Mathematical modeling of the Drosophila neuromuscular junction

Poster presentation: An important challenge in neuroscience is understanding how networks of neurons go about processing information. Synapses are thought to play an essential role in cellular information processing however quantitative and mathematical models of the underlying physiologic processes that occur at synaptic active zones are lacking. We are generating mathematical models of synaptic vesicle dynamics at a well-characterized model synapse, the Drosophila larval neuromuscular junction. This synapse's simplicity, accessibility to various electrophysiological recording and imaging techniques, and the genetic malleability intrinsic to Drosophila system make it ideal for computational and mathematical studies. We have employed a reductionist approach and started by modeling single presynaptic boutons. Synaptic vesicles can be divided into different pools; however, a quantitative understanding of their dynamics at the Drosophila neuromuscular junction is lacking [4]. We performed biologically realistic simulations of high and low release probability boutons [3] using partial differential equations (PDE) taking into account not only the evolution in time but also the spatial structure in two dimensions (the extension to three dimensions will be implemented soon). PDEs are solved using UG, a program library for the calculation of multi-dimensional PDEs solved using a finite volume approach and implicit time stepping methods leading to extended linear equation systems be solvedwith multi-grid methods [3,4]. Numerical calculations are done on multi-processor computers for fast calculations using different parameters in order to asses the biological feasibility of different models. In preliminary simulations, we modeled vesicle dynamics as a diffusion process describing exocytosis as Neumann streams at synaptic active zones. The initial results obtained with these models are consistent with experimental data. However, this should be regarded as a work in progress. Further refinements will be implemented, including simulations using morphologically realistic geometries which were generated from confocal scans of the neuromuscular junction using NeuRA (a Neuron Reconstruction Algorithm). Other parameters such as glutamate diffusion and reuptake dynamics, as well as postsynaptic receptor kinetics will be incorporated as well

Pulse oximetry in the newborn: Is the left hand pre- or post-ductal?

Background: Over the past few years, great efforts have been made to screen duct-dependent congenital heart diseases in the newborn. Arterial pulse oximetry screening (foot and/or right hand) has been put forth as the most useful strategy to prevent circulatory collapse. The left hand, however, has always been ignored, as it was unclear if the ductus arteriosus influences left-hand arterial perfusion. The objective of our study was to evaluate the impact of the arterial duct on neonatal pulse oximetry saturation (POS) on the left hand. Methods: In this observational study, arterial oxygen saturation on both hands and on one foot was measured within the first 4 hours of life. Results: Two hundred fifty-one newborns were studied: 53% males and 47% were delivered by caesarean section. The median gestational age was 38 4/7 weeks (90% CI, 32 6/7 - 41 2/7 weeks), the median birth weight was 3140 g (90% CI, 1655 - 4110 g) and the median age at recording was 60 minutes (90% CI, 15 - 210 minutes). The mean POS for the overall study population was 95.7% (90% CI, 90 - 100%) on the right hand, 95.7% (90% CI, 90 - 100%) on the left hand, and 94.9% (90% CI, 86 - 100%) on the foot. Four subgroups (preterm infants, babies with respiratory disorders, neonates delivered by caesarean section, and newborns ≤15 minutes of age) were formed and analysed separately. None of the subgroups showed a statistically significant difference between the right and left hands. Additionally, multivariate logistic regression did not identify any associated factors influencing the POS on the left hand. Conclusions: With the exception of some children with complex or duct dependent congenital heart defects and some children with persistent pulmonary hypertension, POS on both hands can be considered equally pre-ductal

Stealth Proteins: In Silico Identification of a Novel Protein Family Rendering Bacterial Pathogens Invisible to Host Immune Defense

There are a variety of bacterial defense strategies to survive in a hostile environment. Generation of extracellular polysaccharides has proved to be a simple but effective strategy against the host's innate immune system. A comparative genomics approach led us to identify a new protein family termed Stealth, most likely involved in the synthesis of extracellular polysaccharides. This protein family is characterized by a series of domains conserved across phylogeny from bacteria to eukaryotes. In bacteria, Stealth (previously characterized as SacB, XcbA, or WefC) is encoded by subsets of strains mainly colonizing multicellular organisms, with evidence for a protective effect against the host innate immune defense. More specifically, integrating all the available information about Stealth proteins in bacteria, we propose that Stealth is a D-hexose-1-phosphoryl transferase involved in the synthesis of polysaccharides. In the animal kingdom, Stealth is strongly conserved across evolution from social amoebas to simple and complex multicellular organisms, such as Dictyostelium discoideum, hydra, and human. Based on the occurrence of Stealth in most Eukaryotes and a subset of Prokaryotes together with its potential role in extracellular polysaccharide synthesis, we propose that metazoan Stealth functions to regulate the innate immune system. Moreover, there is good reason to speculate that the acquisition and spread of Stealth could be responsible for future epidemic outbreaks of infectious diseases caused by a large variety of eubacterial pathogens. Our in silico identification of a homologous protein in the human host will help to elucidate the causes of Stealth-dependent virulence. At a more basic level, the characterization of the molecular and cellular function of Stealth proteins may shed light on fundamental mechanisms of innate immune defense against microbial invasion

EPD in its twentieth year: towards complete promoter coverage of selected model organisms

The Eukaryotic Promoter Database (EPD) is an annotated non-redundant collection of eukaryotic POL II promoters, experimentally defined by a transcription start site (TSS). Access to promoter sequences is provided by pointers to positions in the corresponding genomes. Promoter evidence comes from conventional TSS mapping experiments for individual genes, or, starting from release 73, from mass genome annotation projects. Subsets of promoter sequences with customized 5′ and 3′ extensions can be downloaded from the EPD website. The focus of current development efforts is to reach complete promoter coverage for important model organisms as soon as possible. To speed up this process, a new class of preliminary promoter entries has been introduced as of release 83, which requires less stringent admission criteria. As part of a continuous integration process, new web-based interfaces have been developed, which allow joint analysis of promoter sequences with other bioinformatics resources developed by our group, in particular programs offered by the Signal Search Analysis Server, and gene expression data stored in the CleanEx database. EPD can be accessed at

MADAP, a flexible clustering tool for the interpretation of one-dimensional genome annotation data

A recurring task in the analysis of mass genome annotation data from high-throughput technologies is the identification of peaks or clusters in a noisy signal profile. Examples of such applications are the definition of promoters on the basis of transcription start site profiles, the mapping of transcription factor binding sites based on ChIP-chip data and the identification of quantitative trait loci (QTL) from whole genome SNP profiles. Input to such an analysis is a set of genome coordinates associated with counts or intensities. The output consists of a discrete number of peaks with respective volumes, extensions and center positions. We have developed for this purpose a flexible one-dimensional clustering tool, called MADAP, which we make available as a web server and as standalone program. A set of parameters enables the user to customize the procedure to a specific problem. The web server, which returns results in textual and graphical form, is useful for small to medium-scale applications, as well as for evaluation and parameter tuning in view of large-scale applications, requiring a local installation. The program written in C++ can be freely downloaded from ftp://ftp.epd.unil.ch/pub/software/unix/madap. The MADAP web server can be accessed at http://www.isrec.isb-sib.ch/madap/

Synaptic boutons sizes are tuned to best fit their physiological performances

To truly appreciate the myriad of events which relate synaptic function and vesicle dynamics, simulations should be done in a spatially realistic environment. This holds true in particular in order to explain as well the rather astonishing motor patterns which we observed within in vivo recordings which underlie peristaltic contractionsas well as the shape of the EPSPs at different forms of long-term stimulation, presented both here, at a well characterized synapse, the neuromuscular junction (NMJ) of the Drosophila larva (c.f. Figure 1). To this end, we have employed a reductionist approach and generated three dimensional models of single presynaptic boutons at the Drosophila larval NMJ. Vesicle dynamics are described by diffusion-like partial differential equations which are solved numerically on unstructured grids using the uG platform. In our model we varied parameters such as bouton-size, vesicle output probability (Po), stimulation frequency and number of synapses, to observe how altering these parameters effected bouton function. Hence we demonstrate that the morphologic and physiologic specialization maybe a convergent evolutionary adaptation to regulate the trade off between sustained, low output, and short term, high output, synaptic signals. There seems to be a biologically meaningful explanation for the co-existence of the two different bouton types as previously observed at the NMJ (characterized especially by the relation between size and Po), the assigning of two different tasks with respect to short- and long-time behaviour could allow for an optimized interplay of different synapse types. We can present astonishing similar results of experimental and simulation data which could be gained in particular without any data fitting, however based only on biophysical values which could be taken from different experimental results. As a side product, we demonstrate how advanced methods from numerical mathematics could help in future to resolve also other difficult experimental neurobiological issues

Maximum strength benchmarks for difficult static elements on rings in male elite gymnastics

On rings, in men's artistic gymnastics, the general strength requirements for important static elements remain elusive. Therefore, the aim was to describe the relationship between a new conditioning strength test and a maximum strength test of static elements on rings in order to determine the minimal strength level (benchmarks) required to maintain these elements with one's own body weight. Nineteen elite gymnasts performed a concentric (1RM isoinertial) and eccentric (isokinetic: 0.1 m/s) conditioning strength test for swallow/support scale (supine position) and inverted cross (seated position) on a computer-controlled device and a maximum strength test maintaining these elements for 5 s on rings with counterweight or additional weight. High correlation coefficients were found between the conditioning maximum strength for swallow/support scale (r: 0.65 to 0.92; p 0.05) and the maximum strength of the elements on rings. Strength benchmarks varied between 56.66% (inverted cross concentric) and 94.10% (swallow eccentric) of body weight. Differences in biomechanical characteristics and technical requirements of strength elements on rings may (inter alia) explain the differences between correlations. Benchmarks of conditioning strength may help coaches and athletes systematize the training of strength elements on rings

A Simulation Tool Chain for Investigating Future V2X-based Automotive E/E Architectures

Due to the evermore rising number of functions, current E/E architectures are more and more a vulnerable source for faults and a barrier to innovation. This situation is aggravated by the integration of new technologies like Vehicle-to-X Communication (V2XC) which form the basis for a large number of future services and applications. At the same time, this “opening” of the E/E architecture to the outside world increases potential for non-deterministic disturbances. In order to overcome the limitations of current E/E architectures, application of new design principles and methodologies is necessary. Platform-based design (PBD) is a promising solution for the development of safety-critical functions, to increase reliability and to reduce development cost. Within this context, we propose a novel extensible tool chain that targets the facilitation of exploration, validation and verification of future V2X-based automotive E/E architectures. The tool chain supports composition of heterogeneous domain-specific models by integrating a heterogeneous modeling tool with a simulation middleware and serves as starting point for the investigation of PBD concepts in the V2X context. We believe that the tool chain can support modeling and validation of future V2X-based E/E architectures. In the final paper, we will evaluate the proposed approach by means of a case study regarding validation capabilities as well as execution performance

Synaptic bouton sizes are tuned to best fit their physiological performances : poster presentation from Twentieth Annual Computational Neuroscience Meeting: CNS*2011, Stockholm, Sweden, 23 - 28 July 2011

Poster presentation from Twentieth Annual Computational Neuroscience Meeting: CNS*2011 Stockholm, Sweden. 23-28 July 2011. To truly appreciate the myriad of events which relate synaptic function and vesicle dynamics, simulations should be done in a spatially realistic environment. This holds true in particular in order to explain the rather astonishing motor patterns presented here which we observed within in vivo recordings which underlie peristaltic contractions at a well characterized synapse, the neuromuscular junction (NMJ) of the Drosophila larva. To this end, we have employed a reductionist approach and generated three dimensional models of single presynaptic boutons at the Drosophila larval NMJ. Vesicle dynamics are described by diffusion-like partial differential equations which are solved numerically on unstructured grids using the uG platform. In our model we varied parameters such as bouton-size, vesicle output probability (Po), stimulation frequency and number of synapses, to observe how altering these parameters effected bouton function. Hence we demonstrate that the morphologic and physiologic specialization maybe a convergent evolutionary adaptation to regulate the trade off between sustained, low output, and short term, high output, synaptic signals. There seems to be a biologically meaningful explanation for the co-existence of the two different bouton types as previously observed at the NMJ (characterized especially by the relation between size and Po),the assigning of two different tasks with respect to short- and long-time behaviour could allow for an optimized interplay of different synapse types. As a side product, we demonstrate how advanced methods from numerical mathematics could help in future to resolve also other difficult experimental neurobiological issues