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Phenotypic hiding: the carryover of mutations in RNA viruses as shown by detection of mar mutants in influenza virus.

When influenza virus monoclonal antibody-resistant (mar) mutants are selected by incubation in vitro with excess antibody, 90 to 99% of the mutants are not detectable. This observation may be explained by encapsidation of mar mutant RNAs within phenotypically wild-type envelopes. This phenotypic hiding can be revealed by selection of mar mutants in vivo after virus uncoating. Using experimental procedures appropriate to detect all viable mar mutants in a virus population, we determined precisely the mutation rates to the mar genotype by the fluctuation test for two nonoverlapping monoclonal antibodies.

Antibodies, Monoclonal↗

Advances in extracorporeal detoxification by MARS dialysis in patients with liver failure.

Although liver transplantation has become standard procedure for patients with liver failure, a number of issues in the management of these patients remains to be addressed. Alternative approaches have been tested, such as hepatocytes containing liver-support systems and filtration devices. However, the replacement of detoxification has been difficult, as the majority of toxins accumulating in liver failure is albumin-bound. Albumin dialysis (MARS system) is characterized by the specific removal of albumin-bound toxins through an innovative membrane transport. In particular, the albumin acts as a specific molecular adsorbent that is regenerated on line in a recycling system. Nowadays MARS represents the most frequently used liver support system. This treatment has been shown to remove albumin-bound molecules, such as bilirubin, bile acids, aromatic amino acids and copper. The removal of these toxins is clinically accompanied with an improvement of liver, cardiovascular and renal functions and hepatic encephalopathy. In several trials MARS was found to improve the clinical situation in patients with acute exacerbation of chronic liver failure and acute hepatic failure, but also in hepatorenal syndrome and primary graft non function or chronic rejection after liver transplantation. In summary, a critical analysis of the literature confirms that MARS device can be a safe therapeutic choice to achieve a better clinical outcome, and, sometimes, a survival advantage in patients with liver failure, even if a multi-center randomized trial is the only reliable way to enforce today's results. Further advances in the MARS components will definitively state whether albumin dialysis may represent the future in the field of artificial liver devices.

Adsorption↗

The Monitored Atherosclerosis Regression Study (MARS). Design, methods and baseline results.

OBJECTIVE: The Monitored Atherosclerosis Regression Study (MARS) was designed to evaluate the effect of cholesterol lowering by monotherapy with an HMG-CoA reductase inhibitor on progression/regression of atherosclerosis in subjects with angiographically documented coronary artery disease. The purpose of this paper is to present the design, methods, and baseline results of MARS. DESIGN: MARS is a prospective, randomized, double-blind, placebo-controlled trial with baseline, 2-year, and 4-year coronary angiography as well as carotid, brachial, and popliteal ultrasonography. SETTING: Outpatient clinics at the University of Southern California School of Medicine and the University of Wisconsin School of Medicine. SUBJECTS: Two hundred seventy participants of both sexes were recruited directly from the cardiac catheterization laboratory or by chart review of patients having undergone cardiac catheterization in the past. Subjects were considered eligible if they had angiographically demonstrable atherosclerosis in 2 or more coronary artery segments, unaltered by angioplasty, with at least 1 lesion > or = 50% but < 100% diameter stenosis (%S). The inclusion range for total cholesterol (TC) was between 190 and 295 mg/dL. Exclusion factors were: triglycerides > or = 500 mg/dL; premenopausal females; uncontrolled hypertension; diabetes mellitus; untreated thyroid disease; liver dysfunction; renal insufficiency; congestive heart failure; major arrhythmia; left ventricular conduction defects; or any life-threatening disease. INTERVENTION: Subjects were placed on a low-fat, low-cholesterol diet and either 40 mg b.i.d. lovastatin (Mevacor) or placebo. Randomization was stratified by sex, smoking status, and TC. MAIN OUTCOME MEASURES: Per-subject average change in %S as determined by quantitative coronary angiography (QCA) is the primary angiographic endpoint. Secondary endpoints are: categorical analyses of the proportion of subjects with progression; human panel reading of coronary angiograms; and change in minimum lumen diameter (MLD) in mm by QCA. Carotid, brachial, and popliteal ultrasonography is also being performed. RESULTS: The subjects randomized into MARS are 91.5% male with an age range of 37 to 67 years (mean age 57.9 years). For the cohort, baseline lipids are (mean +/- SD): TC, 231 +/- 24 mg/dL; low-density lipoprotein cholesterol (LDL-C) by ultracentrifugation, 153 +/- 24 mg/dL; LDL-C, by calculation, 157 +/- 23 mg/dL; high-density lipoprotein cholesterol (HDL-C), 43 +/- 10 mg/dL; and triglycerides, 160 +/- 73 mg/dL. There were no significant differences between treatment groups in baseline lipid levels or baseline angiographic characteristics. CONCLUSIONS: MARS baseline data show adequacy of randomization with comparability of lovastatin and placebo groups in demographic, lipid, and angiographic characteristics.

Adult↗

[The potential role of nuclear matrix attachment regions (MARs) in regulation of gene expression].

Gene transfer technology is being used to enhance agronomic performance or improve quality traits in a wide variety of crop species. However, it is sometimes severely handicapped by difficulty in obtaining material in which transgene expression is predictable and stable over many generations. Because integration seemed to occur randomly in the plant genome, it was thought that some transgenes would be integrated in a relatively uncondensed, transcriptionally active chromatin environment, while others in a condensed, transcriptionally inert chromatin structure. Nuclear matrix attachment regions (MARs) are defined as DNA sequences that bind preferentially to the proteins of the nuclear matrix. They typically are localized at the borders of gene domains, implicating them in the formation of individual loops of higher order chromatin structure and transcription regulation. When MARs are positioned on either side of a transgene their presence usually results in higher and more stable espression in transgenic plants, most likely by minimizing gene silencing. In this review, we focus mainly on novel findings and our observations concerning the function of MARs in transcription regulation. Our objective is not only to summarize the current data and present several possible models to explain MAR effects on the transcription regulation, but also to point out some open questions involving the utilization of MARs in constructing high efficient expression vectors.

Chromatin↗

Relationship between the direct mixed antiglobulin reaction (MAR) test and spontaneous sperm agglutination in men from infertile couples.

To determine the relationship between the direct MAR test and spontaneous sperm agglutination in men from infertile couples, semen samples from 160 men were studied. Spontaneous sperm agglutination was present in 80 samples, and absent in the others. Routine semen analysis and the direct MAR test were performed on all samples. The incidence of positive MAR tests in samples with and without spontaneous sperm agglutination were 15 and 0 per cent respectively (p < 0.05). There were no significant differences in mean sperm concentration, motility, and morphology between the samples with and without spontaneous sperm agglutination, and between the positive and negative MAR test groups. It can be concluded that spontaneous sperm agglutination relates significantly to antisperm antibodies detected by the direct MAR test, and this factor could be used as indication for antisperm antibody testing of infertile men.

Coombs Test↗

Preservation of biological information in thermal spring deposits: developing a strategy for the search for fossil life on Mars.

Current interpretations of the early history of Mars suggest many similarities with the early Earth and therefore raise the possibility that the Archean and Proterozoic history of life on Earth could have a counterpart on Mars. Terrestrial experience suggests that, with techniques that can be employed remotely, ancient springs, including thermal springs, could well yield important information. By delivering water and various dissolved species to the sunlit surface of Mars, springs very likely created an environment suitable for life, which could have been difficult, if not impossible, to attain elsewhere. The chemical and temperature gradients associated with thermal springs sort organisms into sharply delineated, distinctive and different communities, and so diverse organisms are concentrated into relatively small areas in a predictable and informative fashion. A wide range of metabolic strategies are concentrated into small areas, thus furnishing a useful and representative sampling of the existing biota. Mineral-charged springwaters frequently deposit chemical precipitates of silica and/or carbonate which incorporate microorganisms and preserve them as fossils. The juxtaposition of stream valley headwaters with volcanoes and impact craters on Mars strongly implies that subsurface heating of groundwater created thermal springs. On Earth, thermal springs create distinctive geomorphic features and chemical signatures which can be detected by remote sensing. Spring deposits can be quite different chemically from adjacent rocks. Individual springs can be hundreds of meters wide, and complexes of springs occupy areas up to several kilometers wide. Benthic microbial mats and the resultant stromatolites occupy a large fraction of the available area. The relatively high densities of fossils and microbial mat fabrics within these deposits make them highly prospective in any search for morphological evidence of life, and there are examples of microbial fossils in spring deposits as old as 300 Myr.

Bacteria↗

Life on Mars: chemical arguments and clues from Martian meteorites.

Primitive terrestrial life-defined as a chemical system able to transfer its molecular information via self-replication and to evolve-probably originated from the evolution of reduced organic molecules in liquid water. Several sources have been proposed for the prebiotic organic molecules: terrestrial primitive atmosphere (methane or carbon dioxide), deep-sea hydrothermal systems, and extraterrestrial meteoritic and cometary dust grains. The study of carbonaceous chondrites, which contain up to 5% by weight of organic matter, has allowed close examination of the delivery of extraterrestrial organic material. Eight proteinaceous amino acids have been identified in the Murchison meteorite among more than 70 amino acids. Engel reported that L-alanine was surprisingly more abundant than D-alanine in the Murchison meteorite. Cronin also found excesses of L-enantiomers for nonprotein amino acids. A large collection of micrometeorites has been recently extracted from Antarctic old blue ice. In the 50- to 100-micron size range, carbonaceous micrometeorites represent 80% of the samples and contain 2% of carbon, on average. They might have brought more carbon than that involved in the present surficial biomass. The early histories of Mars and Earth clearly show similarities. Liquid water was once stable on the surface of Mars, attesting the presence of an atmosphere capable of deccelerating C-rich micrometeorites. Therefore, primitive life may have developed on Mars as well and fossilized microorganisms may still be present in the near subsurface. The Viking missions to Mars in 1976 did not find evidence of either contemporary or past life, but the mass spectrometer on the lander aeroshell determined the atmospheric composition, which has allowed a family of meteorites to be identified as Martian. Although these samples are essentially volcanic in origin, it has been recognized that some of them contain carbonate inclusions and even veins that have a carbon isotopic composition indicative of an origin from Martian atmospheric carbon dioxide. The oxygen isotopic composition of these carbonate deposits allows calculation of the temperature regime existing during formation from a fluid that dissolved the carbon dioxide. As the composition of the fluid is unknown, only a temperature range can be estimated, but this falls between 0 degree and 90 degrees C, which would seem entirely appropriate for life processes. It was such carbonate veins that were found to host putative microfossils. Irrespective of the existence of features that could be considered to be fossils, carbonate-rich portions of Martian meteorites tend to have material, at more than 1000 ppm, that combusts at a low temperature; i.e., it is an organic form of carbon. Unfortunately, this organic matter does not have a diagnostic isotopic signature so it cannot be unambiguously said to be indigenous to the samples. However, many circumstantial arguments can be made to the effect that it is cogenetic with the carbonate and hence Martian. If it could be proved that the organic matter was preterrestrial, then the isotopic fractionation between it and the carbon is in the right sense for a biological origin.

Carbonates↗

Could organic matter have been preserved on Mars for 3.5 billion years?

3.5 billion years (byr) ago, when it is thought that Mars and Earth had similar climates, biological evolution on Earth had made considerable progress, such that life was abundant. It is therefore surmised that prior to this time period the advent of chemical evolution and subsequent origin of life occurred on Earth and may have occurred on Mars. Analysis for organic compounds in the soil buried beneath the Martian surface may yield useful information regarding the occurrence of chemical evolution and possibly biological evolution. Calculations based on the stability of amino acids lead to the conclusion that remnants of these compounds, if they existed on Mars 3.5 byr ago, might have been preserved buried beneath the surface oxidizing layer. For example, if phenylalanine, an amino acid of average stability, existed on Mars 3.5 byr ago, then 1.6% would remain buried today, or 25 pg-2.5 ng of C g-1 Martian soil may exist from remnants of meteoritic and cometary bombardment, assuming that 1% of the organics survived impact.

Amino Acids↗

Earth analogs for Martian life. Microbes in evaporites, a new model system for life on Mars.

The prospect of life on Mars today is daunting. Especially problematic for a potential life form is a lack of water, particularly in a liquid state; extremely cold temperatures; ultraviolet and ionizing radiation; and soil oxidants. Yet, "oases" where life might persist have been suggested to occur in rocks (in analogy with endolithic microorganisms described from deserts around the world), in polar ice caps (in analogy with snow and ice algae) and in possible volcanic regions (in analogy with chemoautotrophs living in deep sea hydrothermal vents); all are critically examined. Microorganisms are known to be able to survive in salt crystals, and recently it has been shown that organisms can metabolize while encrusted in evaporites. Because evaporites are thought to occur on Mars and can attenuate light in the UV range while being far more transparent to radiation useful for photosynthesis (400-700 nm), and because of the properties of these "endoevaporitic" organisms, I propose that such communities provide a new model system for studying potential life on Mars. On the basis of this model, I suggest possibilities for site selection for future exobiological experiments on Mars.

Atmosphere↗

Duration of liquid water habitats on early Mars.

We have employed a simple climate model of early Mars in order to estimate the duration of ice-covered lakes after the onset of freezing conditions on Mars. The critical parameter determining the existence of ice-covered lakes is the existence of peak seasonal temperatures above freezing. The peak temperature occurs at the subsolar point at perihelion. We use the weathering model of Pollack et al. (Icarus 71, 203-224, 1987) to compute the pressure and temperature evolution of the atmosphere. We have included the variability of the solar luminosity. We find that if there was a source of ice to provide meltwater, liquid water habitats could have been maintained under relatively thin ice covers for up to 700 million years after mean global temperatures fell below the freezing point. At this point, the mean annual temperature is 227 K, and the pressure of atmospheric CO2 is about 0.5 bar. Without the presence of stable bodies of liquid water, it is not clear what mechanisms were responsible for the removal of this remaining CO2. From a biological point of view, we find that the duration of liquid water habitats on early Mars exceeds the upper limit on the time required for the origin of life on Mars.

Atmosphere↗

On the possibility of chemosynthetic ecosystems in subsurface habitats on Mars.

We have reexamined the question of extant microbial life on Mars in light of the most recent information about the planet and recently discovered nonphotosynthetic microbial ecosystems on Earth--deep sea hydrothermal vent communities and deep subsurface aquifer communities. On Mars, protected subsurface niches associated with hydrothermal activity could have continued to support life even after surface conditions became inhospitable. Geochemical evidence from the SNC meteorites and geomorphological evidence for recent volcanism suggest that such habitats could persist to the present time. There are also extensive geological features that attest to the ubiquitous nature of volcano-ground ice interactions on Mars. We suggest a possible deep subsurface microbial ecology similar to those discovered to depths of several kilometers below the surface of the Earth. We focus on anaerobic systems utilizing CO2 as the primary source of carbon. Liquid water could be provided by the heat of geothermal or volcanic activity melting permafrost or other subsurface water sources. Gases from volcanic activity deep in the planet could provide reducing power (as CH4, H2, or H2S) percolating up from below and enabling the development of a microbial community based upon chemolithoautotrophy. We suggest a methanogen (or acetogen) and sulfur-based microbial ecology as one possible basis for microbial primary production. Our hypothetical ecosystem is neither supported, nor excluded, by current observations of Mars. Tests for such a subsurface system involve locating active geothermal areas associated with ground ice or detecting trace quantities of reduced atmospheric gases that would leak from such a system.

Carbon Dioxide↗

Bio-markers and the search for extinct life on Mars.

Geologic and climatologic studies suggest that conditions on early Mars were similar to early Earth. Because life on Earth is believed to have originated during this early period (3.5 billion years ago), the Martian environment could have also been conducive to the origin of life. To investigate this possibility we must first define the attributes of an early Martian biota. Then, specific geographic locations on Mars must be chosen where life may have occurred (i.e. areas which had long standing water), and within these distinct locations search for key signatures or bio-markers of a possible extinct Martian biota. Some of the key signatures or bio-markers indicative of past biological activity on Earth may be applicable to Mars including: reduced carbon and nitrogen compounds, CO3(2-), SO4(2-), NO3-, NO2- [correction of NO2(2)], Mg, Mn, Fe, and certain other metals, and the isotopic ratios of C, N and S. However, we must also be able to distinguish abiotic from biologic origins for these bio-markers. For example, abiotically fixed N2 would form deposits of NO3- and NO2-, whereas biological processes would have reduced these to ammonium containing compounds, N2O, or N2, which would then be released to the atmosphere. A fully equipped Mars Rover might be able to perform analyses to measure most of these biomarkers while on the Martian surface.

Biological Evolution↗

Stable carbon isotope fractionation in the search for life on early Mars.

Isotopic measurements and, more specifically, ratios of 13C to 12C in organic relative to inorganic deposits, are useful in reconstructing past biological activity on Earth. Organic matter has a lower ratio of 13C to 12C due largely to the preferential fixation of 12C over the heavier isotope by the major carbon-fixation enzyme, ribulose-1,5-bisphosphate carboxylase/oxygenase, although other factors (e.g., availability of source carbon, fixation by other carboxylating enzymes and diagenesis of organic material) also contribute to fractionation. Would carbon isotope discrepancies between inorganic and organic carbon indicate past biological activity on Mars? In order to answer this question, we analyse what is known about terrestrial biologic and abiologic carbon fixation and its preservation in the fossil record, and suggest what the isotope discrimination during possible biologic and abiologic carbon fixation on Mars might have been like. Primarily because isotopic signatures of abiotically fixed carbon overlap with those of biotic fixation, but also because heterotrophy does not significantly alter the isotopic signature of ingested carbon, fractionation alone would not be definitive evidence for life. However, a narrow range of fractionation, including no fractionation, would suggest biotic processes. Never-the-less, isotopic ratios in organic deposits on Mars would be extremely useful in analysing prebiotic, if not biotic, carbon transformations on Mars.

Carbon↗

Planetary protection program for Mars 94/96 mission.

Mars surface in-situ exploration started in 1975 with the American VIKING mission. Two probes landed on the northern hemisphere and provided, for the first time, detailed information on the martian terrain, atmosphere and meteorology. The current goal is to undertake larger surface investigations and many projects are being planned by the major Space Agencies with this objective. Among these projects, the Mars 94/96 mission will make a major contributor toward generating significant information about the martian surface on a large scale. Since the beginning of the Solar System exploration, planets where life could exist have been subject to planetary protection requirements. Those requirements accord with the COSPAR Policy and have two main goals: the protection of the planetary environment from influence or contamination by terrestrial microorganisms, the protection of life science, and particularly of life detection experiments searching extra-terrestrial life, and not life carried by probes and spacecrafts. As the conditions for life and survival for terrestrial microorganisms in the Mars environment became known, COSPAR recommendations were updated. This paper will describe the decontamination requirements which will be applied for the MARS 94/96 mission, the techniques and the procedures which are and will be used to realize and control the decontamination of probes and spacecrafts.

Containment of Biohazards↗

Analysis of a spacecraft life support system for a Mars mission.

This report summarizes a trade study conducted as part of the Fall 2002 semester Spacecraft Life Support System Design course (ASEN 5116) in the Aerospace Engineering Sciences Department at the University of Colorado. It presents an analysis of current life support system technologies and a preliminary design of an integrated system for supporting humans during transit to and on the surface of the planet Mars. This effort was based on the NASA Design Reference Mission (DRM) for the human exploration of Mars [NASA Design Reference Mission (DRM) for Mars, Addendum 3.0, from the world wide web: http://exploration.jsc.nasa.gov/marsref/contents.html.]. The integrated design was broken into four subsystems: Water Management, Atmosphere Management, Waste Processing, and Food Supply. The process started with the derivation of top-level requirements from the DRM. Additional system and subsystem level assumptions were added where clarification was needed. Candidate technologies were identified and characterized based on performance factors. Trade studies were then conducted for each subsystem. The resulting technologies were integrated into an overall design solution using mass flow relationships. The system level trade study yielded two different configurations--one for the transit to Mars and another for the surface habitat, which included in situ resource utilization. Equivalent System Mass analyses were used to compare each design against an open-loop (non-regenerable) baseline system.

Air Conditioning↗

Lunar precursor missions for human exploration of Mars--III: studies of system reliability and maintenance.

Discussions of future human expeditions into the solar system generally focus on whether the next explorers ought to go to the Moon or to Mars. The only mission scenario developed in any detail within NASA is an expedition to Mars with a 500-day stay at the surface. The technological capabilities and the operational experience base required for such a mission do not now exist nor has any self-consistent program plan been proposed to acquire them. In particular, the lack of an Abort-to-Earth capability implies that critical mission systems must perform reliably for 3 years or must be maintainable and repairable by the crew. As has been previously argued, a well-planned program of human exploration of the Moon would provide a context within which to develop the appropriate technologies because a lunar expedition incorporates many of the operational elements of a Mars expedition. Initial lunar expeditions can be carried out at scales consistent with the current experience base but can be expanded in any or all operational phases to produce an experience base necessary to successfully and safely conduct human exploration of Mars.

Astronauts↗

Mars habitat modules: launch, scaling and functional design considerations.

The Sasakawa International Center for Space Architecture (SICSA) is undertaking a multi-year research, planning and design study that is exploring near- and long-term commercial space development opportunities. The central goal of this activity is to conceptualize a scenario of sequential, integrated private enterprise initiatives that can carry humankind forward to Mars. Each development stage is planned as a building block to provide the economic foundation, technology advancements and operational infrastructure to support others that follow. This report presents fundamental issues and requirements associated with planning human Mars initiatives that can transfer crews, habitats and equipment from Earth to Mars orbit, deliver them to the planet's surface, and return people and samples safely back to Earth. The study builds in part upon previous studies which are summarized in SICSA's: Commercial Space Development Plan and the Artificial Gravity Science and Excursion Vehicle reports. Information and conclusions produced in this study provide assumptions and a conceptual foundation for a subsequent report titled The First Mars Outpost: Planning and Concepts.

Air Conditioning↗

Space nuclear power: technology, policy, and risk considerations in human missions to Mars.

There is a large discrepancy between potential needs for nuclear propulsion and power systems for the human exploration of Mars and the current status of R&D funding, public opinion, and governmental support for these technologies. Mission planners and spacecraft designers, energized by the recent claims of possible discovery of life on Mars and responding to increased public interest in the human exploration of Mars, frequently propose nuclear reactors and radioisotope thermoelectric generators (RTGs) for interplanetary spacecraft propulsion and for power supply on the surface of Mars. These plans and designs typically assume that reactors will be available "on-the-shelf," and do not take the extensive R&D costs required to develop such reactors into consideration. However, it is likely that current U.S. policies, if unchanged, will prohibit the launch of nuclear reactors and large RTGs in response to a perceived risk by the public.

Humans↗