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Results for “genetic manipulation”

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All sources NASA NTRS DOE OSTI

NASA NTRS2018

Genetic Regulation of Bone and Cells by Electromagnetic Stimulation Fields and Uses Thereof

The present invention provides methods to modify the genetic regulation of mammalian tissue, bone, cells or any combination thereof by preferential activation, up-regulation and/or down-regulation. The method comprises steps of tuning the predetermined profiles of one or more time-varying stimulation fields by manipulating the B-Field magnitude, rising slew rate, rise time, falling slew rate, fall time, frequency, wavelength, and duty cycle, and exposing mammalian cells or tissues to one or more tuned time-varying stimulation fields with predetermined profiles. Examples of mammalian cells or tissues are chondrocytes, osteoblasts, osteocytes, osteoclasts, nucleus pulposus, associated tissue, or any combination. The resulted modification on gene regulation of these cells, tissues or bones may promote the retention, repair of and reduction of compromised mammalian cartilage, bone, and associated tissue.

Goodwin, Thomas J.↗

NASA NTRS1993

WNN 92; Proceedings of the 3rd Workshop on Neural Networks: Academic/Industrial/NASA/Defense, Auburn Univ., AL, Feb. 10-12, 1992 and South Shore Harbour, TX, Nov. 4-6, 1992

The present conference discusses such neural networks (NN) related topics as their current development status, NN architectures, NN learning rules, NN optimization methods, NN temporal models, NN control methods, NN pattern recognition systems and applications, biological and biomedical applications of NNs, VLSI design techniques for NNs, NN systems simulation, fuzzy logic, and genetic algorithms. Attention is given to missileborne integrated NNs, adaptive-mixture NNs, implementable learning rules, an NN simulator for travelling salesman problem solutions, similarity-based forecasting, NN control of hypersonic aircraft takeoff, NN control of the Space Shuttle Arm, an adaptive NN robot manipulator controller, a synthetic approach to digital filtering, NNs for speech analysis, adaptive spline networks, an anticipatory fuzzy logic controller, and encoding operations for fuzzy associative memories.

Padgett, Mary L.↗

NASA NTRS2002

Leptin regulates bone formation via the sympathetic nervous system

We previously showed that leptin inhibits bone formation by an undefined mechanism. Here, we show that hypothalamic leptin-dependent antiosteogenic and anorexigenic networks differ, and that the peripheral mediators of leptin antiosteogenic function appear to be neuronal. Neuropeptides mediating leptin anorexigenic function do not affect bone formation. Leptin deficiency results in low sympathetic tone, and genetic or pharmacological ablation of adrenergic signaling leads to a leptin-resistant high bone mass. beta-adrenergic receptors on osteoblasts regulate their proliferation, and a beta-adrenergic agonist decreases bone mass in leptin-deficient and wild-type mice while a beta-adrenergic antagonist increases bone mass in wild-type and ovariectomized mice. None of these manipulations affects body weight. This study demonstrates a leptin-dependent neuronal regulation of bone formation with potential therapeutic implications for osteoporosis.

NASA Discipline Regulatory Physiology↗

NASA NTRS1998

Fuzzy Control of Flexible-Link Manipulators: A Review

Several recent research efforts are reviewed here which have applied fuzzy logic in control of flexible-link manipulators. A flexible robot is a distributed parameter system represented by complex nonlinear dynamics, its actuator and the control parameters are non-colocated, and lastly, unstructured/unknown parameters play a significant role in model dynamics of a flexible robot operating in the real world. As a result, control of flexible robots is considered a promising area for application of intelligent control methodologies such as fuzzy logic, genetic algorithms, and neural networks.

Akbarzadeh-T, M.-R.↗

NASA NTRS1990

Intelligent control and adaptive systems; Proceedings of the Meeting, Philadelphia, PA, Nov. 7, 8, 1989

Various papers on intelligent control and adaptive systems are presented. Individual topics addressed include: control architecture for a Mars walking vehicle, representation for error detection and recovery in robot task plans, real-time operating system for robots, execution monitoring of a mobile robot system, statistical mechanics models for motion and force planning, global kinematics for manipulator planning and control, exploration of unknown mechanical assemblies through manipulation, low-level representations for robot vision, harmonic functions for robot path construction, simulation of dual behavior of an autonomous system. Also discussed are: control framework for hand-arm coordination, neural network approach to multivehicle navigation, electronic neural networks for global optimization, neural network for L1 norm linear regression, planning for assembly with robot hands, neural networks in dynamical systems, control design with iterative learning, improved fuzzy process control of spacecraft autonomous rendezvous using a genetic algorithm.

Rodriguez, Guillermo↗

NASA NTRS2000

Genetic dissection of cardiac growth control pathways

Cardiac muscle cells exhibit two related but distinct modes of growth that are highly regulated during development and disease. Cardiac myocytes rapidly proliferate during fetal life but exit the cell cycle irreversibly soon after birth, following which the predominant form of growth shifts from hyperplastic to hypertrophic. Much research has focused on identifying the candidate mitogens, hypertrophic agonists, and signaling pathways that mediate these processes in isolated cells. What drives the proliferative growth of embryonic myocardium in vivo and the mechanisms by which adult cardiac myocytes hypertrophy in vivo are less clear. Efforts to answer these questions have benefited from rapid progress made in techniques to manipulate the murine genome. Complementary technologies for gain- and loss-of-function now permit a mutational analysis of these growth control pathways in vivo in the intact heart. These studies have confirmed the importance of suspected pathways, have implicated unexpected pathways as well, and have led to new paradigms for the control of cardiac growth.

NASA Program Biomedical Research and Countermeasur↗

NASA NTRS2001

Antisense and sense expression of cDNA coding for CYP73A15, a class II cinnamate 4-hydroxylase, leads to a delayed and reduced production of lignin in tobacco

A number of plant species contain the class II of genes encoding the cytochrome P450, CYP73, the cognate protein of which cinnamic acid 4-hydroxylase, is the second enzyme of the phenylpropanoid pathway. In order to begin to determine possible functionality, tobacco has been transformed with a truncated French bean class II cinnamate hydroxylase (CYP73A15) in the sense and antisense orientations. Signals for C4H protein could be detected in vascular tissue from wild-type plants using heterologous probes. The transformed plants showed a normal phenotype, even though detectable C4H protein was much reduced in tissue prints. Young propagated transformants displayed a range of reduced C4H activities, as well as either reduced or no phloroglucinol-stainable lignin. However, all mature tobacco plants showed the accumulation of lignin, even though its deposition was apparently delayed. This was not due to induction of tyrosine ammonia-lyase activity, which was not detected, but instead it is presumed due to sufficient C4H residual activity. Analysis of the lignin content of the plants showed reductions of up to 30% with a slightly reduced syringyl to guaiacyl ratio as compared to wild type. This reduction level was favourable in comparison with some other targets in the lignification pathway that have been manipulated including that of class I cinnamate 4-hydroxylase. It is proposed that the class II cinnamate 4-hydroxylase might also function in lignification in a number of species including French bean and tobacco, based on these data.

NASA Discipline Plant Biology↗

NASA NTRS1998

How do tissues respond to damage at the cellular level? The role of cytokines in irradiated tissues

The capacity of ionizing radiation to affect tissue function, control tumor growth and elicit pathological sequelae has been attributed in great part to its effects on cellular DNA, which, as the transmitter of genetic information, can both register damage and perpetuate it. Nonetheless, multicellular organisms function as the result of the cooperation of many cell types. What then occurs when individual cells are damaged by ionizing radiation? Is tissue response a sum of cellular effects such as cell death and DNA damage? Or does the tissue respond as a coherent unit to the damage of its parts? In this paper, data in support of the latter model that indicate a role for cytokines, in particular transforming growth factor beta1, as critical components of extracellular signaling pathways that mediate tissue response to radiation will be reviewed. The key to manipulating the consequences of radiation exposure lies in understanding the complex interplay of events initiated at the cellular level, but acting on the tissue.

Review↗

NASA NTRS2014

NASA Tech Briefs, February 2014

Topics include: JWST Integrated Simulation and Test (JIST) Core; Software for Non-Contact Measurement of an Individual's Heart Rate Using a Common Camera; Rapid Infrared Pixel Grating Response Testbed; Temperature Measurement and Stabilization in a Birefringent Whispering Gallery Resonator; JWST IV and V Simulation and Test (JIST) Solid State Recorder (SSR) Simulator; Development of a Precision Thermal Doubler for Deep Space; Improving Friction Stir Welds Using Laser Peening; Methodology of Evaluating Margins of Safety in Critical Brazed Joints; Interactive Inventory Monitoring; Sensor for Spatial Detection of Single-Event Effects in Semiconductor-Based Electronics; Reworked CCGA-624 Interconnect Package Reliability for Extreme Thermal Environments; Current-Controlled Output Driver for Directly Coupled Loads; Bulk Metallic Glasses and Matrix Composites as Spacecraft Shielding; Touch Temperature Coating for Electrical Equipment on Spacecraft; Li-Ion Electrolytes Containing Flame-Retardant Additives; Autonomous Robotic Manipulation (ARM); CARVE Log; Platform Perspective Toolkit; Convex Hull-Based Plume and Anomaly Detection; Pre-Filtration of GOSAT Data Using Only Level 1 Data and an Intelligent Filter to Remove Low Clouds; Affordability Comparison Tool - ACT; "Ascent - Commemorating Shuttle" for iPad; Cassini Mission App; Light-Weight Workflow Engine: A Server for Executing Generic Workflows; Model for System Engineering of the CheMin Instrument; Timeline Central Concepts; Parallel Particle Filter Toolkit; Particle Filter Simulation and Analysis Enabling Non-Traditional Navigation; Quasi-Terminator Orbits for Mapping Small Primitive Bodies; The Subgrid-Scale Scalar Variance Under Supercritical Pressure Conditions; Sliding Gait for ATHLETE Mobility; and Automated Generation of Adaptive Filter Using a Genetic Algorithm and Cyclic Rule Reduction.

Source record↗

NASA NTRS2001

Whole-cell biocomputing

The ability to manipulate systems on the molecular scale naturally leads to speculation about the rational design of molecular-scale machines. Cells might be the ultimate molecular-scale machines and our ability to engineer them is relatively advanced when compared with our ability to control the synthesis and direct the assembly of man-made materials. Indeed, engineered whole cells deployed in biosensors can be considered one of the practical successes of molecular-scale devices. However, these devices explore only a small portion of cellular functionality. Individual cells or self-organized groups of cells perform extremely complex functions that include sensing, communication, navigation, cooperation and even fabrication of synthetic nanoscopic materials. In natural systems, these capabilities are controlled by complex genetic regulatory circuits, which are only partially understood and not readily accessible for use in engineered systems. Here, we focus on efforts to mimic the functionality of man-made information-processing systems within whole cells.

Non-NASA Center↗

NASA NTRS2002

Ordered nanoparticle arrays formed on engineered chaperonin protein templates

Traditional methods for fabricating nanoscale arrays are usually based on lithographic techniques. Alternative new approaches rely on the use of nanoscale templates made of synthetic or biological materials. Some proteins, for example, have been used to form ordered two-dimensional arrays. Here, we fabricated nanoscale ordered arrays of metal and semiconductor quantum dots by binding preformed nanoparticles onto crystalline protein templates made from genetically engineered hollow double-ring structures called chaperonins. Using structural information as a guide, a thermostable recombinant chaperonin subunit was modified to assemble into chaperonins with either 3 nm or 9 nm apical pores surrounded by chemically reactive thiols. These engineered chaperonins were crystallized into two-dimensional templates up to 20 microm in diameter. The periodic solvent-exposed thiols within these crystalline templates were used to size-selectively bind and organize either gold (1.4, 5 or 10nm) or CdSe-ZnS semiconductor (4.5 nm) quantum dots into arrays. The order within the arrays was defined by the lattice of the underlying protein crystal. By combining the self-assembling properties of chaperonins with mutations guided by structural modelling, we demonstrate that quantum dots can be manipulated using modified chaperonins and organized into arrays for use in next-generation electronic and photonic devices.

Chaperonins/chemistry/ultrastructure↗

NASA NTRS2006

In-Space Radiator Shape Optimization using Genetic Algorithms

Future space exploration missions will require the development of more advanced in-space radiators. These radiators should be highly efficient and lightweight, deployable heat rejection systems. Typical radiators for in-space heat mitigation commonly comprise a substantial portion of the total vehicle mass. A small mass savings of even 5-10% can greatly improve vehicle performance. The objective of this paper is to present the development of detailed tools for the analysis and design of in-space radiators using evolutionary computation techniques. The optimality criterion is defined as a two-dimensional radiator with a shape demonstrating the smallest mass for the greatest overall heat transfer, thus the end result is a set of highly functional radiator designs. This cross-disciplinary work combines topology optimization and thermal analysis design by means of a genetic algorithm The proposed design tool consists of the following steps; design parameterization based on the exterior boundary of the radiator, objective function definition (mass minimization and heat loss maximization), objective function evaluation via finite element analysis (thermal radiation analysis) and optimization based on evolutionary algorithms. The radiator design problem is defined as follows: the input force is a driving temperature and the output reaction is heat loss. Appropriate modeling of the space environment is added to capture its effect on the radiator. The design parameters chosen for this radiator shape optimization problem fall into two classes, variable height along the width of the radiator and a spline curve defining the -material boundary of the radiator. The implementation of multiple design parameter schemes allows the user to have more confidence in the radiator optimization tool upon demonstration of convergence between the two design parameter schemes. This tool easily allows the user to manipulate the driving temperature regions thus permitting detailed design of in-space radiators for unique situations. Preliminary results indicate an optimized shape following that of the temperature distribution regions in the "cooler" portions of the radiator. The results closely follow the expected radiator shape.

Hull, Patrick V.↗

NASA NTRS2023

Automated Fluidics Device for Extraction and Quantification of miRNA Biomarkers From Blood

Radiation Assessment DuRing Exposure And long-Duration Spaceflight (RADREADS) demonstrates space-compatible point-of-care technology for quantitative biological monitoring of blood miRNA biomarkers in response to long-term low dose radiation exposure. This individualized monitoring approach will inform targeted treatment strategies to maximize medical resource utilization by accounting for individual susceptibility to radiation-related illnesses. As human spaceflight progresses beyond Earth’s magnetic shielding, radiation exposure poses a significant risk to astronaut health and safety. Extended operation in this environment comes with an increased risk of radiation exposure, leading to higher risks of radiation sickness, cancer, central nervous system effects, and degenerative diseases. While conventional physical dosimetry techniques capture radiation dose, individualistic susceptibility to radiation damage is varied. Multiple characteristics, including age, body weight, sex, genetics, and immune status, have been found to influence radiosensitivity (Liu et al. 2011, and Bouffler 2016). This differential response necessitates individualized monitoring and targeted treatment strategies to maximize medical resource utilization; however, a practical diagnostic platform for quantifying long-term, low dose radiation-induced tissue damage does not currently exist. MicroRNAs (miRNAs) are a class of small, non-coding RNAs that regulate gene expression by mediating the degradation of messenger RNA. The levels of particular miRNAs are influenced by biological processes such as inflammation and serve as biomarkers for a variety of conditions including cancer (Singh et al. 2017). MicroRNAs are found in various bodily fluids and are amenable to collection via liquid biopsies, providing a minimally invasive and easily quantifiable readout for a variety of radiosensitive reporters. A preliminary signature of 15 spaceflight sensitive miRNA has been identified in rodent and human studies, including miR-21-5p, miR-24-3p, miR-92a-3p, miR-17-5p, miR-16a-3p, miR-34a-3p, and miR-223-3p. These targets generally increased expression with radiation dose and linear energy transfer, though variation between individuals is not yet described. Current gaps in the field include a lack of understanding of longitudinal biological responses to long-term, low dose radiation exposure and the absence of space-compatible point-of-care technology for quantitative biological monitoring. In this body of work, we aim to develop an automated bleed-to-read system to process whole blood for the detection of miRNA biomarkers in order to monitor individualistic responses to radiation exposure. This will be achieved via separating serum (or plasma) from whole blood, followed by extraction, amplification, and quantification of the miRNA using a RT-qPCR reaction. Previously, the WetLab-2 hardware enabled execution of a RT-qPCR reaction aboard ISS; however, it is a manual system that requires crew manipulation and bulky components (Parra et al. 2017). To address these issues, automated fluid handling hardware was developed for each stage of sample preparation. Extraction of total RNA is achieved by sequentially pumping reagents through an off-the-shelf nucleic acid binding column (miRNeasy Serum/Plasma Advanced Kit, Qiagen). This approach eliminates several manual pipetting and centrifuging steps and limits the use of toxic chemicals commonly found in other sample processing techniques. The resulting elution will then be automatically dispensed for RT-qPCR analysis using a compact rotary qPCR (Mic qPCR Cycler, Bio Molecular Systems) that will improve spaceflight compatibility by removing bubbles from the detection region, another challenge highlighted by WetLab-2 (Parra et al. 2017). Efforts are also being made to simplify the RT-qPCR reaction to a 1-step air-dryable mix to improve long-term reagent stability at room temperature and reduce system complexity. By automating the RT-qPCR processes via microfluidic manipulation, RADREADS will reduce crewmember hands-on time and enable the personalized detection of radiation-induced tissue damage during long duration missions. Minimally invasive, longitudinal monitoring of individual’s response to radiation exposure will inform how the physiological system responds to long-term low dose space radiation and enables development of targeted countermeasures by the medical team. Ultimately, this portable technology will require minimal technical expertise and can also be used to monitor miRNA biomarkers associated with other diseases.

Tristen Head↗

NASA NTRS1999

Molecular Mechanisms Regulating Muscle Fiber Composition Under Microgravity

The overall goal of this project is to reveal the molecular mechanisms underlying the selective and debilitating atrophy of specific skeletal muscle fiber types that accompanies sustained conditions of microgravity. Since little is currently known about the regulation of fiber-specific gene expression programs in mammalian muscle, elucidation of the basic mechanisms of fiber diversification is a necessary prerequisite to the generation of therapeutic strategies for attenuation of muscle atrophy on earth or in space. Vertebrate skeletal muscle development involves the fusion of undifferentiated mononucleated myoblasts to form multinucleated myofibers, with a concomitant activation of muscle-specific genes encoding proteins that form the force-generating contractile apparatus. The regulatory circuitry controlling skeletal muscle gene expression has been well studied in a number of vertebrate animal systems. The goal of this project has been to achieve a similar level of understanding of the mechanisms underlying the further specification of muscles into different fiber types, and the role played by innervation and physical activity in the maintenance and adaptation of different fiber phenotypes into adulthood. Our recent research on the genetic basis of fiber specificity has focused on the emergence of mature fiber types and have implicated a group of transcriptional regulatory proteins, known as E proteins, in the control of fiber specificity. The restriction of E proteins to selected muscle fiber types is an attractive hypothetical mechanism for the generation of muscle fiber-specific patterns of gene expression. To date our results support a model wherein different E proteins are selectively expressed in muscle cells to determine fiber-restricted gene expression. These studies are a first step to define the molecular mechanisms responsible for the shifts in fiber type under conditions of microgravity, and to determine the potential importance of E proteins as upstream targets for the effects of weightlessness. In the past year we have determined that the expression of E Proteins is restricted to specific fiber types by post-transcriptional mechanisms. By far, the most prevalent mechanism of cellular control for achieving post-transcriptional regulation of gene expression is selective proteolysis -through the ubiquitin -proteasome pathway. Steady-state levels of HEB message are similar in all fast and slow skeletal muscle fiber types, yet the protein is restricted to Type IIX fibers. HEB appears to be a nodal point for regulating fiber-specific transcription, as expression of the transcription factor is regulated at the post-transcriptional level. It is not clear at present whether the regulation is at the level of protein synthesis or degradation. We are now poised to evaluate the biological role of ubiquitination in fiber specific-gene expression by controlling the post-transcriptional expression of E Proteins. The use of metabolic labelling and pharmacological inhibitors of the ubiquitin pathway will be used to identify the mode of regulation of the Type IIX expression pattern. The potential role of specific kinases in effecting the restriction of HEB expression will be examined by using both inhibitors and activators. The results of these studies will provide the necessary information to evaluate the biological role of E proteins in controlling fiber type transitions, and in potentially attenuating the atrophic effects of microgravity conditions. We have also recently shown that ectopic expression of the HEB protein transactivates the Type IIX-specific skeletal a-actin reporter. The 218 bp skeletal a-actin promoter drives transgene expression solely in mature Type IIX fibers. A mouse also carrying the transgene MLCI/HEB (which ectopically expresses the E Protein HEB in Type IIB fibers) forces expression of the skeletal a-actin reporter gene in Type IIB fibers. We can now dissect the composition of this fiber-specific cis-element. The skeletal a-actin promoter is quite compact and has been extensively characterized in vitro for activity and binding factors. The single E box may act as a binding target of myogenic factor/HEB heterodimer to allow for IIX expression. The HEB transcription factor may recognize either the precise flanking sequences of the E Box, or perhaps interacting with other proteins bound nearby, and activating expression in Type IIX fibers. This E box will be both ablated, and alternatively, as ablation may well destroy any muscle-specific transcriptional activity, flanking sequences substituted with those surrounding the E box (El) of the myogenin promoter. Modification of fiber-specific transgene expression will be tested in transgenic mice. The results of these studies will provide basic information on the regulatory circuitry underlying fiber specificity, and will form the basis for building appropriate transgenic regulatory cassettes to effect fiber transitions in subsequent experimental manipulations on unweighted muscles.

Rosenthal, Nadia A.↗