Regulation of Bestrophins by Ca2+: A Theoretical and Experimental Study

Bestrophins are a recently discovered family of Cl− channels, for which no structural information is available. Some family members are activated by increased intracellular Ca2+ concentration. Bestrophins feature a well conserved Asp-rich tract in their COOH terminus (Asp-rich domain), which is homologous to Ca2+-binding motifs in human thrombospondins and in human big-conductance Ca2+- and voltage-gated K+ channels (BKCa). Consequently, the Asp-rich domain is also a candidate for Ca2+ binding in bestrophins. Based on these considerations, we constructed homology models of human bestrophin-1 (Best1) Asp-rich domain using human thrombospondin-1 X-ray structure as a template. Molecular dynamics simulations were used to identify Asp and Glu residues binding Ca2+ and to predict the effects of their mutations to alanine. We then proceeded to test selected mutations in the Asp-rich domain of the highly homologous mouse bestrophin-2. The mutants expressed in HEK-293 cells were investigated by electrophysiological experiments using the whole-cell voltage-clamp technique. Based on our molecular modeling results, we predicted that Asp-rich domain has two defined binding sites and that D301A and D304A mutations may impact the binding of the metal ions. The experiments confirmed that these mutations do actually affect the function of the protein causing a large decrease in the Ca2+-activated Cl− current, fully consistent with our predictions. In addition, other studied mutations (E306A, D312A) did not decrease Ca2+-activated Cl− current in agreement with modeling results

Regulation of Bestrophins by Ca2+: A Theoretical and Experimental Study

Bestrophins are a recently discovered family of Cl− channels, for which no structural information is available. Some family members are activated by increased intracellular Ca2+ concentration. Bestrophins feature a well conserved Asp-rich tract in their COOH terminus (Asp-rich domain), which is homologous to Ca2+-binding motifs in human thrombospondins and in human big-conductance Ca2+- and voltage-gated K+ channels (BKCa). Consequently, the Asp-rich domain is also a candidate for Ca2+ binding in bestrophins. Based on these considerations, we constructed homology models of human bestrophin-1 (Best1) Asp-rich domain using human thrombospondin-1 X-ray structure as a template. Molecular dynamics simulations were used to identify Asp and Glu residues binding Ca2+ and to predict the effects of their mutations to alanine. We then proceeded to test selected mutations in the Asp-rich domain of the highly homologous mouse bestrophin-2. The mutants expressed in HEK-293 cells were investigated by electrophysiological experiments using the whole-cell voltage-clamp technique. Based on our molecular modeling results, we predicted that Asp-rich domain has two defined binding sites and that D301A and D304A mutations may impact the binding of the metal ions. The experiments confirmed that these mutations do actually affect the function of the protein causing a large decrease in the Ca2+-activated Cl− current, fully consistent with our predictions. In addition, other studied mutations (E306A, D312A) did not decrease Ca2+-activated Cl− current in agreement with modeling results

Multi-objective turbomachinery optimization using a gradient-enhanced multi-layer perceptron

Response surface models (RSMs) have found widespread use to reduce the overall computational cost of turbomachinery blading design optimization. Recent developments have seen the successful use of gradient information alongside sampled response values in building accurate response surfaces. This paper describes the use of gradients to enhance the performance of the RSM provided by a multi-layer perceptron. Gradient information is included in the perceptron by modifying the error function such that the perceptron is trained to fit the gradients as well as the response values. As a consequence, the back-propagation scheme that assists the training is also changed. The paper formulates the gradient-enhanced multi-layer perceptron using algebraic notation, with an emphasis on the ease of use and efficiency of computer code implementation. To illustrate the benefit of using gradient information, the enhanced neural network model is used in a multi-objective transonic fan blade optimization exercise of engineering relevance. Copyright © 2008 John Wiley and Sons, Ltd

US patent no: 7,426,449 B2: Sensor fusion using self-evaluating process sensors

A measurement processing system is disclosed for fusing measurement data from a set of independent self-validating (SEVA™) process sensors monitoring the same real-time measurand in order to generate a combined best estimate for the value, uncertainty and measurement status of the measurand. The system also provides consistency checking between the measurements. The measurement processing system includes a first process sensor and a second process sensor. Each of the first and second process sensors receive a measurement signal from a transducer and generate independent process metrics. A measurement fusion block is connected to the first and second process sensors, the measurement fusion block is operable to receive the independent process metrics and execute a measurement analysis process to analyze the independent process metrics and generate the combined best estimate of the independent process metrics

US patent no. 8,090,552 B2: Sensor fusion using self-evaluating process sensors

A measurement processing system is disclosed for fusing measurement data from a set of independent self-validating (SEVA™) process sensors monitoring the same real-time measurand in order to generate a combined best estimate for the value, uncertainty and measurement status of the measurand. The system also provides consistency checking between the measurements. The measurement processing system includes a first process sensor and a second process sensor. Each of the first and second process sensors receive a measurement signal from a transducer and generate independent process metrics. A measurement fusion block is connected to the first and second process sensors, the measurement fusion block is operable to receive the independent process metrics and execute a measurement analysis process to analyze the independent process metrics and generate the combined best estimate of the independent process metrics

US patent no: 7,426,449 B2: Sensor fusion using self-evaluating process sensors

A measurement processing system is disclosed for fusing measurement data from a set of independent self-validating (SEVA™) process sensors monitoring the same real-time measurand in order to generate a combined best estimate for the value, uncertainty and measurement status of the measurand. The system also provides consistency checking between the measurements. The measurement processing system includes a first process sensor and a second process sensor. Each of the first and second process sensors receive a measurement signal from a transducer and generate independent process metrics. A measurement fusion block is connected to the first and second process sensors, the measurement fusion block is operable to receive the independent process metrics and execute a measurement analysis process to analyze the independent process metrics and generate the combined best estimate of the independent process metrics

Consistency checking and combining measurement results for a wireless sensor network

Two similar approaches are presented for performing consistency checking of measured data in cases where associated uncertainty values are provided. The key differences between the approaches concern the determination of a consistent subset, and the treatment of measured data deemed to fall outside that subset. The different approaches reflect the priorities of their respective domains of application, namely on-line sensor monitoring, and interlaboratory comparisons

US patent no. 8,090,552 B2: Sensor fusion using self-evaluating process sensors

A measurement processing system is disclosed for fusing measurement data from a set of independent self-validating (SEVA™) process sensors monitoring the same real-time measurand in order to generate a combined best estimate for the value, uncertainty and measurement status of the measurand. The system also provides consistency checking between the measurements. The measurement processing system includes a first process sensor and a second process sensor. Each of the first and second process sensors receive a measurement signal from a transducer and generate independent process metrics. A measurement fusion block is connected to the first and second process sensors, the measurement fusion block is operable to receive the independent process metrics and execute a measurement analysis process to analyze the independent process metrics and generate the combined best estimate of the independent process metrics

Coriolis frequency tracking

Motion is induced in a conduit such that the conduit vibrates in a major mode of vibration having a major amplitude and a minor mode of vibration having a minor amplitude. The major amplitude is larger than the minor amplitude, the major mode of vibration has a first frequency of vibration and the minor mode of vibration has a second frequency of vibration, and the minor mode of vibration interferes with the major mode of vibration to cause a beat signal having a frequency related to the first frequency of vibration and the second frequency of vibration. The frequency of the beat signal is determined, and the second frequency of vibration is determined based on the determined frequency of the beat signal