury. After mTBI, numbers of IBA-1 positive cells with microglial morphology increased in both brain hemispheres; however, uptake of [\(^{18}\)F]DPA-714 was not increased in autoradiography or in μPET imaging.
Conclusions
[\(^{18}\)F]DPA-714 uptake in μPET/autoradiography correlates with trauma severity, brain metabolic deficits, and microglia activation after closed head TBI.
From October 30–November 1, 2015, the 7th NEUROWIND e.V. meeting was held in Motzen, Brandenburg, Germany. Seventy doctoral students and postdocs from over 25 different groups working in German and Swiss University Hospitals or Research Institutes attended the meeting to discuss their latest experiments and findings in the fields of neuroimmunology, neurodegeneration and neurovascular research. This meeting report summarizes the many diverse presentations and the new preclinical to clinical neurology research data that were shared by the participants at the meeting.
Background
Precise and complete documentation of in-hospital cardiopulmonary resuscitations is important but data quality can be poor. In the present study, we investigated the effect of a tablet-based application for real-time resuscitation documentation used by the emergency team leader on documentation quality and clinical performance of the emergency team.
Methods
Senior anaesthesiologists either used the tablet-based application during the simulated resuscitation for documentation and also used the application for the final documentation or conducted the full documentation at the end of the scenario using the local hospital information system. The latter procedure represents the current local documentation method. All scenarios were video recorded. To assess the documentation, we compared the precision of intervention delivery times, documentation completeness, and final documentation time. To assess clinical performance, we compared adherence to guidelines for defibrillation and adrenaline administration, the no-flow fraction, and the time to first defibrillation.
Results
The results showed significant benefits for the tablet-based application compared to the hospital information system for precision of the intervention delivery times, the final documentation time, and the no-flow fraction. We observed no differences between the groups for documentation completeness, adherence to guidelines for defibrillation and adrenaline administration, and the time to first defibrillation.
Discussion
In the presented study, we observed that a tablet-based application can improve documentation data quality. Furthermore, we demonstrated that a well-designed application can be used in real-time by a member of the emergency team with possible beneficial effects on clinical performance.
Conclusion
The present evaluation confirms the advantage of tablet-based documentation tools and also shows that the application can be used by an active member of an emergency team without compromising clinical performance.
To protect the health of human and environment, the European Union implemented the REACH regulation for chemical substances. REACH is an acronym for Registration, Evaluation, Authorization, and Restriction of Chemicals. Under REACH, the authorities have the task of assessing chemical substances, especially those that might pose a risk to human health or environment. The work under REACH is scientifically, technically and procedurally a complex and knowledge-intensive task that is jointly performed by the European Chemicals Agency and member state authorities in Europe. The assessment of substances under REACH conducted in the German Environment Agency is supported by the knowledge-based system KnowSEC, which is used for the screening, documentation, and decision support when working on chemical substances. The software KnowSEC integrates advanced semantic technologies and strong problem solving methods. It allows for the collaborative work on substances in the context of the European REACH regulation. We discuss the applied methods and process models and we report on experiences with the implementation and use of the system.
Background
Early developmental patterns of flatworms are extremely diverse and difficult to compare between distant groups. In parasitic flatworms, such as tapeworms, this is confounded by highly derived life cycles involving indirect development, and even the true orientation of the tapeworm antero-posterior (AP) axis has been a matter of controversy. In planarians, and metazoans generally, the AP axis is specified by the canonical Wnt pathway, and we hypothesized that it could also underpin axial formation during larval metamorphosis in tapeworms.
Results
By comparative gene expression analysis of Wnt components and conserved AP markers in the tapeworms Echinococcus multilocularis and Hymenolepis microstoma, we found remarkable similarities between the early stages of larval metamorphosis in tapeworms and late embryonic and adult development in planarians. We demonstrate posterior expression of specific Wnt factors during larval metamorphosis and show that scolex formation is preceded by localized expression of Wnt inhibitors. In the highly derived larval form of E. multilocularis, which proliferates asexually within the mammalian host, we found ubiquitous expression of posterior Wnt factors combined with localized expression of Wnt inhibitors that correlates with the asexual budding of scoleces. As in planarians, muscle cells are shown to be a source of secreted Wnt ligands, providing an explanation for the retention of a muscle layer in the immotile E. multilocularis larva.
Conclusions
The strong conservation of gene expression between larval metamorphosis in tapeworms and late embryonic development in planarians suggests, for the first time, a homologous developmental period across this diverse phylum. We postulate these to represent the phylotypic stages of these flatworm groups. Our results support the classical notion that the scolex is the true anterior end of tapeworms. Furthermore, the up-regulation of Wnt inhibitors during the specification of multiple anterior poles suggests a mechanism for the unique asexual reproduction of E. multilocularis larvae.
Purpose: In hepatocellular carcinoma patients with large or multinodal tumors, where curative treatment options are not feasible, transarterial therapies play a major role. Transarterial chemoembolization (TACE) with drug-eluting beads (DEB-TACE) is a promising new approach due to higher intratumoral and lower systemic concentration of the chemotherapeutic agent compared to conventional TACE (cTACE).
Patients and methods: In a retrospective analysis, 32 patients with hepatocellular carcinoma who received either DEB or a cTACE were compared regarding survival time, disease recurrence, and side effects such as pain and fever.
Results: No significant differences could be detected between the cTACE and DEB-TACE groups with regard to mean hospital stay, appearance of postinterventional fever, or 30-day mortality. However, the application of intravenous analgesics as postinterventional pain medication was needed more often in patients treated with DEB-TACE (57.1% vs 12.5%, P=0.0281). The overall median survival after the initial procedure was 10.8 months in the cTACE group and 9.2 months in the DEB-TACE group, showing no significant difference.
Conclusion: No survival benefit for patients treated with either DEB-TACE or cTACE was observed. Surprisingly, a higher rate of postinterventional pain could be detected after DEB-TACE.
Background
Enteric glial cells (EGCs) are the main constituent of the enteric nervous system and share similarities with astrocytes from the central nervous system including their reactivity to an inflammatory microenvironment. Previous studies on EGC pathophysiology have specifically focused on mucosal glia activation and its contribution to mucosal inflammatory processes observed in the gut of inflammatory bowel disease (IBD) patients. In contrast knowledge is scarce on intestinal inflammation not locally restricted to the mucosa but systemically affecting the intestine and its effect on the overall EGC network.
Methods and Results
In this study, we analyzed the biological effects of a systemic LPS-induced hyperinflammatory insult on overall EGCs in a rat model in vivo, mimicking the clinical situation of systemic inflammation response syndrome (SIRS). Tissues from small and large intestine were removed 4 hours after systemic LPS-injection and analyzed on transcript and protein level. Laser capture microdissection was performed to study plexus-specific gene expression alterations. Upon systemic LPS-injection in vivo we observed a rapid and dramatic activation of Glial Fibrillary Acidic Protein (GFAP)-expressing glia on mRNA level, locally restricted to the myenteric plexus. To study the specific role of the GFAP subpopulation, we established flow cytometry-purified primary glial cell cultures from GFAP promotor-driven EGFP reporter mice. After LPS stimulation, we analyzed cytokine secretion and global gene expression profiles, which were finally implemented in a bioinformatic comparative transcriptome analysis. Enriched GFAP+ glial cells cultured as gliospheres secreted increased levels of prominent inflammatory cytokines upon LPS stimulation. Additionally, a shift in myenteric glial gene expression profile was induced that predominantly affected genes associated with immune response.
Conclusion and Significance
Our findings identify the myenteric GFAP-expressing glial subpopulation as particularly susceptible and responsive to acute systemic inflammation of the gut wall and complement knowledge on glial involvement in mucosal inflammation of the intestine.
African trypanosomes thrive in the bloodstream and tissue spaces of a wide range of mammalian hosts. Infections of cattle cause an enormous socio-economic burden in sub-Saharan Africa. A hallmark of the trypanosome lifestyle is the flagellate’s incessant motion. This work details the cell motility behavior of the four livestock-parasites Trypanosoma vivax, T. brucei, T. evansi and T. congolense. The trypanosomes feature distinct swimming patterns, speeds and flagellar wave frequencies, although the basic mechanism of flagellar propulsion is conserved, as is shown by extended single flagellar beat analyses. Three-dimensional analyses of the trypanosomes expose a high degree of dynamic pleomorphism, typified by the ‘cellular waveform’. This is a product of the flagellar oscillation, the chirality of the flagellum attachment and the stiffness of the trypanosome cell body. The waveforms are characteristic for each trypanosome species and are influenced by changes of the microenvironment, such as differences in viscosity and the presence of confining obstacles. The distinct cellular waveforms may be reflective of the actual anatomical niches the parasites populate within their mammalian host. T. vivax displays waveforms optimally aligned to the topology of the bloodstream, while the two subspecies T. brucei and T. evansi feature distinct cellular waveforms, both additionally adapted to motion in more confined environments such as tissue spaces. T. congolense reveals a small and stiff waveform, which makes these parasites weak swimmers and destined for cell adherence in low flow areas of the circulation. Thus, our experiments show that the differential dissemination and annidation of trypanosomes in their mammalian hosts may depend on the distinct swimming capabilities of the parasites.
Background
Homeostatic mechanisms to maintain the T cell compartment diversity indicate an ongoing process of thymic activity and peripheral T cell renewal during human life. These processes are expected to be accelerated after childhood thymectomy and by the influence of cytomegalovirus (CMV) inducing a prematurely aged immune system.
The study aimed to investigate proportional changes and replicative history of CD8+ T cells, of recent thymic emigrants (RTEs) and CD103+ T cells (mostly gut-experienced) and the role of Interleukin-(IL)-7 and IL-7 receptor (CD127)-expressing T cells in thymectomized patients compared to young and old healthy controls.
Results
Decreased proportions of naive and CD31 + CD8+ T cells were demonstrated after thymectomy, with higher proliferative activity of CD127-expressing T cells and significantly shorter relative telomere lengths (RTLs) and lower T cell receptor excision circles (TRECs). Increased circulating CD103+ T cells and a skewed T cell receptor (TCR) repertoire were found after thymectomy similar to elderly persons. Naive T cells were influenced by age at thymectomy and further decreased by CMV.
Conclusions
After childhood thymectomy, the immune system demonstrated constant efforts of the peripheral CD8+ T cell compartment to maintain homeostasis. Supposedly it tries to fill the void of RTEs by peripheral T cell proliferation, by at least partly IL-7-mediated mechanisms and by proportional increase of circulating CD103+ T cells, reminiscent of immune aging in elderly. Although other findings were less significant compared to healthy elderly, early thymectomy demonstrated immunological alterations of CD8+ T cells which mimic features of premature immunosenescence in humans.
Patients with panic and post-traumatic stress disorders seem to show increased psychophysiological reactions to conditions of unpredictable (U) threat, which has been discussed as a neurobiological marker of elevated levels of sustained fear in these disorders. Interestingly, a recent study found that the right inferior frontal gyrus (rIFG) is correlated to the successful regulation of sustained fear during U threat. Therefore this study aimed to examine the potential use of non-invasive brain stimulation to foster the rIFG by means of anodal transcranial direct current stimulation (tDCS) in order to reduce psychophysiological reactions to U threat. Twenty six participants were randomly assigned into an anodal and sham stimulation group in a double-blinded manner. Anodal and cathodal electrodes (7 * 5 cm) were positioned right frontal to target the rIFG. Stimulation intensity was I = 2 mA applied for 20 min during a task including U threat conditions (NPU-task). The effects of the NPU paradigm were measured by assessing the emotional startle modulation and the skin conductance response (SCR) at the outset of the different conditions. We found a significant interaction effect of condition × tDCS for the SCR (F(2,48) = 6.3, p < 0.01) without main effects of condition and tDCS. Post hoc tests revealed that the increase in SCR from neutral (N) to U condition was significantly reduced in verum compared to the sham tDCS group (t(24) = 3.84, p < 0.001). Our results emphasize the causal role of rIFG for emotional regulation and the potential use of tDCS to reduce apprehension during U threat conditions and therefore as a treatment for anxiety disorders.
Background
HIV-disease progression correlates with immune activation. Here we investigated whether corticosteroid treatment can attenuate HIV disease progression in antiretroviral-untreated patients.
Methods
Double-blind, placebo-controlled randomized clinical trial including 326 HIV-patients in a resource-limited setting in Tanzania (clinicaltrials.gov NCT01299948). Inclusion criteria were a CD4 count above 300 cells/μl, the absence of AIDS-defining symptoms and an ART-naïve therapy status. Study participants received 5 mg prednisolone per day or placebo for 2 years. Primary endpoint was time to progression to an AIDS-defining condition or to a CD4-count below 200 cells/μl.
Results
No significant change in progression towards the primary endpoint was observed in the intent-to-treat (ITT) analysis (19 cases with prednisolone versus 28 cases with placebo, p = 0.1407). In a per-protocol (PP)-analysis, 13 versus 24 study participants progressed to the primary study endpoint (p = 0.0741). Secondary endpoints: Prednisolone-treatment decreased immune activation (sCD14, suPAR, CD38/HLA-DR/CD8+) and increased CD4-counts (+77.42 ± 5.70 cells/μl compared to -37.42 ± 10.77 cells/μl under placebo, p < 0.0001). Treatment with prednisolone was associated with a 3.2-fold increase in HIV viral load (p < 0.0001). In a post-hoc analysis stratifying for sex, females treated with prednisolone progressed significantly slower to the primary study endpoint than females treated with placebo (ITT-analysis: 11 versus 21 cases, p = 0.0567; PP-analysis: 5 versus 18 cases, p = 0.0051): No changes in disease progression were observed in men.
Conclusions
This study could not detect any significant effects of prednisolone on disease progression in antiretroviral-untreated HIV infection within the intent-to-treat population. However, significant effects were observed on CD4 counts, immune activation and HIV viral load. This study contributes to a better understanding of the role of immune activation in the pathogenesis of HIV infection.
To compare the effects of a 3‐week multimodal rehabilitation involving supervised high‐intensity interval training (HIIT) on female breast cancer survivors with respect to key variables of aerobic fitness, body composition, energy expenditure, cancer‐related fatigue, and quality of life to those of a standard multimodal rehabilitation program. A randomized controlled trial design was administered. Twenty‐eight women, who had been treated for cancer were randomly assigned to either a group performing exercise of low‐to‐moderate intensity (LMIE; n = 14) or a group performing high‐intensity interval training (HIIT; n = 14) as part of a 3‐week multimodal rehabilitation program. No adverse events related to the exercise were reported. Work economy improved following both HIIT and LMIE, with improved peak oxygen uptake following LMIE. HIIT reduced mean total body fat mass with no change in body mass, muscle or fat‐free mass (best P < 0.06). LMIE increased muscle and total fat‐free body mass. Total energy expenditure (P = 0.45) did not change between the groups, whereas both improved quality of life to a similar high extent and lessened cancer‐related fatigue. This randomized controlled study demonstrates that HIIT can be performed by female cancer survivors without adverse health effects. Here, HIIT and LMIE both improved work economy, quality of life and cancer‐related fatigue, body composition or energy expenditure. Since the outcomes were similar, but HIIT takes less time, this may be a time‐efficient strategy for improving certain aspects of the health of female cancer survivors.
Limited comprehension of aneurysm pathology has led to inconclusive results from clinical trials. miRNAs are key regulators of post-translational gene modification and are useful tools in elucidating key features of aneurysm pathogenesis in distinct entities of abdominal and popliteal aneurysms. Here, surgically harvested specimens from 19 abdominal aortic aneurysm (AAA) and 8 popliteal artery aneurysm (PAA) patients were analyzed for miRNA expression and histologically classified regarding extracellular matrix (ECM) remodeling and inflammation. DIANA-based computational target prediction and pathway enrichment analysis verified our results, as well as previous ones. miRNA-362, -19b-1, -194, -769, -21 and -550 were significantly down-regulated in AAA samples depending on degree of inflammation. Similar or inverse regulation was found for miR-769, 19b-1 and miR-550, -21, whereas miR-194 and -362 were unaltered in PAA. In situ hybridization verified higher expression of miR-550 and -21 in PAA compared to AAA and computational analysis for target genes and pathway enrichment affirmed signal transduction, cell-cell-interaction and cell degradation pathways, in line with previous results. Despite the vague role of miRNAs for potential diagnostic and treatment purposes, the number of candidates from tissue signature studies is increasing. Tissue morphology influences subsequent research, yet comparison of distinct entities of aneurysm disease can unravel core pathways.
Background
Natural surfactant preparations, commonly isolated from porcine or bovine lungs, are used to treat respiratory distress syndrome in preterm infants. Besides biophysical effectiveness, several studies have documented additional immunomodulatory properties. Within the near future, synthetic surfactant preparations may be a promising alternative. CHF5633 is a new generation reconstituted synthetic surfactant preparation with defined composition, containing dipalmitoyl-phosphatidylcholine, palmitoyl-oleoyl-phosphatidylglycerol and synthetic analogs of surfactant protein (SP-) B and SP-C. While its biophysical effectiveness has been demonstrated in vitro and in vivo, possible immunomodulatory abilities are currently unknown.
Aim
The aim of the current study was to define a potential impact of CHF5633 and its single components on pro- and anti-inflammatory cytokine responses in human CD4\(^+\) lymphocytes.
Methods
Purified human CD4\(^+\) T cells were activated using anti CD3/CD28 antibodies and exposed to CHF5633, its components, or to the well-known animal-derived surfactant Poractant alfa (Curosurf®). Proliferative response and cell viability were assessed using flow cytometry and a methylthiazolyldiphenyltetrazolium bromide colorimetric assay. The mRNA expression of IFNγ, IL-2, IL-17A, IL-22, IL-4, and IL-10 was measured by quantitative PCR, while intracellular protein expression was assessed by means of flow cytometry.
Results
Neither CHF5633 nor any of its phospholipid components with or without SP-B or SP-C analogs had any influence on proliferative ability and viability of CD4\(^+\) lymphocytes under the given conditions. IFNγ, IL-2, IL-17A, IL-22, IL-4, and IL-10 mRNA as well as IFNγ, IL-2, IL-4 and IL-10 protein levels were unaffected in both non-activated and activated CD4+ lymphocytes after exposure to CHF5633 or its constituents compared to non-exposed controls. However, in comparison to Curosurf®, expression levels of anti-inflammatory IL-4 and IL-10 mRNA were significantly increased in CHF5633 exposed CD4\(^+\) lymphocytes.
Conclusion
For the first time, the immunomodulatory capacity of CHF5633 on CD4\(^+\) lymphocytes was evaluated. CHF5633 did not show any cytotoxicity on CD4\(^+\) cells. Moreover, our in vitro data indicate that CHF5633 does not exert unintended pro-inflammatory effects on non-activated and activated CD4+ T cells. As far as anti-inflammatory cytokines are concerned, it might lack an overall reductive ability in comparison to animal-derived surfactants, potentially leaving pro- and anti-inflammatory cytokine response in balance.
Background
Washing of platelets is an important procedure commonly used for experimental studies, e.g. in cardiovascular research. As a known phenomenon, responsiveness to adenosine diphosphate (ADP) is reduced in washed platelets, although underlying molecular mechanisms—potentially interfering with experimental results—have not been thoroughly studied.
Objectives
Since ADP mediates its effects via three purinergic receptors P2Y1, P2X1 and P2Y12, their surface expression and function were investigated in washed platelets and, for comparison, in platelet-rich-plasma (PRP) at different time points for up to 2 hours after preparation.
Results
In contrast to PRP, flow cytometric analysis of surface expression in washed platelets revealed an increase of all receptors during the first 60 minutes after preparation followed by a significant reduction, which points to an initial preactivation of platelets and consecutive degeneration. The activity of the P2X1 receptor (measured by selectively induced calcium flux) was substantially maintained in both PRP and washed platelets. P2Y12 function (determined by flow cytometry as platelet reactivity index) was partially reduced after platelet washing compared to PRP, but remained stable in course of ongoing storage. However, the function of the P2Y1 receptor (measured by selectively induced calcium flux) continuously declined after preparation of washed platelets.
Conclusion
In conclusion, decreasing ADP responsiveness in washed platelets is particularly caused by impaired activity of the P2Y1 receptor associated with disturbed calcium regulation, which has to be considered in the design of experimental studies addressing ADP mediated platelet function.
Background
Serotonin (5-hydroxytryptamin, 5-HT) is an indolamine platelet agonist, biochemically derived from tryptophan. 5-HT is secreted from the enterochromaffin cells into the gastrointestinal tract and blood. Blood 5-HT has been proposed to regulate hemostasis by acting as a vasoconstrictor and by triggering platelet signaling through 5-HT receptor 2A (5HTR2A). Although platelets do not synthetize 5-HT, they take 5-HT up from the blood and store it in their dense granules which are secreted upon platelet activation.
Objective
To identify the molecular composite of the 5-HT uptake system in platelets and elucidate the role of platelet released 5-HT in thrombosis and ischemic stroke. Methods: 5-HT transporter knockout mice (5Htt\(^{-/-}\)) were analyzed in different in vitro and in vivo assays and in a model of ischemic stroke.
Results
In 5Htt\(^{-/-}\) platelets, 5-HT uptake from the blood was completely abolished and agonist-induced Ca2+ influx through store operated Ca\(^{2+}\) entry (SOCE), integrin activation, degranulation and aggregation responses to glycoprotein VI (GPVI) and C-type lectin-like receptor 2 (CLEC-2) were reduced. These observed in vitro defects in 5Htt\(^{-/-}\) platelets could be normalized by the addition of exogenous 5-HT. Moreover, reduced 5-HT levels in the plasma, an increased bleeding time and the formation of unstable thrombi were observed ex vivo under flow and in vivo in the abdominal aorta and carotid artery of 5Htt\(^{-/-}\) mice. Surprisingly, in the transient middle cerebral artery occlusion (tMCAO) model of ischemic stroke 5Htt\(^{-/-}\) mice showed nearly normal infarct volume and the neurological outcome was comparable to control mice.
Conclusion
Although secreted platelet 5-HT does not appear to play a crucial role in the development of reperfusion injury after stroke, it is essential to amplify the second phase of platelet activation through SOCE and plays an important role in thrombus stabilization.
Background
Mobile 3D fluoroscopes have become increasingly available in neurosurgical operating rooms. In this series, the image quality and value of intraoperative 3D fluoroscopy with intravenous contrast agent for the evaluation of aneurysm occlusion and vessel patency after clip placement was assessed in patients who underwent surgery for intracranial aneurysms.
Materials and methods
Twelve patients were included in this retrospective analysis. Prior to surgery, a 360° rotational fluoroscopy scan was performed without contrast agent followed by another scan with 50 ml of intravenous iodine contrast agent. The image files of both scans were transferred to an Apple PowerMac® workstation, subtracted and reconstructed using OsiriX® free software. The procedure was repeated after clip placement. Both image sets were compared for assessment of aneurysm occlusion and vessel patency.
Results
Image acquisition and contrast administration caused no adverse effects. Image quality was sufficient to follow the patency of the vessels distal to the clip. Metal artifacts reduce the assessability of the immediate vicinity of the clip. Precise image subtraction and post-processing can reduce metal artifacts and make the clip-site assessable and depict larger neck-remnants.
Conclusion
This technique quickly supplies images at adequate quality to evaluate distal vessel patency after aneurysm clipping. Significant aneurysm remnants may be depicted as well. As it does not require visual control of all vessels that are supposed to be evaluated intraoperatively, this technique may be complementary to other intraoperative tools like indocyanine green videoangiography and micro-Doppler, especially for the assessment of larger aneurysms. At the momentary state of this technology, it cannot replace postoperative conventional angiography. However, 3D fluoroscopy and image post-processing are young technologies. Further technical developments are likely to result in improved image quality.
Despite substantial advances in the imaging techniques and pathophysiological understanding over the last decades, identification of the underlying causes of left ventricular hypertrophy by means of echocardiographic examination remains a challenge in current clinical practice. The longitudinal strain bull’s eye plot derived from 2D speckle tracking imaging offers an intuitive visual overview of the global and regional left ventricular myocardial function in a single diagram. The bull’s eye mapping is clinically feasible and the plot patterns could provide clues to the etiology of cardiomyopathies. The present review summarizes the longitudinal strain, bull’s eye plot features in patients with various cardiomyopathies and concentric left ventricular hypertrophy and the bull’s eye plot features might serve as one of the cardiac workup steps on evaluating patients with left ventricular hypertrophy.
Developmental differentiation is a universal biological process that allows cells to adapt to different environments to perform specific functions. African trypanosomes progress through a tightly regulated life cycle in order to survive in different host environments when they shuttle between an insect vector and a vertebrate host. Transcriptomics has been useful to gain insight into RNA changes during stage transitions; however, RNA levels are only a moderate proxy for protein abundance in trypanosomes. We quantified 4270 protein groups during stage differentiation from the mammalian-infective to the insect form and provide classification for their expression profiles during development. Our label-free quantitative proteomics study revealed previously unknown components of the differentiation machinery that are involved in essential biological processes such as signaling, posttranslational protein modifications, trafficking and nuclear transport. Furthermore, guided by our proteomic survey, we identified the cause of the previously observed differentiation impairment in the histone methyltransferase DOT1B knock-out strain as it is required for accurate karyokinesis in the first cell division during differentiation. This epigenetic regulator is likely involved in essential chromatin restructuring during developmental differentiation, which might also be important for differentiation in higher eukaryotic cells. Our proteome dataset will serve as a resource for detailed investigations of cell differentiation to shed more light on the molecular mechanisms of this process in trypanosomes and other eukaryotes.
Background
Fibromyalgia syndrome (FMS) is a complex chronic condition that makes high demands on patients’ self-management skills. Thus, patient education is considered an important component of multimodal therapy, although evidence regarding its effectiveness is scarce. The main objective of this study is to assess the effectiveness of an advanced self-management patient education program for patients with FMS as compared to usual care in the context of inpatient rehabilitation.
Methods/Design
We conducted a multicenter cluster randomized controlled trial in 3 rehabilitation clinics. Clusters are groups of patients with FMS consecutively recruited within one week after admission. Patients of the intervention group receive the advanced multidisciplinary self-management patient education program (considering new knowledge on FMS, with a focus on transfer into everyday life), whereas patients in the control group receive standard patient education programs including information on FMS and coping with pain. A total of 566 patients are assessed at admission, at discharge and after 6 and 12 months, using patient reported questionnaires. Primary outcomes are patients’ disease- and treatment-specific knowledge at discharge and self-management skills after 6 months. Secondary outcomes include satisfaction, attitudes and coping competences, health-promoting behavior, psychological distress, health impairment and participation. Treatment effects between groups are evaluated using multilevel regression analysis adjusting for baseline values.
Discussion
The study evaluates the effectiveness of a self-management patient education program for patients with FMS in the context of inpatient rehabilitation in a cluster randomized trial. Study results will show whether self-management patient education is beneficial for this group of patients.
A centralized heterogeneous formation flight position control scheme has been formulated using an explicit model following design, based on a Linear Quadratic Regulator Proportional Integral (LQR PI) controller. The leader quadcopter is a stable reference model with desired dynamics whose output is perfectly tracked by the two wingmen quadcopters. The leader itself is controlled through the pole placement control method with desired stability characteristics, while the two followers are controlled through a robust and adaptive LQR PI control method. Selected 3-D formation geometry and static stability are maintained under a number of possible perturbations. With this control scheme, formation geometry may also be switched to any arbitrary shape during flight, provided a suitable collision avoidance mechanism is incorporated. In case of communication loss between the leader and any of the followers, the other follower provides the data, received from the leader, to the affected follower. The stability of the closed-loop system has been analyzed using singular values. The proposed approach for the tightly coupled formation flight of mini unmanned aerial vehicles has been validated with the help of extensive simulations using MATLAB/Simulink, which provided promising results.
A standardized curriculum back school (CBS) has been recommended for further dissemination in medical rehabilitation in Germany. However, implementation of self-management education programs into practice is challenging. In low back pain care, individual factors of professionals could be decisive regarding implementation fidelity. The study aim was to explore attitudes and experiences of professionals who conducted the back school. Qualitative interviews were led with 45 rehabilitation professionals. The data were examined using thematic analysis. Three central themes were identified: (a) “back school as a common thread,” (b) “theory versus practice,” and (c) “participation and patient-centeredness.” The CBS and its manual were frequently described positively because they provide structure. However, specified time was mentioned critically and there were heterogeneous perceptions regarding flexibility in conducting the CBS. Theory and practice in the CBS were discussed concerning amount, distribution, and conjunction. Participation and patient-centeredness were mainly mentioned in terms of amount and heterogeneity of participation as well as the demand for competences of professionals. Factors were detected that may either positively or negatively influence the implementation fidelity of self-management education programs. The results are explorative and provide potential explanatory mechanisms for behavior and acceptance of rehabilitation professionals regarding the implementation of biopsychosocial back schools.
Background
The key for successful delivery in minimally-invasive hip replacement lies in the exact knowledge about the surgical anatomy. The minimally-invasive direct anterior approach to the hip joint makes it necessary to clearly identify the tensor fasciae latae muscle in order to enter the Hueter interval without damaging the lateral femoral cutaneous nerve. However, due to the inherently restricted overview in minimally-invasive surgery, this can be difficult even for experienced surgeons.
Methods and Surgical Technique
In this technical note, we demonstrate for the first time how to use the tensor fasciae latae perforator as anatomical landmark to reliably identify the tensor fasciae latae muscle in orthopaedic surgery. Such perforators are used for flaps in plastic surgery as they are constant and can be found at the lateral third of the tensor fasciae latae muscle in a direct line from the anterior superior iliac spine.
Conclusion
As demonstrated in this article, a simple knowledge transfer between surgical disciplines can minimize the complication rate associated with minimally-invasive hip replacement.
Background
A growing number of studies report an abnormal expression of Piwi-interacting RNAs (piRNAs) and the piRNA processing enzyme Piwi in many cancers. Whether this finding is an epiphenomenon of the chaotic molecular biology of the fast dividing, neoplastically transformed cells or is functionally relevant to tumorigenesisis is difficult to discern at present. To better understand the role of piRNAs in cancer development small laboratory fish models can make a valuable contribution. However, little is known about piRNAs in somatic and neoplastic tissues of fish.
Results
To identify piRNA clusters that might be involved in melanoma pathogenesis, we use several transgenic lines of medaka, and platyfish/swordtail hybrids, which develop various types of melanoma. In these tumors Piwi, is expressed at different levels, depending on tumor type. To quantify piRNA levels, whole piRNA populations of testes and melanomas of different histotypes were sequenced. Because no reference piRNA cluster set for medaka or Xiphophorus was yet available we developed a software pipeline to detect piRNA clusters in our samples and clusters were selected that were enriched in one or more samples. We found several loci to be overexpressed or down-regulated in different melanoma subtypes as compared to hyperpigmented skin. Furthermore, cluster analysis revealed a clear distinction between testes, low-grade and high-grade malignant melanoma in medaka.
Conclusions
Our data imply that dysregulation of piRNA expression may be associated with development of melanoma. Our results also reinforce the importance of fish as a suitable model system to study the role of piRNAs in tumorigenesis.
Background
Fermented wheat germ extract (FWGE) sold under the trade name Avemar exhibits anticancer activity in vitro and in vivo. Its mechanisms of action are divided into antiproliferative and antimetabolic effects. Its influcence on cancer cell metabolism needs further investigation. One objective of this study, therefore, was to further elucidate the antimetabolic action of FWGE. The anticancer compound 2,6-dimethoxy-1,4-benzoquinone (DMBQ) is the major bioactive compound in FWGE and is probably responsible for its anticancer activity. The second objective of this study was to compare the antiproliferative properties in vitro of FWGE and the DMBQ compound.
Methods
The IC\(_{50}\) values of FWGE were determined for nine human cancer cell lines after 24 h of culture. The DMBQ compound was used at a concentration of 24 μmol/l, which is equal to the molar concentration of DMBQ in FWGE. Cell viability, cell cycle, cellular redox state, glucose consumption, lactic acid production, cellular ATP levels, and the NADH/NAD\(^+\) ratio were measured.
Results
The mean IC\(_{50}\) value of FWGE for the nine human cancer cell lines tested was 10 mg/ml. Both FWGE (10 mg/ml) and the DMBQ compound (24 μmol/l) induced massive cell damage within 24 h after starting treatment, with changes in the cellular redox state secondary to formation of intracellular reactive oxygen species. Unlike the DMBQ compound, which was only cytotoxic, FWGE exhibited cytostatic and growth delay effects in addition to cytotoxicity. Both cytostatic and growth delay effects were linked to impaired glucose utilization which influenced the cell cycle, cellular ATP levels, and the NADH/NAD\(^+\) ratio. The growth delay effect in response to FWGE treatment led to induction of autophagy.
Conclusions
FWGE and the DMBQ compound both induced oxidative stress-promoted cytotoxicity. In addition, FWGE exhibited cytostatic and growth delay effects associated with impaired glucose utilization which led to autophagy, a possible previously unknown mechanism behind the influence of FWGE on cancer cell metabolism.
Draft genome of the \(Arabidopsis\) \(thaliana\) phyllosphere bacterium, \(Williamsia\) sp. ARP1
(2016)
The Gram-positive actinomycete \(Williamsia\) sp. ARP1 was originally isolated from the \(Arabidopsis\) \(thaliana\) phyllosphere. Here we describe the general physiological features of this microorganism together with the draft genome sequence and annotation. The 4,745,080 bp long genome contains 4434 protein-coding genes and 70 RNA genes. To our knowledge, this is only the second reported genome from the genus \(Williamsia\) and the first sequenced strain from the phyllosphere. The presented genomic information is interpreted in the context of an adaptation to the phyllosphere habitat.
Functional and structural characterization of axonal opioid receptors as targets for analgesia
(2016)
Background
Opioids are the gold standard for the treatment of acute pain despite serious side effects in the central and enteric nervous system. µ-opioid receptors (MOPs) are expressed and functional at the terminals of sensory axons, when activated by exogenous or endogenous ligands. However, the presence and function of MOP along nociceptive axons remains controversial particularly in naïve animals. Here, we characterized axonal MOPs by immunofluorescence, ultrastructural, and functional analyses. Furthermore, we evaluated hypertonic saline as a possible enhancer of opioid receptor function.
Results
Comparative immunolabeling showed that, among several tested antibodies, which all provided specific MOP detection in the rat central nervous system (CNS), only one monoclonal MOP-antibody yielded specificity and reproducibility for MOP detection in the rat peripheral nervous system including the sciatic nerve. Double immunolabeling documented that MOP immunoreactivity was confined to calcitonin gene-related peptide (CGRP) positive fibers and fiber bundles. Almost identical labeling and double labeling patterns were found using mcherry-immunolabeling on sciatic nerves of mice producing a MOP-mcherry fusion protein (MOP-mcherry knock-in mice). Preembedding immunogold electron microscopy on MOP-mcherry knock-in sciatic nerves indicated presence of MOP in cytoplasm and at membranes of unmyelinated axons. Application of [D-Ala\(^2\), N-MePhe\(^4\), Gly-ol]-enkephalin (DAMGO) or fentanyl dose-dependently inhibited depolarization-induced CGRP release from rat sciatic nerve axons ex vivo, which was blocked by naloxone. When the lipophilic opioid fentanyl was applied perisciatically in naïve Wistar rats, mechanical nociceptive thresholds increased. Subthreshold doses of fentanyl or the hydrophilic opioid DAMGO were only effective if injected together with hypertonic saline. In vitro, using β-arrestin-2/MOP double-transfected human embryonic kidney cells, DAMGO as well as fentanyl lead to a recruitment of β-arrestin-2 to the membrane followed by a β-arrestin-2 reappearance in the cytosol and MOP internalization. Pretreatment with hypertonic saline prevented MOP internalization.
Conclusion
MOPs are present and functional in the axonal membrane from naïve animals. Hypertonic saline acutely decreases ligand-induced internalization of MOP and thereby might improve MOP function. Further studies should explore potential clinical applications of opioids together with enhancers for regional analgesia.
Background
Enhanced macromolecule biosynthesis is integral to growth and proliferation of cancer cells. Lipid biosynthesis has been predicted to be an essential process in cancer cells. However, it is unclear which enzymes within this pathway offer the best selectivity for cancer cells and could be suitable therapeutic targets.
Results
Using functional genomics, we identified stearoyl-CoA desaturase (SCD), an enzyme that controls synthesis of unsaturated fatty acids, as essential in breast and prostate cancer cells. SCD inhibition altered cellular lipid composition and impeded cell viability in the absence of exogenous lipids. SCD inhibition also altered cardiolipin composition, leading to the release of cytochrome C and induction of apoptosis. Furthermore, SCD was required for the generation of poly-unsaturated lipids in cancer cells grown in spheroid cultures, which resemble those found in tumour tissue. We also found that SCD mRNA and protein expression is elevated in human breast cancers and predicts poor survival in high-grade tumours. Finally, silencing of SCD in prostate orthografts efficiently blocked tumour growth and significantly increased animal survival.
Conclusions
Our data implicate lipid desaturation as an essential process for cancer cell survival and suggest that targeting SCD could efficiently limit tumour expansion, especially under the metabolically compromised conditions of the tumour microenvironment.
Background
Medulloblastoma is the most common malignant brain tumor in children and can be divided in different molecular subgroups. Patients whose tumor is classified as a Group 3 tumor have a dismal prognosis. However only very few tumor models are available for this subgroup.
Methods
We established a robust orthotopic xenograft model with a cell line derived from the malignant pleural effusions of a child suffering from a Group 3 medulloblastoma.
Results
Besides classical characteristics of this tumor subgroup, the cells display cancer stem cell characteristics including neurosphere formation, multilineage differentiation, CD133/CD15 expression, high ALDH-activity and high tumorigenicity in immunocompromised mice with xenografts exactly recapitulating the original tumor architecture.
Conclusions
This model using unmanipulated, human medulloblastoma cells will enable translational research, specifically focused on Group 3 medulloblastoma.
First-order proximal methods that solve linear and bilinear elliptic optimal control problems with a sparsity cost functional are discussed. In particular, fast convergence of these methods is proved. For benchmarking purposes, inexact proximal schemes are compared to an inexact semismooth Newton method. Results of numerical experiments are presented to demonstrate the computational effectiveness of proximal schemes applied to infinite-dimensional elliptic optimal control problems and to validate the theoretical estimates.
In the present work, a simulation system is proposed that can be used as an educational tool by physicians in training basic skills of minimally invasive vascular interventions. In order to accomplish this objective, initially the physical model of the wire proposed by Konings has been improved. As a result, a simpler and more stable method was obtained to calculate the equilibrium configuration of the wire. In addition, a geometrical method is developed to perform relaxations. It is particularly useful when the wire is hindered in the physical method because of the boundary conditions. Then a recipe is given to merge the physical and the geometrical methods, resulting in efficient relaxations. Moreover, tests have shown that the shape of the virtual wire agrees with the experiment. The proposed algorithm allows real-time executions, and furthermore, the hardware to assemble the simulator has a low cost.
This article introduces a new consistent variance-based estimator called ordinal consistent partial least squares (OrdPLSc). OrdPLSc completes the family of variance-based estimators consisting of PLS, PLSc, and OrdPLS and permits to estimate structural equation models of composites and common factors if some or all indicators are measured on an ordinal categorical scale. A Monte Carlo simulation (N =500) with different population models shows that OrdPLSc provides almost unbiased estimates. If all constructs are modeled as common factors, OrdPLSc yields estimates close to those of its covariance-based counterpart, WLSMV, but is less efficient. If some constructs are modeled as composites, OrdPLSc is virtually without competition.
Highly Strained Heterocycles Constructed from Boron–Boron Multiple Bonds and Heavy Chalcogens
(2016)
The reactions of a diborene with elemental selenium or tellurium are shown to afford a diboraselenirane or diboratellurirane, respectively. These reactions are reminiscent of the sequestration of subvalent oxygen and nitrogen in the formation of oxiranes and aziridines; however, such reactivity is not known between alkenes and the heavy chalcogens. Although carbon is too electronegative to affect the reduction of elements with lower relative electronegativity, the highly reducing nature of the B B double bond enables reactions with Se0 and Te0. The capacity of multiple bonds between boron atoms to donate electron density is highlighted in reactions where diborynes behave as nucleophiles, attacking one of the two Te atoms of diaryltellurides, forming salts consisting of diboratellurenium cations and aryltelluride anions.
Ficaria calthifolia (diploide Form, Typ1) wurde kürzlich nord-westlich des geschlossenen südosteuropäischen Verbreitungsgebiet auch in Deutschland gefunden, nämlich in Würzburg (2006) und an Elbedeichen in Brandenburg (2014) und Sachsen (2015). Ficaria calthifolia ist durch das Fehlen von verlängerten mehrgliedrigen Stängeln und die Abwesenheit von Brutknollen in den Blattachseln gekennzeichnet. Die 1–2 (3) Stängel von Ficaria calthifolia verbleiben überwiegend im Boden (hypogäisch), können aber im Laufe der Anthese aus dem Boden hervorwachsen. Die gestielten Laubblätter setzen sich aus Grundblättern und einer Rosette von bis zu 8 Stängelblättern pro Stängel zusammen. Letztere entspringen aus dem terminalen Stängelknoten (Stängelblatt-rosette). In Würzburg kommen zwei Populationen von Ficaria calthifolia vor, diploide Typ1-Pflanzen und triploide Typ2-Pflanzen. Letztere sind robuster, besitzen größere Blüten (bis 4 cm) und entwickeln nur vereinzelte reife Nüsschen. Pflanzen mit höherem Ploidiegrad (wahrscheinlich pentaploid, Typ3) wurden auch gefunden. Etwa 60% der 3 bis 8 Blütenstiele von Typ1-Pflanzen besitzt kein Stängelblatt, der Rest einen Knoten mit 1 bis 2 (3) Hochblättern. Die Zahl der Kronblätter beträgt 8 (vereinzelt 9), die durchschnittliche Zahl reifer, eiförmiger Nüsschen pro Fruchtstand beträgt 7 (Würzburg) / 14 (Elbe) (maximal 26). Aus vom Rhizom abgebrochenen und im Mai gepflanzten Speicherknollen keimten im Spätherbst desselben Jahrs neue Pflanzen. Der Jahreszyklus des Wurzelsystems wird beschrieben. Durch spontane Ablösungen einzelner Speicherknollen findet eine vegetative Vermehrung statt. Neben Nüsschen wären abgebrochene Speicherknollen für die Fernansiedlung der Sippe an Elbe (u.a. Verschleppung durch Hochwasser) und Main (Verschleppung durch Schiffe und andere Vektoren) ausreichend.
The Venus Flytrap Dionaea muscipula Counts Prey-Induced Action Potentials to Induce Sodium Uptake
(2016)
Carnivorous plants, such as the Venus flytrap (Dionaea muscipula), depend on an animal diet when grown in nutrient-poor soils. When an insect visits the trap and tilts the mechanosensors on the inner surface, action potentials (APs) are fired. After a moving object elicits two APs, the trap snaps shut, encaging the victim. Panicking preys repeatedly touch the trigger hairs over the subsequent hours, leading to a hermetically closed trap, which via the gland-based endocrine system is flooded by a prey-decomposing acidic enzyme cocktail. Here, we asked the question as to how many times trigger hairs have to be stimulated (e.g., now many APs are required) for the flytrap to recognize an encaged object as potential food, thus making it worthwhile activating the glands. By applying a series of trigger-hair stimulations, we found that the touch hormone jasmonic acid (JA) signaling pathway is activated after the second stimulus, while more than three APs are required to trigger an expression of genes encoding prey-degrading hydrolases, and that this expression is proportional to the number of mechanical stimulations. A decomposing animal contains a sodium load, and we have found that these sodium ions enter the capture organ via glands. We identified a flytrap sodium channel DmHKT1 as responsible for this sodium acquisition, with the number of transcripts expressed being dependent on the number of mechano-electric stimulations. Hence, the number of APs a victim triggers while trying to break out of the trap identifies the moving prey as a struggling Na+-rich animal and nutrition for the plant.
A site specific perturbation of a photo-excited molecular aggregate can lead to a localization of excitonic energy. We investigate this localization dynamics for laser-prepared excited states. Changing the parameters of the electric field significantly influences the exciton localization which offers the possibility for a selective control of this process. This is demonstrated for aggregates possessing a single vibrational degree of freedom per monomer unit. It is shown that the effects identified for the molecular dimer can be generalized to larger aggregates with a high density of vibronic states.