Translating neuronal activity at the synapse: presynaptic calcium sensors in short-term plasticity

The complex manner in which patterns of presynaptic neural activity are translated into short-term plasticity (STP) suggests the existence of multiple presynaptic calcium (Ca2+) sensors, which regulate the amplitude and time-course of STP and are the focus of this review. We describe two canonical Ca2+-binding protein domains (C2 domains and EF-hands) and define criteria that need to be met for a protein to qualify as a Ca2+ sensor mediating STP. With these criteria in mind, we discuss various forms of STP and identify established and putative Ca2+ sensors. We find that despite the multitude of proposed sensors, only three are well established in STP: Munc13, protein kinase C (PKC) and synaptotagmin-7. For putative sensors, we pinpoint open questions and potential pitfalls. Finally, we discuss how the molecular properties and modes of action of Ca2+ sensors can explain their differential involvement in STP and shape net synaptic output

Integrated sampling-and-sensing using microdialysis and biosensing by particle motion for continuous cortisol monitoring

Microdialysis catheters are small probes that allow sampling from biological systems and human subjects with minimal perturbation. Traditionally, microdialysis samples are collected in vials, transported to a laboratory, and analysed with typical turnaround times of hours to days. To realize a continuous sampling-and-sensing methodology with minimal time delay, we studied the integration of microdialysis sampling with a sensor for continuous biomolecular monitoring based on Biosensing by Particle Motion (BPM). A microfluidic flow cell was designed with a volume of 12 μl in order to be compatible with flowrates of microdialysis sampling. The analyte recovery and the time characteristics of the sampling-and-sensing system were studied using a food colorant in buffer and using cortisol in buffer and in blood plasma. Concentration step functions were applied, and the system response was measured using optical absorption and a continuous BPM cortisol sensor. The cortisol recovery was around 80% for a 30 mm microdialysis membrane with a 20 kDa molecular weight cut-off and a flowrate of 2 μl min−1. The concentration-time data could be fitted with a transport delay time and single-exponential relaxation curves. The total delay time of the sampling-and-sensing methodology was about 15 minutes. Continuous sampling-and-sensing was demonstrated over a period of 5 hours. These results represent an important step toward integrated sampling-and-sensing for the continuous monitoring of a wide variety of low-concentration biomolecular substances for applications in biological and biomedical research.</p

Integrated sampling-and-sensing using microdialysis and biosensing by particle motion for continuous cortisol monitoring

Microdialysis catheters are small probes that allow sampling from biological systems and human subjects with minimal perturbation. Traditionally, microdialysis samples are collected in vials, transported to a laboratory, and analysed with typical turnaround times of hours to days. To realize a continuous sampling-and-sensing methodology with minimal time delay, we studied the integration of microdialysis sampling with a sensor for continuous biomolecular monitoring based on Biosensing by Particle Motion (BPM). A microfluidic flow cell was designed with a volume of 12 μl in order to be compatible with flowrates of microdialysis sampling. The analyte recovery and the time characteristics of the sampling-and-sensing system were studied using a food colorant in buffer and using cortisol in buffer and in blood plasma. Concentration step functions were applied, and the system response was measured using optical absorption and a continuous BPM cortisol sensor. The cortisol recovery was around 80% for a 30 mm microdialysis membrane with a 20 kDa molecular weight cut-off and a flowrate of 2 μl min−1. The concentration-time data could be fitted with a transport delay time and single-exponential relaxation curves. The total delay time of the sampling-and-sensing methodology was about 15 minutes. Continuous sampling-and-sensing was demonstrated over a period of 5 hours. These results represent an important step toward integrated sampling-and-sensing for the continuous monitoring of a wide variety of low-concentration biomolecular substances for applications in biological and biomedical research.</p

Price Variations in a Stock Market With Many Agents

Large variations in stock prices happen with sufficient frequency to raise doubts about existing models, which all fail to account for non-Gaussian statistics. We construct simple models of a stock market, and argue that the large variations may be due to a crowd effect, where agents imitate each other's behavior. The variations over different time scales can be related to each other in a systematic way, similar to the Levy stable distribution proposed by Mandelbrot to describe real market indices. In the simplest, least realistic case, exact results for the statistics of the variations are derived by mapping onto a model of diffusing and annihilating particles, which has been solved by quantum field theory methods. When the agents imitate each other and respond to recent market volatility, different scaling behavior is obtained. In this case the statistics of price variations is consistent with empirical observations. The interplay between ``rational'' traders whose behavior is derived from fundamental analysis of the stock, including dividends, and ``noise traders'', whose behavior is governed solely by studying the market dynamics, is investigated. When the relative number of rational traders is small, ``bubbles'' often occur, where the market price moves outside the range justified by fundamental market analysis. When the number of rational traders is larger, the market price is generally locked within the price range they define.Comment: 39 pages (Latex) + 20 Figures and missing Figure 1 (sorry), submitted to J. Math. Eco

The validity of family size preference measurements in rural Latin America

Includes bibliograph

Towards continuous monitoring of TNF-α at picomolar concentrations using biosensing by particle motion

The ability to continuously monitor cytokines is desirable for fundamental research studies and healthcare applications. Cytokine release is characterized by picomolar circulating concentrations, short half-lives, and rapid peak times. Here, we describe the characteristics and feasibility of a particle-based biosensing technique for continuous monitoring of TNF-α at picomolar concentrations. The technique is based on the optical tracking of particle motion and uses an antibody sandwich configuration. Experimental results show how the analyte concentration influences the particle diffusivity and characteristic response time of the sensor, and how the sensitivity range depends on the antibody functionalization density. Furthermore, the data clarifies how antibodies supplemented in solution can shorten the characteristic response time. Finally, we demonstrate association rate-based sensing as a first step towards continuous monitoring of picomolar TNF-α concentrations, over a period of 2 h with delay times under 15 min. The insights from this research will enable the development of continuous monitoring sensors using high-affinity binders, providing the sensitivity and speed needed in applications like cytokine monitoring.</p

Sandwich Immunosensor Based on Particle Motion:How Do Reactant Concentrations and Reaction Pathways Determine the Time-Dependent Response of the Sensor?

To control and optimize the speed of a molecular biosensor, it is crucial to quantify and understand the mechanisms that underlie the time-dependent response of the sensor. Here, we study how the kinetic properties of a particle-based sandwich immunosensor depend on underlying parameters, such as reactant concentrations and the size of the reaction chamber. The data of the measured sensor responses could be fitted with single-exponential curves, with characteristic response times that depend on the analyte concentration and the binder concentrations on the particle and substrate. By comparing characteristic response times at different incubation configurations, the data clarifies how two distinct reaction pathways play a role in the sandwich immunosensor, namely, analyte binding first to particles and thereafter to the substrate, and analyte binding first to the substrate and thereafter to a particle. For a concrete biosensor design, we found that the biosensor is dominated by the reaction pathway where analyte molecules bind first to the substrate and thereafter to a particle. Within this pathway, the binding of a particle to the substrate-bound analyte dominates the sensor response time. Thus, the probability of a particle interacting with the substrate was identified as the main direction to improve the speed of the biosensor while maintaining good sensitivity. We expect that the developed immunosensor and research methodology can be generally applied to understand the reaction mechanisms and optimize the kinetic properties of sandwich immunosensors with particle labels.</p

Mass Models for Spiral Galaxies from 2-D Velocity Maps

We model the mass distributions of 40 high surface brightness spiral galaxies inside their optical radii, deriving parameters of mass models by matching the predicted velocities to observed velocity maps. We use constant mass-to-light disk and bulge models, and we have tried fits with no halo and with three different halo density profiles. The data require a halo in most, but not all, cases, while in others the best fit occurs with negligible mass in the luminous component, which we regard as unphysical. All three adopted halo profiles lead to fits of about the same quality, and our data therefore do not constrain the functional form of the halo profile. The halo parameters display large degeneracies for two of the three adopted halo functions, but the separate luminous and dark masses are better constrained. However, the fitted disk and halo masses vary substantially between the adopted halo models, indicating that even high quality 2-D optical velocity maps do not provide significant constraints on the dark matter content of a galaxy. We demonstrate that data from longslit observations are likely to provide still weaker constraints. We conclude that additional information is needed in order to constrain the separate disk and halo masses in a galaxy.Comment: 41 pages, 13 figures, accepted for publication in A

Protein kinase C is a calcium sensor for presynaptic short-term plasticity

In presynaptic boutons, calcium (Ca2+) triggers both neurotransmitter release and short-term synaptic plasticity. Whereas synaptotagmins are known to mediate vesicle fusion through binding of high local Ca2+ to their C2 domains, the proteins that sense smaller global Ca2+ increases to produce short-term plasticity have remained elusive. Here, we identify a Ca2+ sensor for post-tetanic potentiation (PTP), a form of plasticity thought to underlie short-term memory. We find that at the functionally mature calyx of Held synapse the Ca2+-dependent protein kinase C isoforms α and β are necessary for PTP, and the expression of PKCβ in PKCαβ double knockout mice rescues PTP. Disruption of Ca2+ binding to the PKCβ C2 domain specifically prevents PTP without impairing other PKCβ-dependent forms of synaptic enhancement. We conclude that different C2-domain-containing presynaptic proteins are engaged by different Ca2+ signals, and that Ca2+ increases evoked by tetanic stimulation are sensed by PKCβ to produce PTP. DOI: http://dx.doi.org/10.7554/eLife.03011.00