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Evidence for a Clathrin-independent mode of endocytosis at a continuously active sensory synapse
Michaela Fuchs,Johann Helmut Brandst?tter,Hanna Regus-Leidig
Frontiers in Cellular Neuroscience , 2014, DOI: 10.3389/fncel.2014.00060
Abstract: Synaptic vesicle exocytosis at chemical synapses is followed by compensatory endocytosis. Multiple pathways including Clathrin-mediated retrieval of single vesicles, bulk retrieval of large cisternae, and kiss-and-run retrieval have been reported to contribute to vesicle recycling. Particularly at the continuously active ribbon synapses of retinal photoreceptor and bipolar cells, compensatory endocytosis plays an essential role to provide ongoing vesicle supply. Yet, little is known about the mechanisms that contribute to endocytosis at these highly complex synapses. To identify possible specializations in ribbon synaptic endocytosis during different states of activity, we exposed mice to controlled lighting conditions and compared the distribution of endocytotic proteins at rod and cone photoreceptor, and ON bipolar cell ribbon synapses with light and electron microscopy. In mouse ON bipolar cell terminals, Clathrin-mediated endocytosis seemed to be the dominant mode of endocytosis at all adaptation states analyzed. In contrast, in mouse photoreceptor terminals in addition to Clathrin-coated pits, clusters of membranously connected electron-dense vesicles appeared during prolonged darkness. These clusters labeled for Dynamin3, Endophilin1, and Synaptojanin1, but not for AP180, Clathrin LC, and hsc70. We hypothesize that rod and cone photoreceptors possess an additional Clathrin-independent mode of vesicle retrieval supporting the continuous synaptic vesicle supply during prolonged high activity.
Very Low Tidal Volume Ventilation with Associated Hypercapnia - Effects on Lung Injury in a Model for Acute Respiratory Distress Syndrome
Hans Fuchs, Marc R. Mendler, Dominik Scharnbeck, Michael Ebsen, Helmut D. Hummler
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0023816
Abstract: Background Ventilation using low tidal volumes with permission of hypercapnia is recommended to protect the lung in acute respiratory distress syndrome. However, the most lung protective tidal volume in association with hypercapnia is unknown. The aim of this study was to assess the effects of different tidal volumes with associated hypercapnia on lung injury and gas exchange in a model for acute respiratory distress syndrome. Methodology/Principal Findings In this randomized controlled experiment sixty-four surfactant-depleted rabbits were exposed to 6 hours of mechanical ventilation with the following targets: Group 1: tidal volume = 8–10 ml/kg/PaCO2 = 40 mm Hg; Group 2: tidal volume = 4–5 ml/kg/PaCO2 = 80 mm Hg; Group 3: tidal volume = 3–4 ml/kg/PaCO2 = 120 mm Hg; Group 4: tidal volume = 2–3 ml/kg/PaCO2 = 160 mm Hg. Decreased wet-dry weight ratios of the lungs, lower histological lung injury scores and higher PaO2 were found in all low tidal volume/hypercapnia groups (group 2, 3, 4) as compared to the group with conventional tidal volume/normocapnia (group 1). The reduction of the tidal volume below 4–5 ml/kg did not enhance lung protection. However, oxygenation and lung protection were maintained at extremely low tidal volumes in association with very severe hypercapnia and no adverse hemodynamic effects were observed with this strategy. Conclusion Ventilation with low tidal volumes and associated hypercapnia was lung protective. A tidal volume below 4–5 ml/kg/PaCO2 80 mm Hg with concomitant more severe hypercapnic acidosis did not increase lung protection in this surfactant deficiency model. However, even at extremely low tidal volumes in association with severe hypercapnia lung protection and oxygenation were maintained.
Rod Photoreceptor Ribbon Synapses in DBA/2J Mice Show Progressive Age-Related Structural Changes
Michaela Fuchs, Michael Scholz, Anna Sendelbeck, Jenny Atorf, Christine Schlegel, Ralf Enz, Johann Helmut Brandst?tter
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0044645
Abstract: The DBA/2J mouse is a commonly used animal model in glaucoma research. The eyes of DBA/2J mice show severe age-related changes that finally lead to the degeneration of retinal ganglion cells and the optic nerve. Recent electroretinogram studies identified functional deficits, which suggest that also photoreceptor cells are involved in the pathological processes occurring in the DBA/2J mouse retina. In a comparative study, we examined anatomical and molecular changes in the retinae of DBA/2J and C57BL/6 control mice with light and electron microscopy and with PCR analyses. In the retina of the DBA/2J mouse, we found a thinning of the outer plexiform layer, the first synaptic layer in the transfer of visual signals, and age-dependent and progressive degenerative structural changes at rod photoreceptor ribbon synapses. The structural ribbon changes represent a photoreceptor synaptic phenotype that has not yet been described in this animal model of secondary angle-closure glaucoma. Furthermore, genes of the classical complement cascade were upregulated in the photoreceptor cells of aging DBA/2J mice, suggesting a putative link between ribbon synapse degradation and the innate immune system.
Stabilization of Circadian Rhythm, Its Augmentation by Bright Light Treatment and Its Importance for ADHD and Depression of Adolescents  [PDF]
Helmut Niederhofer
Neuroscience & Medicine (NM) , 2013, DOI: 10.4236/nm.2013.43024
Abstract:

Objective: ADHD is characterized by the progressive development of, impulsiveness, attentional difficulties and sometimes also excessive hyperactivity. Main biological reason is a quantitative reduction of the neurotransmitter dopamine in the forebrain. A lack of dopamine is also typical for depressive disorders. Methods: Bright light therapy is proven to be effective in treating depression. Purpose of our study is to verify the therapeutic effectiveness of Bright light therapy in subjects affected by ADHD. Results: Results show a significant improvement which lasts for at least 4 weeks, which is superposed by regulation of the circadian rhythm. Initial decrease of especially morning saliva melatonin levels, due to regular sleep under in-patient conditions, is followed by symptom improvement and a raising evening melatonin level, due to activation during the day. This level decreases as soon as activation is ceased. Conclusion: Bright light therapy seems to be effective as add-on therapy for ADHD, but in fact, stabilization of the circadian rhythm is the most important therapeutic intervention, either for ADHD or for depression, as demonstrated in another study.

Recent Developments and Current Issues in the Treatment of Pancreatic Cancer  [PDF]
Helmut Oettle
Journal of Cancer Therapy (JCT) , 2013, DOI: 10.4236/jct.2013.410A003
Abstract:

Presently, many questions exist about what the optimal regimen comprises for all stages and treatment settings for pancreatic cancer. Since the CONKO-001 trial, adjuvant therapy following resection has become standard of care; however, outcomes are poor, with most patients experiencing disease recurrence, and new therapies have yet to be validated. Furthermore, the value of adjuvant radiotherapy has still not been clearly defined. Targeted treatment in combination with chemotherapy has been mostly disappointing so far in the adjuvant setting but immunotherapy holds potential for improving survival outcomes. Neoadjuvant treatment does not appear to provide much benefit in resectable patients but in the small subgroup of patients with borderline resectable/unresectable locally advanced disease it may increase the possibility of an R0 resection and, consequently, a substantial increase in survival duration. Use of capecitabine-based radiotherapy in patients with unresectable locally advanced disease appears to be more efficacious and better tolerated than gemcitabine-based chemoradiotherapy, with respect to survival outcomes. However, as with adjuvant treatment, the benefit of adding radiotherapy has not yet been definitively demonstrated. In patients with metastatic pancreatic cancer, targeting the stroma with nab-paclitaxel has shown promising results in a phase III trial setting when administered in combination with gemcitabine and, furthermore, this regimen is suitable for a broad range of patients due to its generally good tolerability profile. Because of its high toxicity, FOLFIRINOX is more suitable for younger patients with an excellent performance status who can withstand aggressive treatment and in patients with a worse performance status, gemcitabine monotherapy is considered to be a more appropriate treatment. Alternatively, gemcitabine in combination with erlotinib, the only targeted compound that has resulted in significant albeit small improvements in survival in patients with advanced disease, could be selected. However, the benefit-risk profile of this regimen is only favorable in a strictly defined, small patient subgroup who develop a treatment-related rash. Finally, with the elucidation of prognostic and predictive markers, treatment is expected to become ever more individualized, leading to improved efficacy outcomes and less unnecessary

Analysis of the Navier-Stokes Equations  [PDF]
Helmut Martin
Journal of Applied Mathematics and Physics (JAMP) , 2014, DOI: 10.4236/jamp.2014.210106
Abstract: The Navier-Stokes equations for incompressible fluid flows with impervious boundary and free surface are analyzed by means of a perturbation procedure involving dimensionless variables and a dimensionless perturbation parameter which is composed of kinematic viscosity of fluid, the acceleration of gravity and a characteristic length. The new dimensionless variables are introduced into the equation system. In addition, the perturbation parameter is introduced into terms for deriving approximations systems of different orders. Such systems are obtained by equating coefficients of like powers of perturbation parameter for the successive coefficients in the series. In these systems several terms are analyzed with regards to size and significance. Based on those systems, suitable solutions of NS equations can be found for different boundary conditions. For example, a relation for stationary channel flow is obtained as approximation to the NS equations of the lowest order after transformation back to dimensional variables.
Whole-Body Vibration in Automated Residential Solid Waste Collection  [PDF]
Helmut Paschold
Open Journal of Safety Science and Technology (OJSST) , 2015, DOI: 10.4236/ojsst.2015.54011
Abstract: Drivers of residential solid waste collection trucks are exposed to a wide variety of physical and health hazards. Automated robotic arm collection methods are intended to eliminate physical and ergonomic hazards associated with manual waste collection. However, whole-body vibration (WBV) exposure is a hazard that may be significant and greater than being found in semi-automated or manual methods. WBV is measured in a pilot field study of automated waste collection trucks during normal operation for nearly eight-hour periods on two consecutive days. All four trials are run under similar route conditions. Vibrations are measured at the seat-driver interface using a tri-axial accelerometer seat pad and portable vibration monitors. Measured WBV levels are compared with prior published data from waste collection trucks and health standards. The average WBV exposure value, corresponding to 0.99 m.s-2 for frequency-weighted r.m.s. acceleration, is above the ISO 2631-1 action value of 0.50 m.s-2 and below a limit value of 1.15 m.s-2 as given in the European Parliament Directive 2002/44/EC. This exposure level suggests the presence of potential health risks.
MausDB: An open source application for phenotype data and mouse colony management in large-scale mouse phenotyping projects
Holger Maier, Christoph Lengger, Bruno Simic, Helmut Fuchs, Valérie Gailus-Durner, Martin Hrabé de Angelis
BMC Bioinformatics , 2008, DOI: 10.1186/1471-2105-9-169
Abstract: We present MausDB, the German Mouse Clinic web-based database application that integrates standard mouse colony management, phenotyping workflow scheduling features and mouse phenotyping result data management. It links mouse phenotype data with genotype data, metadata and external data such as public web databases, which is a prerequisite for comprehensive data analysis and mining. We describe how this can be achieved with a lean and user-friendly system built on open standards.MausDB is suited for large-scale, high-throughput phenotyping facilities but can also be used exclusively for mouse colony management within smaller units or projects. The system is successfully used as the primary mouse and data management tool of the German Mouse Clinic and other mouse facilities. We offer MausDB to the scientific community as open source software to provide a system for storage of data from functional genomics projects in a well-structured, easily accessible form.The concept of standardized, high-throughput and comprehensive screening of mice has proven to be successful for identifying new phenotypes in mutant mouse lines by the German Mouse Clinic (GMC) [1-7] and others [8,9].In the GMC, experts from various fields of mouse behavior, physiology, morphology, metabolism and pathology work side-by-side in one building in 14 individual modules (allergy, behavior, cardiovascular system, clinical chemistry, dysmorphology, energy metabolism, eye development and vision, immunology, lung function, molecular phenotyping, neurology, nociception, pathology and steroid metabolism) in close collaboration with clinicians and veterinarians [2].Mouse mutants and their littermate controls pass through the different modules of the GMC in multi-parallel phenotyping pipelines following a standardized workflow. In the course of the high-throughput primary screen, up to 320 parameters per mouse line are measured, and these findings may be supplemented by results from secondary and tertiary scr
Modelling Consumer Behavior by Inverse Demand Functions  [PDF]
Susanne Fuchs-Seliger
Theoretical Economics Letters (TEL) , 2013, DOI: 10.4236/tel.2013.34039
Abstract:

In this article a model of consumer behavior will be developed, based on preferences on the price space reflecting the individuals willingness to pay for certain quantities of commodities under the supposition that the individual is restricted to his or her income. Firms offer certain amounts of commodities at the market and consumers react to these offers by their willingness to pay. Existence and continuity of the inverse demand function describing consumers behavior under appropriate conditions will be shown. Furthermore, differences between a model of consumer behavior based on preferences on the commodity space and that which is based on preferences on the price space will be pointed out.

Comparison of particle-exposure triggered pulmonary and systemic inflammation in mice fed with three different diets
Alexander A G?tz, Jan Rozman, Heiko G R?del, Helmut Fuchs, Valérie Gailus-Durner, Martin Hrabě de Angelis, Martin Klingenspor, Tobias Stoeger
Particle and Fibre Toxicology , 2011, DOI: 10.1186/1743-8977-8-30
Abstract: In this study we addressed the question, whether a diet challenge increases the inflammatory response in the alveolar and the blood compartment in response to carbon nanoparticles (CNP), as a surrogate for ambient/urban particulate air pollutants.Mice were fed a high caloric carbohydrate-rich (CA) or a fat-rich (HF) diet for six weeks and were compared to mice kept on a purified low fat (LF) diet, respectively. Bronchoalveolar lavage (BAL) and blood samples were taken 24 h after intratracheal CNP instillation and checked for cellular and molecular markers of inflammation.The high caloric diets resulted in distinct effects when compared with LF mice, respectively: CA resulted in increased body and fat mass without affecting blood cellular immunity. Conversely, HF activated the blood system, increasing lymphocyte and neutrophil counts, and resulted in slightly increased body fat content. In contrast to higher pro-inflammatory BAL Leptin in CA and HF mice, on a cellular level, both diets did not lead to an increased pro-inflammatory basal status in the alveolar compartment per se, nor did result in differences in the particle-triggered response. However both diets resulted in a disturbance of the alveolar capillary barrier as indicated by enhanced BAL protein and lactate-dehydrogenase concentrations. Systemically, reduced serum Adiponectin in HF mice might be related to the observed white blood cell increase.The increase in BAL pro-inflammatory factors in high caloric groups and reductions in serum concentrations of anti-inflammatory factors in HF mice, clearly show diet-specific effects, pointing towards augmented systemic inflammatory conditions. Our data suggest that extended feeding periods, leading to manifest obesity, are necessary to generate an increased susceptibility to particle-induced lung inflammation; although the diet-challenge already was efficient in driving pro-inflammatory systemic events.Obesity and its common sequelae (e.g. type II diabetes and car
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