The astronaut and the banana peel: An EVA retriever scenario

To prepare for the problem of accidents in Space Station activities, the Extravehicular Activity Retriever (EVAR) robot is being constructed, whose purpose is to retrieve astronauts and tools that float free of the Space Station. Advanced Decision Systems is at the beginning of a project to develop research software capable of guiding EVAR through the retrieval process. This involves addressing problems in machine vision, dexterous manipulation, real time construction of programs via speech input, and reactive execution of plans despite the mishaps and unexpected conditions that arise in uncontrolled domains. The problem analysis phase of this work is presented. An EVAR scenario is used to elucidate major domain and technical problems. An overview of the technical approach to prototyping an EVAR system is also presented

A Proposal for Sniffer: a System that Understands Bugs

This paper proposes an interactive debugging aid that exhibits a deep understanding of a narrow class of bugs. This system, called Sniffer, will be able to find and identify errors, and explain them in terms which are relevant to the programmer. Sniffer is knowledgeable about side-effects. It is capable of citing the data which was in effect at the time an error became manifest. The debugging knowledge in Sniffer is organized as a collection of independent experts which know about particular errors. The experts (sniffers) perform their function by applying a feature recognition process to the text for the program, and to the events which took place during the execution of the code. No deductive machinery is involved. The experts are supported by two systems; the cliche finder which identifies small portions of algorithms from a plan for the code, and the time rover which provides complete access to all program states that ever existed. Sniffer is embedded in a run-time debugging aid. The user of the system interacts with the debugger to focus attention onto a manageable subset of the code, and then submits a complaint to the sniffer system that describes the behavior which was desired. Sniffer outputs a detailed report about any error which is discovered.MIT Artificial Intelligence Laborator

Microfluidic chromatography for early stage evaluation of biopharmaceutical binding and separation conditions

Optimization of separation conditions for biopharmaceuticals requires evaluation of a large number of process variables. To miniaturize this evaluation a microfluidic column (1.5 mu L volume and 1cm height) was fabricated and packed with a typical process scale resin. The device was assessed by comparison to a protein separation at conventional laboratory scale. This was based upon measurement of the quality of packing and generation of breakthrough and elution curves. Dynamic binding capacities from the microfluidic column compared well with the laboratory scale. Microfluidic scale gradient elution separations also equated to the laboratory column three orders of magnitude larger in scale

Ultrasound Imaging of Gene Expression in Mammalian Cells

The study of cellular processes occurring inside intact organisms requires methods to visualize cellular functions such as gene expression in deep tissues. Ultrasound is a widely used biomedical technology enabling noninvasive imaging with high spatial and temporal resolution. However, no genetically encoded molecular reporters are available to connect ultrasound contrast to gene expression in mammalian cells. To address this limitation, we introduce mammalian acoustic reporter genes. Starting with a gene cluster derived from bacteria, we engineered a eukaryotic genetic program whose introduction into mammalian cells results in the expression of intracellular air-filled protein nanostructures called gas vesicles, which produce ultrasound contrast. Mammalian acoustic reporter genes allow cells to be visualized at volumetric densities below 0.5% and permit high-resolution imaging of gene expression in living animals

Variability in Pediatric Infectious Disease Consultants' Recommendations for Management of Community-Acquired Pneumonia

Community-acquired pneumonia (CAP) is a common childhood infection. CAP complications, such as parapneumonic empyema (PPE), are increasing and are frequently caused by antibiotic-resistant organisms. No clinical guidelines currently exist for management of pediatric CAP and no published data exist about variations in antibiotic prescribing patterns. Our objectives were to describe variation in CAP clinical management for hospitalized children by pediatric infectious disease consultants and to examine associations between recommended antibiotic regimens and local antibiotic resistance levels. (MRSA) in their community.e or clindamycin use and clindamycin resistance, however, respondents were more likely to recommend an anti-MRSA agent when MRSA prevalence increased.Substantial variability exists in recommendations for CAP management. Development of clinical guidelines via antimicrobial stewardship programs and dissemination of data about local antibiotic resistance patterns represent opportunities to improve care

Acoustic biosensors for ultrasound imaging of enzyme activity

Visualizing biomolecular and cellular processes inside intact living organisms is a major goal of chemical biology. However, existing molecular biosensors, based primarily on fluorescent emission, have limited utility in this context due to the scattering of light by tissue. In contrast, ultrasound can easily image deep tissue with high spatiotemporal resolution, but lacks the biosensors needed to connect its contrast to the activity of specific biomolecules such as enzymes. To overcome this limitation, we introduce the first genetically encodable acoustic biosensors—molecules that ‘light up’ in ultrasound imaging in response to protease activity. These biosensors are based on a unique class of air-filled protein nanostructures called gas vesicles, which we engineered to produce nonlinear ultrasound signals in response to the activity of three different protease enzymes. We demonstrate the ability of these biosensors to be imaged in vitro, inside engineered probiotic bacteria, and in vivo in the mouse gastrointestinal tract

Complementary Patents and Market Structure

Many high technology goods are based on standards that require several essential patents owned by different IP holders. This gives rise to a complements and a double mark-up problem. We compare the welfare effects of two different business strategies dealing with these problems. Vertical integration of an IP holder and a downstream producer solves the double mark-up problem between these firms. Nevertheless, it may raise royalty rates and reduce output as compared to non-integration. Horizontal integration of IP holders solves the complements problem but not the double mark-up problem. Vertical integration discourages entry and reduces innovation incentives, while horizontal integration always benefits from entry and innovatio

Nonlinear X-Wave Ultrasound Imaging of Acoustic Biomolecules

The basic physics of sound waves enables ultrasound to visualize biological tissues with high spatial and temporal resolution. Recently, this capability was enhanced with the development of acoustic biomolecules—proteins with physical properties enabling them to scatter sound. The expression of these unique air-filled proteins, known as gas vesicles (GVs), in cells allows ultrasound to image cellular functions such as gene expression in vivo, providing ultrasound with its analog of optical fluorescent proteins. Acoustical methods for the in vivo detection of GVs are now required to maximize the impact of this technology in biology and medicine. We previously engineered GVs exhibiting a nonlinear scattering behavior in response to acoustic pressures above 300 kPa and showed that amplitude-modulated (AM) ultrasound pulse sequences that excite both the linear and nonlinear GV scattering regimes were highly effective at distinguishing GVs from linear scatterers like soft biological tissues. Unfortunately, the in vivo specificity of AM ultrasound imaging is systematically compromised by the nonlinearity added by the GVs to propagating waves, resulting in strong image artifacts from linear scatterers downstream of GV inclusions. To address this issue, we present an imaging paradigm, cross-amplitude modulation (xAM), which relies on cross-propagating plane-wave transmissions of finite aperture X waves to achieve quasi-artifact-free in vivo imaging of GVs. The xAM method derives from counterpropagating wave interaction theory, which predicts that, in media exhibiting quadratic elastic nonlinearity like biological tissue, the nonlinear interaction of counterpropagating acoustic waves is inefficient. By transmitting cross-propagating plane waves, we minimize cumulative nonlinear interaction effects due to collinear wave propagation while generating a transient wave-amplitude modulation at the two plane waves’ intersection. In both simulations and experiments, we show that residual xAM nonlinearity due to wave propagation decreases as the plane-wave cross-propagation angle increases. We demonstrate in tissue-mimicking phantoms that imaging artifacts distal to GV inclusions decrease as the plane-wave cross-propagation angle opens, nearing complete extinction at angles above 16.5 degrees. Finally, we demonstrate that xAM enables highly specific in vivo imaging of GVs located in the gastrointestinal tract, a target of prime interest for future cellular imaging. These results advance the physical facet of the emerging field of biomolecular ultrasound and are also relevant to synthetic ultrasound contrast agents

Ultrasound Imaging of Gene Expression in Mammalian Cells

The study of cellular processes occurring inside intact organisms requires methods to visualize cellular functions such as gene expression in deep tissues. Ultrasound is a widely used biomedical technology enabling noninvasive imaging with high spatial and temporal resolution. However, no genetically encoded molecular reporters are available to connect ultrasound contrast to gene expression in mammalian cells. To address this limitation, we introduce mammalian acoustic reporter genes. Starting with a gene cluster derived from bacteria, we engineered a eukaryotic genetic program whose introduction into mammalian cells results in the expression of intracellular air-filled protein nanostructures called gas vesicles, which produce ultrasound contrast. Mammalian acoustic reporter genes allow cells to be visualized at volumetric densities below 0.5% and permit high-resolution imaging of gene expression in living animals