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At least 289 records · Page 16

Predicting Cell Death and Mutation Frequency for a Wide Spectrum of LET by Assuming DNA Break Clustering Inside Repair Domains

Cosmic radiation, which is composed of high charged and energy (HZE) particles, is responsible for cell death and mutation, which may be involved in cancer induction. Mutations are consequences of mis-repaired DNA breaks – especially double-strand breaks (DSBs) – that induce inter- and intra-chromosomal rearrangements (translocations, deletions, inversion). In this study, a computer simulation model is used to investigate the clustering of DSBs in repair domains, previously evidenced by our group in human breast cells [1]. This model is calibrated with experimental data measuring persistent 53BP1 radiation-induced foci (RIF) and is used to explain the high relative biological effectiveness (RBE) of HZE for both cell death and DNA mutation frequencies. We first validate our DSB cluster model using a new track structure model deployed on a simple geometrical configuration for repair domains in the nucleus; then we extend the scope from cell death to mutation induction. This work suggests that mechanism based on DSB repair process can explain several biological effects induced by HZE particles on different type of living cells

Plante, Ianik↗

Predicting cell death and mutation frequency for a wide spectrum of LET and across cell lines from DNA break clustering inside repair domains

Cosmic radiation, which is composed of high charged and energy (HZE) particles, is responsible for cell death and mutation, which may be involved in cancer induction. Mutations are consequences of mis-repaired DNA breaks – especially double-strand breaks (DSBs) – that induce inter- and intra-chromosomal rearrangements (translocations, deletions, inversion). In this study, a computer simulation model is used to investigate the clustering of DSBs in repair domains, previously evidenced by our group in human breast cells. This model is calibrated with experimental data measuring persistent 53BP1 radiation-induced foci (RIF) and is used to explain the high relative biological effectiveness (RBE) of HZE for both cell death and DNA mutation frequencies. We first validate our DSB cluster model using a new track structure model deployed on a simple geometrical configuration for repair domains in the nucleus; then we extend the scope from cell death to mutation induction. This work suggests that mechanism based on DSB repair process can explain several biological effects induced by HZE particles on different type of living cells.

Ianik Plante↗

On Beyond Star Trek: Synthetic Biology and the Future of Space Exploration

A turtle carries its own habitat. While it is reliable, it costs energy. NASA makes the same trade-off when it transports habitats and other structures needed to lunar and planetary surfaces increasing upmass, and affecting other mission goals. Long-term human space presence requires periodic replenishment, adding a massive cost overhead. Even robotic missions often sacrifice science goals for heavy radiation and thermal protection. Biology has the potential to solve these problems because it can replicate and repair itself, and do a wide variety of chemical reactions including making food, fuel and materials. Synthetic biology enhances and expands life's evolved repertoire. Using organisms as feedstock, additive manufacturing could make possible the dream of producing bespoke tools, food, smart fabrics and even replacement organs on demand. Imagine what new products can be enabled by such a technology, on earth or beyond!

Rothschild, Lynn J.↗

Structural Basis for Flip-Flop Action of Thiamin Pyrophosphate-Dependent Enzymes Revealed by Human Pyruvate Dehydrogenase

Thiamin pyrophosphate (TPP), the biologically active form of vitamin BI, is a cofactor of enzymes catalyzing reactions involving the cleavage of a carbon-carbon bond adjacent to an oxo group. TPP-dependent enzymes show a common mechanism of TPP activation by: (1) forming the ionic N-H...O(sup -) hydrogen bonding between the N1' atom of the aminopirymidine ring of the coenzyme and intrinsic gamma-carboxylate group of glutamate and (2) imposing an "active" V-conformation that brings the N4' atom of the aminopirymidine to the distance required for the intramolecular C-H.. .N hydrogen bonding with the thiazolium C2 atom. Within these two hydrogen bonds that rapidly exchange protons, protonation of the N1' atom is strictly coordinated with the deprotonation of the 4' -amino group and eventually abstraction of the proton from C2. The human pyruvate dehydrogenase Elp, component of human pyruvate dehydrogenase complex, catalyzes the irreversible decarboxylation of the pyruvate followed by the reductive acetylation of the lipoyl group of dihydrolipoyl acyltransferase. Elp is alpha(sub 2)beta(sub2)-heterotetrameric with a molecular mass of I54 kDa, which has two catalytic sites, each providing TPP and magnesium ion as cofactors and each formed on the interface between the PP and PYR domains. The dynamic nonequivalence of two otherwise chemically equivalent catalytic sites has been observed and the flip-flop mechanism was suggested, according to which two active sites affect each other and in which different steps of the catalytic reaction are performed in each of the sites at any given moment. Based on specific futures of human pyruvate dehydrogenase including rigid and flexible connections between domains that bind the cofactor we propose a mechanistic model for the flip-flop action of this enzyme. We postulate that the dynamic protein environment drives the exchange of tautomers in the 4' -aminopyrimidine ring of the cofactor through a concerted shuttl-like motion of tightly connected domains. The dynamic exchange of those tautomers, in turns, is required during the reactions of pyruvate decarboxylation and reductive acetylation of lipoamide. Thus the shuttle-like motion of the domains is coordinated with the reactions of decarboxylation and acetylation, which are carried out in each of the cofactor sites resulting in a flip-flop action of the enzyme. The structure-derived mechanism of action of human pyruvate dehydrogenase may be likely common for other TPP-dependent enzymes.

Dominiak, Paulina↗

Opportunities for research on Space Station Freedom

NASA has allocated research accommodations on Freedom (equipment, utilities, etc.) to the program offices that sponsor space-based research and development as follows: Space Science and Applications (OSSA)--52 percent, Commercial Programs (OCP)--28 percent, Aeronautics and Space Technology (OAST)--12 percent, and Space Flight (OSF)--8 percent. Most of OSSA's allocation will be used for microgravity and life science experiments; although OSSA's space physics, astrophysics, earth science and applications, and solar system exploration divisions also will use some of this allocation. Other Federal agencies have expressed an interest in using Space Station Freedom. They include the National Institutes of Health (NIH), U.S. Geological Survey, National Science Foundation, National Oceanic and Atmospheric Administration, and U.S. Departments of Agriculture and Energy. Payload interfaces with space station lab support equipment must be simple, and experiment packages must be highly contained. Freedom's research facilities will feature International Standard Payload Racks (ISPR's), experiment racks that are about twice the size of a Spacelab rack. ESA's Columbus lab will feature 20 racks, the U.S. lab will have 12 racks, and the Japanese lab will have 10. Thus, Freedom will have a total of 42 racks versus 8 for Space lab. NASA is considering outfitting some rack space to accommodate small, self-contained payloads similar to the Get-Away-Special canisters and middeck-locker experiment packages flown on Space Shuttle missions. Crew time allotted to experiments on Freedom at permanently occupied capability will average 25 minutes per rack per day, compared to six hours per rack per day on Spacelab missions. Hence, telescience--the remote operation of space-based experiments by researchers on the ground--will play a very important role in space station research. Plans for supporting life sciences research on Freedom focus on the two basic goals of NASA 's space life sciences program: to ensure the health, safety, and productivity of humans in space and to acquire fundamental knowledge of biological processes. Space-based research has already shown that people and plants respond the same way to the microgravity environment: they lose structure. However, the mechanisms by which they respond are different, and researchers do not yet know much about these mechanisms. Life science research accommodations on Freedom will include facilities for experiments designed to address this and other questions, in fields such as gravitational biology, space physiology, and biomedical monitoring and countermeasures research.

Phillips, Robert W.↗

Studying Host-Pathogen Interactions In 3-D: Organotypic Models For Infectious Disease And Drug Development

Representative, reproducible and high-throughput models of human cells and tissues are critical for a meaningful evaluation of host-pathogen interactions and are an essential component of the research developmental pipeline. The most informative infection models - animals, organ explants and human trials - are not suited for extensive evaluation of pathogenesis mechanisms and screening of candidate drugs. At the other extreme, more cost effective and accessible infection models such as conventional cell culture and static co-culture may not capture physiological and three-dimensional aspects of tissue biology that are important in assessing pathogenesis, and effectiveness and cytotoxicity of therapeutics. Our lab has used innovative bioengineering technology to establish biologically meaningful 3-D models of human tissues that recapitulate many aspects of the differentiated structure and function of the parental tissue in vivo, and we have applied these models to study infectious disease. We have established a variety of different 3-D models that are currently being used in infection studies - including small intestine, colon, lung, placenta, bladder, periodontal ligament, and neuronal models. Published work from our lab has shown that our 3-D models respond to infection with bacterial and viral pathogens in ways that reflect the infection process in vivo. By virtue of their physiological relevance, 3-D cell cultures may also hold significant potential as models to provide insight into the neuropathogenesis of HIV infection. Furthermore, the experimental flexibility, reproducibility, cost-efficiency, and high throughput platform afforded by these 3-D models may have important implications for the design and development of drugs with which to effectively treat neurological complications of HIV infection.

Nickerson, Cheryl A.↗

Development of Ballistic Limit Equations in Support of the Mars Sample Return Mission

NASA and the European Space Agency (ESA) are currently planning the Mars Sample Return campaign, comprising missions whose combined objective is to bring the first samples of Mars material back to Earth for detailed study. At present, the NASA-ESA plan is to return samples to Earth using three missions to be launched over the next 5-10 years. The final component, the Earth Entry System (EES), is intended to bring the Mars samples back to the Earth, where it will land following safe entry through the Earth's atmosphere. There is a concern regarding the risk of biological contamination of the Earth’s biosphere from returned Martian samples if, for example, the structural integrity of the EES were compromised during its return mission due to a perforation of a critical surface resulting from a high-speed meteoroid impact. To assess the risks associated with such an event, NASA is developing equations that predict the damage that various EES elements will sustain as a result of such an impact, as well as equations that predict whether or not a particular system will sustain a critical failure following such an impact. In this paper, we review recent progress in the development of such equations for the EES forebody and the EES aftbody, the two elements of the EES that are most exposed to the meteoroid environment. Limitations of the BLEs are also discussed, which can also be used to further inform the next steps in the BLE development.

William P. Schonberg↗

RF Characterization of a Photocurable PEDOT:PSS:PEGDA Conductive Biomaterial for 3D-Printing Implantable Antennas

In this work, we demonstrate photocurable PEDOT:PSS:PEGDA biomaterial as a promising candidate for intracorporeal 3D printing. Intracorporeal 3D printing offers a less invasive method which offer flexibility to tailor the form factor of printed structures. Previous work has demonstrated the feasibility of a robotic probe to 3D-print biological tissues intracorporeally via a minor incision. This same probe could also 3D-print implantable antennas as long as a suitable conductive material is identified in terms of conductivity, biocompatibility, and ability to cure at room/body temperature for safety purposes. We assess the frequency-dependent conductivity of this biomaterial and explore the Radio-Frequency (RF) performance of resulting antennas operating in free-space and inside tissue-emulating phantoms. Results show that PEDOT:PSS biomaterial with 21% and 30% PEGDA content exhibit a conductivity of ~10 4 S/m up to 5 GHz, suitable for wireless implants. Comparing the two, 21% PEGDA content exhibits poorer curing abilities, while 30% PEGDA exhibits slightly lower conductivity. Measurements for 2.4 GHz free-space dipoles conducted in an anechoic chamber reveal only ~0.8 dB and ~1 dB lower gain for PEDOT:PSS:21%PEGDA and PEDOT:PSS:30%PEGDA biomaterial, respectively, as compared to their copper counterpart. For a 5 mm-deep implanted patch antenna, these two biomaterials exhibit 3.05 dB and 3.84 dB higher transmission loss than copper, respectively. If deemed necessary, this performance degradation can be overcome by increasing the overall antenna size since the printing process is now minimally invasive and miniaturization requirements can be relaxed.

3D-printing↗

The spatial and temporal expression of Ch-en, the engrailed gene in the polychaete Chaetopterus, does not support a role in body axis segmentation

We are interested in understanding whether the annelids and arthropods shared a common segmented ancestor and have approached this question by characterizing the expression pattern of the segment polarity gene engrailed (en) in a basal annelid, the polychaete Chaetopterus. We have isolated an en gene, Ch-en, from a Chaetopterus cDNA library. Genomic Southern blotting suggests that this is the only en class gene in this animal. The predicted protein sequence of the 1.2-kb cDNA clone contains all five domains characteristic of en proteins in other taxa, including the en class homeobox. Whole-mount in situ hybridization reveals that Ch-en is expressed throughout larval life in a complex spatial and temporal pattern. The Ch-en transcript is initially detected in a small number of neurons associated with the apical organ and in the posterior portion of the prototrochophore. At later stages, Ch-en is expressed in distinct patterns in the three segmented body regions (A, B, and C) of Chaetopterus. In all segments, Ch-en is expressed in a small set of segmentally iterated cells in the CNS. In the A region, Ch-en is also expressed in a small group of mesodermal cells at the base of the chaetal sacs. In the B region, Ch-en is initially expressed broadly in the mesoderm that then resolves into one band/segment coincident with morphological segmentation. The mesodermal expression in the B region is located in the anterior region of each segment, as defined by the position of ganglia in the ventral nerve cord, and is involved in the morphogenesis of segment-specific feeding structures late in larval life. We observe banded mesodermal and ectodermal staining in an anterior-posterior sequence in the C region. We do not observe a segment polarity pattern of expression of Ch-en in the ectoderm, as is observed in arthropods. Copyright 2001 Academic Press.

Non-NASA Center↗

A comparative study of prebiotic and present day translational models

It is generally recognized that the understanding of the molecular basis of primitive translation is a fundamental step in developing a theory of the origin of life. However, even in modern molecular biology, the mechanism for the decoding of messenger RNA triplet codons into an amino acid sequence of a protein on the ribosome is understood incompletely. Most of the proposed models for prebiotic translation lack, not only experimental support, but also a careful theoretical scrutiny of their compatibility with well understood stereochemical and energetic principles of nucleic acid structure, molecular recognition principles, and the chemistry of peptide bond formation. Present studies are concerned with comparative structural modelling and mechanistic simulation of the decoding apparatus ranging from those proposed for prebiotic conditions to the ones involved in modern biology. Any primitive decoding machinery based on nucleic acids and proteins, and most likely the modern day system, has to satisfy certain geometrical constraints. The charged amino acyl and the peptidyl termini of successive adaptors have to be adjacent in space in order to satisfy the stereochemical requirements for amide bond formation. Simultaneously, the same adaptors have to recognize successive codons on the messenger. This translational complex has to be realized by components that obey nucleic acid conformational principles, stabilities, and specificities. This generalized condition greatly restricts the number of acceptable adaptor structures.

Rein, R.↗

Two-Fluid Models and Interfacial Area Transport in Microgravity Condition

The objective of the present study is to develop a two-fluid model formulation with interfacial area transport equation applicable for microgravity conditions. The new model is expected to make a leapfrog improvement by furnishing the constitutive relations for the interfacial interaction terms with the interfacial area transport equation, which can dynamically model the changes of the interfacial structures. In the first year of this three-year project supported by the U.S. NASA, Office of Biological and Physics Research, the primary focus is to design and construct a ground-based, microgravity two-phase flow simulation facility, in which two immiscible fluids with close density will be used. In predicting the two-phase flow behaviors in any two-phase flow system, the interfacial transfer terms are among the most essential factors in the modeling. These interfacial transfer terms in a two-fluid model specify the rate of phase change, momentum exchange, and energy transfer at the interface between the two phases. For the two-phase flow under the microgravity condition, the stability of the fluid particle interface and the interfacial structures are quite different from those under normal gravity condition. The flow structure may not reach an equilibrium condition and the two fluids may be loosely coupled such that the inertia terms of each fluid should be considered separately by use of the two-fluid model. Previous studies indicated that, unless phase-interaction terms are accurately modeled in the two-fluid model, the complex modeling does not necessarily warrant an accurate solution.

Ishii, Mamoru↗

NanoSIMS Reveals New Structural and Elemental Signatures of Early Life

The young technology of NanoSIMS is unlocking new information from organic matter in ancient sediments. We have used this technique to characterize sub-micron scale element composition of Proterozoic organics that are clearly biogenic as a guide for interpreting problematic structures in terrestrial or extraterrestrial samples. We used the NanoSIMS 50 of the National Museum of Natural History in Paris to map carbon, nitrogen (as CN), and sulfur in organic structures from the approximately 0.8 Ga Bitter Springs Formation. We analyzed spheroidal and filamentous microfossils as well as organic laminae that appeared amorphous by optical and scanning electron microscopy. In clear-cut microfossils, a coincidence between optical images and NanoSIMS element maps suggests a biological origin for the mapped carbon, sulfur, and nitrogen; this conclusion is supported by high resolution NanoSIMS maps showing identical spatial distributions of C, CN and S. High resolution images also demonstrate distinctive nano structure of the filaments and spheroids. In the amorphous laminae, NanoSIMS reveals morphologies reminiscent of compressed microfossils. Distinct CN/C ratios of the spheroids, filaments, and laminae may reflect their biological precursors (cell walls, cyanobacterial sheaths, and microbial communities/biofilms, respectively). Similar amorphous laminae comprise a preponderance of the organic matter in many Precambrian deposits. Thus it is possible that NanoSIMS will provide fresh insight into a large body of previously uninterpretable material. Additionally, NanoSIMS analysis may establish new biosignatures that will be helpful for assessing the origin and biogenicity of controversial Archean structures and any organic materials that may occur in Martian or other extraterrestrial samples.

Oehler, Dorothy Z.↗

The Future of Bio-technology

Hosts of technologies, most notably in electronics, have been on the path of miniaturization for decades and in 2005 they have crossed the threshold of the nano-scale. Crossing the nano-scale threshold is a milestone in miniaturization, setting impressive new standards for component-packing densities. It also brings technology to a scale at which quantum effects and fault tolerance play significant roles and approaches the feasible physical limit form many conventional "top-down" manufacturing methods. I will suggest that the most formidable manufacturing problems in nanotechnology will be overcome and major breakthroughs will occur in a host of technologies, when nanotechnology converges with bio-technology; i.e. I will argue that the future of bio-technology is in nanotechnology. In 2005, methods in molecular biology, microscopy, bioinformatics, biochemistry, and genetic engineering have focused considerable attention on the nano-scale. On this scale, biology is a kind of recursive chemistry in which molecular recognition, self-assembly, self-organization and self-referencing context-control lead to the emergence of the complexity of structures and processes that are fundamental to all life forms. While we are still far from understanding this complexity, we are on the threshold of being able to use at least some of these biological properties for .technology. I will discuss the use of biomolecules, such as DNA, RNA, and proteins as "tools" for the bio-technologist of the future. More specifically, I will present in some detail an example of how we are using a genetically engineered 60-kDa protein (HSP60) from an organism living in near boiling sulfuric acid to build nano-scale templates for arranging metallic nanoparticles. These "extremophile" HSP60s self-assemble into robust double-ring structures called "chaperonins," which further assemble into filaments and arrays with nanometer accuracy. I will discuss our efforts to use chaperonins to organize quantum dots, electronic and magnetic nano-particles for electronic and photonic applications.

Trent, Jonathan↗

Radiation biology of HZE particles

The biological effects of heavy charged particle (HZE) radiation are of particular interest to travellers and planners for long duration space flights where exposure levels represent a potential health hazard. The unique feature of HZE radiation is the structured pattern of its energy deposition in targets which may be related to charge, velocity, or rate of energy loss. There are many consequences of this feature to biological endpoints when compared to effects of ionizing photons. Dose vs response and dose rate kinetics are modified, DNA and cellular repair systems are altered in their abilities to cope with damage and, the qualitative features of damage are unique for different ions. These features must be incorporated into any risk assessment system for radiation health management. HZE induced mutation, cell inactivation and altered organogenesis will be discussed emphasizing studies with the nematode Caenorhabditis elegans and cultured cells. Observations from radiobiology experiments in space will also be reviewed along with plans for future space-based studies.

Nelson, Gregory A.↗

Radiation transfer in plant canopies - Transmission of direct solar radiation and the role of leaf orientation

Understanding the details of the interaction between the radiation field and plant structures is important climatically because of the influence of vegetation on the surface water and energy balance, but also biologically, since solar radiation provides the energy necessary for photosynthesis. The problem is complex because of the extreme variety of vegetation forms in space and time, as well as within and across plant species. This one-dimensional vertical multilayer model describes the transfer of direct solar radiation through a leaf canopy, accounting explicitly for the vertical inhomogeneities of a plant stand and leaf orientation, as well as heliotropic plant behavior. This model reproduces observational results on homogeneous canopies, but it is also well adapted to describe vertically inhomogeneous canopies. Some of the implications of leaf orientation and plant structure as far as light collection is concerned are briefly reviewed.

Verstraete, Michel M.↗

Imaging Schwarzschild multilayer X-ray microscope

We have designed, analyzed, fabricated, and tested Schwarzschild multilayer X-ray microscopes. These instruments use flow-polished Zerodur mirror substrates which have been coated with multilayers optimized for maximum reflectivity at normal incidence at 135 A. They are being developed as prototypes for the Water Window Imaging X-Ray Microscope. Ultrasmooth mirror sets of hemlite grade sapphire have been fabricated and they are now being coated with multilayers to reflect soft X-rays at 38 A, within the biologically important 'water window'. In this paper, we discuss the fabrication of the microscope optics and structural components as well as the mounting of the optics and assembly of the microscopes. We also describe the optical alignment, interferometric and visible light testing of the microscopes, present interferometrically measured performance data, and provide the first results of optical imaging tests.

Hoover, Richard B.↗