TACCLE tests an automated assembly system in which the expected outcomes cannot be precisely defi... more TACCLE tests an automated assembly system in which the expected outcomes cannot be precisely defined and the actual results cannot be directly observed.
Proceedings of Tencon 93 Ieee Region 10 International Conference on Computers Communications and Automation, Nov 19, 1993
This paper presents an integrated programming language I which incorporates the logic and the fun... more This paper presents an integrated programming language I which incorporates the logic and the functional paradigms in an object-oriented framework. Our integration technique is based on dividing objects as either logic or functional objects. Methods in logic objects are modified Horn clauses which can invoke methods in functional objects. Methods in functional objects are applicative functions and are permitted to invoke methods in logic objects. The object-oriented nature makes methods be inheritable and have distributed execution environment (object). In addition, different levels of parallelism can be exploited in I.<<ETX>>
Functional, object-oriented and logic programming are widely regarded as the three most dominant ... more Functional, object-oriented and logic programming are widely regarded as the three most dominant programming paradigms nowadays. For the past decade, many attempts have been made to integrate these three paradigms into a single language. This paper is a survey of some of this new breed of multiparadigm languages. First we give a succinct introduction to the three paradigms. Then we discuss a variety of approaches to the integration of the three paradigms through an overview of 24 multiparadigm languages. All possible combinations of the three paradigms, namely logic + object-oriented, functional + logic, functional + object-oriented, and object-oriented + logic + functional, are considered separately. For the purpose of classification, we have proposed a design space of programming languages called the FOOL-space.
The latency of accessing instructions and data from the memory subsystem is an increasingly cruci... more The latency of accessing instructions and data from the memory subsystem is an increasingly crucial performance bottleneck in modern computer systems. While cache hierarchies are an important first step, they alone cannot solve the problem. Further, though a variety of latency-hiding techniques have been proposed, their success has been largely limited to regular, numeric applications. Few promising latency-hiding techniques that can handle irregular, non-numeric codes have been proposed, in spite of the popularity of such codes in computer applications. This dissertation investigates hardware and software techniques for coping with the instruction-access latency and data-access latency in non-numeric applications. To deal with instruction-access latency, we propose cooperative instruction prefetching , a novel technique which significantly outperforms state-of-the-art instruction prefetching schemes by being able to prefetch more aggressively and much further ahead of time while at the same time substantially reducing the amount of useless prefetches. To cope with data-access latency, we investigate three complementary techniques. First, we study how to use compiler-inserted data prefetching to tolerate the latency of accessing pointer-based data structures. To schedule prefetches early enough, we design three prefetching schemes to overcome the pointer-chasing problem associated with these data structures, and we automate them in an optimizing research compiler. Second, we study how to safely perform an important class of locality optimizations, namely dynamic data layout optimizations, in non-numeric codes. Specifically, we propose the use of an architectural mechanism called memory forwarding which can guarantee the safety of data relocation, thereby enabling many aggressive data layout optimizations (which also facilitate prefetching) that cannot be safely performed using current hardware or compiler technology. Finally, in an effort to minimize the overheads of latency tolerance techniques, we propose new cache miss prediction techniques based on correlation profiling. By correlating cache miss behaviors with dynamic execution contexts, these techniques can accurately isolate dynamic miss instances and so pay the latency tolerance overhead only when there would have been cache misses. Detailed design considerations and experimental evaluations are provided for our proposed techniques, confirming them as viable solutions for coping with memory latency in non-numeric applications.
Gold to gold interconnection (GGI) flip chip bonding technology has been developed to bond the dr... more Gold to gold interconnection (GGI) flip chip bonding technology has been developed to bond the drive IC chip on the integrated circuit suspension used in hard disk drives. GGI is a lead free process where the Au bumps and Au bond pads are joined together by heat and ultrasonic power under a pressure head. The use of GGI flip chip
ABSTRACT Microelectrode array (MEA) is a noninvasive method for recording brain cell activity and... more ABSTRACT Microelectrode array (MEA) is a noninvasive method for recording brain cell activity and has been successfully applied to an array of neurons. However, using MEAs to consistently stimulate neurons over an extended period of time has been less successful and continues to be problematic. In order to optimize the neuron stimulation in a physiological manner, it is necessary to design a more effective neuron-electrode junction. Several finite element models have been used for neuronal simulation, with investigations considering: the influence of electrode size on the recorded signal amplitude, current and potential field distributions around a stimulating MEA, different cell and electrode radii and various sealing gap thicknesses. However, optimized microelectrode size, shape, material, adhesion material and thickness used at the cell-electrode interface have not been investigated. In the present research, the electric field pattern for different stimulation voltages, electrode dimensions and materials is being investigated, in order to optimize the electrode geometry to obtain the largest electric field in the cell.
We report on a simple and high-yield manufacturing process for silicon planar patch-clamp chips, ... more We report on a simple and high-yield manufacturing process for silicon planar patch-clamp chips, which allow low capacitance and series resistance from individually identified cultured neurons. Apertures are etched in a high-quality silicon nitride film on a silicon wafer; wells are opened on the backside of the wafer by wet etching and passivated by a thick deposited silicon dioxide film to reduce the capacitance of the chip and to facilitate the formation of a high-impedance cell to aperture seal. The chip surface is suitable for culture of neurons over a small orifice in the substrate with minimal leak current. Collectively, these features enable high-fidelity electrophysiological recording of transmembrane currents resulting from ion channel activity in cultured neurons. Using cultured Lymnaea neurons we demonstrate whole-cell current recordings obtained from a voltage-clamp stimulation protocol, and in current-clamp mode we report action potentials stimulated by membrane depolarization steps. Despite the relatively large size of these neurons, good temporal and spatial control of cell membrane voltage was evident. To our knowledge this is the first report of recording of ion channel activity and action potentials from neurons cultured directly on a planar patch-clamp chip. This interrogation platform has enormous potential as a novel tool to readily provide high-information content during pharmaceutical assays to investigate in vitro models of disease, as well as neuronal physiology and synaptic plasticity.
Planar patch-clamp chip technology has been developed to enhance the assessment of novel compound... more Planar patch-clamp chip technology has been developed to enhance the assessment of novel compounds for therapeutic efficacy and safety. However, this technology has been limited to recording ion channels expressed in isolated suspended cells, making the study of ion channel function in synaptic transmission impractical. Recently, we developed single- and dual-recording site planar patch-clamp chips and demonstrated their capacity to
Current market conditions demand that hard disk drive (HDD) manufacturers adopt advanced technolo... more Current market conditions demand that hard disk drive (HDD) manufacturers adopt advanced technology in every area of drive design to improve drive capacity and performance and simultaneously reduce unit cost. Head stack suppliers in HDD industry are constantly working on high density interconnect technologies to provide faster and higher capacity and cheaper head stack components for disk drives. A low
We present a polymer microchip capable of monitoring neuronal activity with a fidelity never befo... more We present a polymer microchip capable of monitoring neuronal activity with a fidelity never before obtained on a planar patch-clamp device. Cardio-respiratory neurons Left Pedal Dorsal 1 (LPeD1) from mollusc Lymnaea were cultured on the microchip's polyimide surface for 2 to 4 hours. Cultured neurons formed high resistance seals (gigaseals) between the cell membrane and the surface surrounding apertures etched in the polyimide. Gigaseal formation was observed without applying external force, such as suction, on neurons. The formation of gigaseals, as well as the low access resistance and shunt capacitance values of the polymer microchip resulted in high-fidelity recordings. On-chip culture of neurons permitted, for the first time on a polymeric patch-clamp device, the recording of high fidelity physiological action potentials. Microfabrication of the hybrid poly(dimethylsiloxane)-poly-imide (PDMS-PI) microchip is discussed, including a two-layer PDMS processing technique resulting in minimized shrinking variations.
TACCLE tests an automated assembly system in which the expected outcomes cannot be precisely defi... more TACCLE tests an automated assembly system in which the expected outcomes cannot be precisely defined and the actual results cannot be directly observed.
Current treatment regimes for a variety of mental disorders involve various selective serotonin r... more Current treatment regimes for a variety of mental disorders involve various selective serotonin reuptake inhibitors such as Fluoxetine (Prozac). Although these drugs may 'manage' the patient better, there has not been a significant change in the treatment paradigm over the years and neither have the outcomes improved. There is also considerable debate as to the effectiveness of various selective serotonin reuptake inhibitors and their potential side-effects on neuronal architecture and function. In this study, using mammalian cortical neurons, a dorsal root ganglia cell line (F11 cells) and identified Lymnaea stagnalis neurons, we provide the first direct and unequivocal evidence that clinically relevant concentrations of Fluoxetine induce growth cone collapse and neurite retraction of both serotonergic and non-serotonergic neurons alike in a dose-dependent manner. Using intracellular recordings and calcium imaging techniques, we further demonstrate that the mechanism underlying Fluoxetine-induced effects on neurite retraction from Lymnaea neurons may involve lowering of intracellular calcium and a subsequent retardation of growth cone cytoskeleton. Using soma-soma synapses between identified presynaptic and postsynaptic Lymnaea neurons, we provide further direct evidence that clinically used concentrations of Fluoxetine also block synaptic transmission and synapse formation between cholinergic neurons. Our study raises alarms over potentially devastating side-effects of this antidepressant drug on neurite outgrowth and synapse formation in a developing ⁄ regenerating brain. Our data also demonstrate that drugs such as Fluoxetine may not just affect communication between serotonergic neurons but that the detrimental effects are widespread and involve neurons of various phenotypes from both vertebrate and invertebrate species.
TACCLE tests an automated assembly system in which the expected outcomes cannot be precisely defi... more TACCLE tests an automated assembly system in which the expected outcomes cannot be precisely defined and the actual results cannot be directly observed.
Proceedings of Tencon 93 Ieee Region 10 International Conference on Computers Communications and Automation, Nov 19, 1993
This paper presents an integrated programming language I which incorporates the logic and the fun... more This paper presents an integrated programming language I which incorporates the logic and the functional paradigms in an object-oriented framework. Our integration technique is based on dividing objects as either logic or functional objects. Methods in logic objects are modified Horn clauses which can invoke methods in functional objects. Methods in functional objects are applicative functions and are permitted to invoke methods in logic objects. The object-oriented nature makes methods be inheritable and have distributed execution environment (object). In addition, different levels of parallelism can be exploited in I.<<ETX>>
Functional, object-oriented and logic programming are widely regarded as the three most dominant ... more Functional, object-oriented and logic programming are widely regarded as the three most dominant programming paradigms nowadays. For the past decade, many attempts have been made to integrate these three paradigms into a single language. This paper is a survey of some of this new breed of multiparadigm languages. First we give a succinct introduction to the three paradigms. Then we discuss a variety of approaches to the integration of the three paradigms through an overview of 24 multiparadigm languages. All possible combinations of the three paradigms, namely logic + object-oriented, functional + logic, functional + object-oriented, and object-oriented + logic + functional, are considered separately. For the purpose of classification, we have proposed a design space of programming languages called the FOOL-space.
The latency of accessing instructions and data from the memory subsystem is an increasingly cruci... more The latency of accessing instructions and data from the memory subsystem is an increasingly crucial performance bottleneck in modern computer systems. While cache hierarchies are an important first step, they alone cannot solve the problem. Further, though a variety of latency-hiding techniques have been proposed, their success has been largely limited to regular, numeric applications. Few promising latency-hiding techniques that can handle irregular, non-numeric codes have been proposed, in spite of the popularity of such codes in computer applications. This dissertation investigates hardware and software techniques for coping with the instruction-access latency and data-access latency in non-numeric applications. To deal with instruction-access latency, we propose cooperative instruction prefetching , a novel technique which significantly outperforms state-of-the-art instruction prefetching schemes by being able to prefetch more aggressively and much further ahead of time while at the same time substantially reducing the amount of useless prefetches. To cope with data-access latency, we investigate three complementary techniques. First, we study how to use compiler-inserted data prefetching to tolerate the latency of accessing pointer-based data structures. To schedule prefetches early enough, we design three prefetching schemes to overcome the pointer-chasing problem associated with these data structures, and we automate them in an optimizing research compiler. Second, we study how to safely perform an important class of locality optimizations, namely dynamic data layout optimizations, in non-numeric codes. Specifically, we propose the use of an architectural mechanism called memory forwarding which can guarantee the safety of data relocation, thereby enabling many aggressive data layout optimizations (which also facilitate prefetching) that cannot be safely performed using current hardware or compiler technology. Finally, in an effort to minimize the overheads of latency tolerance techniques, we propose new cache miss prediction techniques based on correlation profiling. By correlating cache miss behaviors with dynamic execution contexts, these techniques can accurately isolate dynamic miss instances and so pay the latency tolerance overhead only when there would have been cache misses. Detailed design considerations and experimental evaluations are provided for our proposed techniques, confirming them as viable solutions for coping with memory latency in non-numeric applications.
Gold to gold interconnection (GGI) flip chip bonding technology has been developed to bond the dr... more Gold to gold interconnection (GGI) flip chip bonding technology has been developed to bond the drive IC chip on the integrated circuit suspension used in hard disk drives. GGI is a lead free process where the Au bumps and Au bond pads are joined together by heat and ultrasonic power under a pressure head. The use of GGI flip chip
ABSTRACT Microelectrode array (MEA) is a noninvasive method for recording brain cell activity and... more ABSTRACT Microelectrode array (MEA) is a noninvasive method for recording brain cell activity and has been successfully applied to an array of neurons. However, using MEAs to consistently stimulate neurons over an extended period of time has been less successful and continues to be problematic. In order to optimize the neuron stimulation in a physiological manner, it is necessary to design a more effective neuron-electrode junction. Several finite element models have been used for neuronal simulation, with investigations considering: the influence of electrode size on the recorded signal amplitude, current and potential field distributions around a stimulating MEA, different cell and electrode radii and various sealing gap thicknesses. However, optimized microelectrode size, shape, material, adhesion material and thickness used at the cell-electrode interface have not been investigated. In the present research, the electric field pattern for different stimulation voltages, electrode dimensions and materials is being investigated, in order to optimize the electrode geometry to obtain the largest electric field in the cell.
We report on a simple and high-yield manufacturing process for silicon planar patch-clamp chips, ... more We report on a simple and high-yield manufacturing process for silicon planar patch-clamp chips, which allow low capacitance and series resistance from individually identified cultured neurons. Apertures are etched in a high-quality silicon nitride film on a silicon wafer; wells are opened on the backside of the wafer by wet etching and passivated by a thick deposited silicon dioxide film to reduce the capacitance of the chip and to facilitate the formation of a high-impedance cell to aperture seal. The chip surface is suitable for culture of neurons over a small orifice in the substrate with minimal leak current. Collectively, these features enable high-fidelity electrophysiological recording of transmembrane currents resulting from ion channel activity in cultured neurons. Using cultured Lymnaea neurons we demonstrate whole-cell current recordings obtained from a voltage-clamp stimulation protocol, and in current-clamp mode we report action potentials stimulated by membrane depolarization steps. Despite the relatively large size of these neurons, good temporal and spatial control of cell membrane voltage was evident. To our knowledge this is the first report of recording of ion channel activity and action potentials from neurons cultured directly on a planar patch-clamp chip. This interrogation platform has enormous potential as a novel tool to readily provide high-information content during pharmaceutical assays to investigate in vitro models of disease, as well as neuronal physiology and synaptic plasticity.
Planar patch-clamp chip technology has been developed to enhance the assessment of novel compound... more Planar patch-clamp chip technology has been developed to enhance the assessment of novel compounds for therapeutic efficacy and safety. However, this technology has been limited to recording ion channels expressed in isolated suspended cells, making the study of ion channel function in synaptic transmission impractical. Recently, we developed single- and dual-recording site planar patch-clamp chips and demonstrated their capacity to
Current market conditions demand that hard disk drive (HDD) manufacturers adopt advanced technolo... more Current market conditions demand that hard disk drive (HDD) manufacturers adopt advanced technology in every area of drive design to improve drive capacity and performance and simultaneously reduce unit cost. Head stack suppliers in HDD industry are constantly working on high density interconnect technologies to provide faster and higher capacity and cheaper head stack components for disk drives. A low
We present a polymer microchip capable of monitoring neuronal activity with a fidelity never befo... more We present a polymer microchip capable of monitoring neuronal activity with a fidelity never before obtained on a planar patch-clamp device. Cardio-respiratory neurons Left Pedal Dorsal 1 (LPeD1) from mollusc Lymnaea were cultured on the microchip's polyimide surface for 2 to 4 hours. Cultured neurons formed high resistance seals (gigaseals) between the cell membrane and the surface surrounding apertures etched in the polyimide. Gigaseal formation was observed without applying external force, such as suction, on neurons. The formation of gigaseals, as well as the low access resistance and shunt capacitance values of the polymer microchip resulted in high-fidelity recordings. On-chip culture of neurons permitted, for the first time on a polymeric patch-clamp device, the recording of high fidelity physiological action potentials. Microfabrication of the hybrid poly(dimethylsiloxane)-poly-imide (PDMS-PI) microchip is discussed, including a two-layer PDMS processing technique resulting in minimized shrinking variations.
TACCLE tests an automated assembly system in which the expected outcomes cannot be precisely defi... more TACCLE tests an automated assembly system in which the expected outcomes cannot be precisely defined and the actual results cannot be directly observed.
Current treatment regimes for a variety of mental disorders involve various selective serotonin r... more Current treatment regimes for a variety of mental disorders involve various selective serotonin reuptake inhibitors such as Fluoxetine (Prozac). Although these drugs may 'manage' the patient better, there has not been a significant change in the treatment paradigm over the years and neither have the outcomes improved. There is also considerable debate as to the effectiveness of various selective serotonin reuptake inhibitors and their potential side-effects on neuronal architecture and function. In this study, using mammalian cortical neurons, a dorsal root ganglia cell line (F11 cells) and identified Lymnaea stagnalis neurons, we provide the first direct and unequivocal evidence that clinically relevant concentrations of Fluoxetine induce growth cone collapse and neurite retraction of both serotonergic and non-serotonergic neurons alike in a dose-dependent manner. Using intracellular recordings and calcium imaging techniques, we further demonstrate that the mechanism underlying Fluoxetine-induced effects on neurite retraction from Lymnaea neurons may involve lowering of intracellular calcium and a subsequent retardation of growth cone cytoskeleton. Using soma-soma synapses between identified presynaptic and postsynaptic Lymnaea neurons, we provide further direct evidence that clinically used concentrations of Fluoxetine also block synaptic transmission and synapse formation between cholinergic neurons. Our study raises alarms over potentially devastating side-effects of this antidepressant drug on neurite outgrowth and synapse formation in a developing ⁄ regenerating brain. Our data also demonstrate that drugs such as Fluoxetine may not just affect communication between serotonergic neurons but that the detrimental effects are widespread and involve neurons of various phenotypes from both vertebrate and invertebrate species.
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