The COSPAR planetary protection policy for missions to Icy Worlds: A review of history, current scientific knowledge, and future directions.

Recent discoveries related to the habitability and astrobiological relevance of the outer Solar System have expanded our understanding of where and how life may have originated. As a result, the Icy Worlds of the outer Solar System have become among the highest priority targets for future spacecraft missions dedicated to astrobiology-focused and/or direct life detection objectives. This, in turn, has led to a renewed interest in planetary protection concerns and policies for the exploration of these worlds and has been a topic of discussion within the COSPAR (Committee on Space Research) Panel on Planetary Protection. This paper summarizes the results of those discussions, reviewing the current knowledge and the history of planetary protection considerations for Icy Worlds as well as suggesting ways forward. Based on those discussions, we therefore suggest to (1) Establish a new definition for Icy Worlds for Planetary Protection that captures the outer Solar System moons and dwarf planets like Pluto, but excludes more primitive bodies such as comets, centaurs, and asteroids: Icy Worlds in our Solar System are defined as all bodies with an outermost layer that is believed to be greater than 50 % water ice by volume and have enough mass to assume a nearly round shape. (2) Establish indices for the lower limits of Earth life with regards to water activity (LLAw) and temperature (LLT) and apply them into all areas of the COSPAR Planetary Protection Policy. These values are currently set at 0.5 and -28 °C and were originally established for defining Mars Special Regions; (3) Establish LLT as a parameter to assign categorization for Icy Worlds missions. The suggested categorization will have a 1000-year period of biological exploration, to be applied to all Icy Worlds and not just Europa and Enceladus as is currently the case. (4) Have all missions consider the possibility of impact. Transient thermal anomalies caused by impact would be acceptable so long as there is less than 10-4 probability of a single microbe reaching deeper environments where temperature is >LLT in the period of biological exploration. (5) Restructure or remove Category II* from the policy as it becomes largely redundant with this new approach, (6) Establish that any sample return from an Icy World should be Category V restricted Earth return.

Comparison of pcr diagnostic method and mass spectrometry of microbial markers method as applied to the evaluation of oral microbiota.

Rapid informative methods for assessing the species and quantitative composition of the microflora of the periodontal and oropharyngeal covering tissues are necessary for operative diagnostics, including those of the dentofacial system. The use of classical bacteriological methods, including seeding, incubation, counting and identification of microorganisms takes up to 5 days, resulting in a significant delay in obtaining the necessary information, which makes it difficult to carry out operative treatment measures. Therefore, the search for means and methods of operative microbiological control is urgent. The present work is devoted to substantiation of MSMM (mass spectrometry of microbial markers) technology application as a means of microbiological control of periodontal and other oropharyngeal biotopes.

A Novel Method for Amyloid Detection in Human Tissue Load Using a Fluorescent Dye - Congo Red Analogue.

The aim of the study was to develop a new technology for the detection of amyloid in human tissues based on the fluorescent dye, disodium salt of 2,7-(1-amino-4-sulfo-2-naphthylazo)fluorene (DSNAF). MATERIALS AND METHODS: Synthesis of DSNAF was performed by diazotization of 2,7-diaminofluorene in a stream of argon followed by azo coupling with naphthionic acid. Identification of DSNAF was performed using MALDI mass spectrometry. Human myocardial samples from males and females aged from 85 to 98 years (n=11) were the material for the histochemical study. Myocardial paraffin sections were stained with a 0.1% aqueous solution of Congo red or with an aqueous solution (0.1 or 0.034%) of DSNAF under the same conditions. RESULTS: It has been demonstrated for the first time that a new fluorene-based analogue of Congo red, DSNAF, can be successfully used to identify amyloid deposits in histological sections of human myocardium. In terms of the specificity and intensity of amyloid staining, DSNAF is comparable to Congo red, which is the gold standard for detecting amyloid deposits. The fluorescence intensity of DSNAF when binding to amyloid fibrils is significantly higher than the intensity of Congo red fluorescence (with a lower intensity of background fluorescence of heart muscle tissue). This is especially useful for identifying small deposits of amyloid in the human tissues which is important when using small biopsies. CONCLUSION: The advantages of using DSNAF allow us to consider the developed technology for the detection of amyloid as a new promising method of identifying amyloid deposits in human tissues.

Non-truncating LIFR mutation: causal for prominent congenital pain insensitivity phenotype with progressive vertebral destruction?

We present a Qatari family with two children who displayed a characteristic phenotype of congenital marked pain insensitivity with hypohidrosis and progressive aseptic destruction of joints and vertebrae resembling that of hereditary sensory and autonomic neuropathies (HSANs). The patients, aged 10 and 14, remained of uncertain genetic diagnosis until whole genome sequencing was pursued. Genome sequencing identified a novel homozygous C65S mutation in the LIFR gene that is predicted to markedly destabilize and alter the structure of a particular domain and consequently to affect the functionality of the whole multi-domain LIFR protein. The C65S mutant LIFR showed altered glycosylation and an elevated expression level that might be attributed to a slow turnover of the mutant form. LIFR mutations have been reported in Stüve-Wiedemann syndrome (SWS), a severe autosomal recessive skeletal dysplasia often resulting in early death. Our patients share some clinical features of rare cases of SWS long-term survivors; however, they also phenocopy HSAN due to the marked pain insensitivity phenotype and progressive bone destruction. Screening for LIFR mutations might be warranted in genetically unresolved HSAN phenotypes.

SOME CHARACTERISTICS OF THE ORAL CAVITY AND TEETH OF COSMONAUTS ON MISSIONS TO THE INTERNATIONAL SPACE STATION.

Earlier studies were furthered by examination of parodentium anaerobic microbiota and investigation of gingival liquid immunological factors in space flight. Immunoglobulins were measured using the .enzyme immunoassay (EM). The qualitative content of keya parodentium pathogens is determined with state-of-the-art molecular biology technologies such as the polymerase chain reaction. Statistical data processing was performed using the principle component analysis and ensuing standard statistical analysis. Thereupon, recommendations on cosmonaut's oral and dental hygiene during space mission were developed.

Sorting algorithms for single-particle imaging experiments at X-ray free-electron lasers.

Modern X-ray free-electron lasers (XFELs) operating at high repetition rates produce a tremendous amount of data. It is a great challenge to classify this information and reduce the initial data set to a manageable size for further analysis. Here an approach for classification of diffraction patterns measured in prototypical diffract-and-destroy single-particle imaging experiments at XFELs is presented. It is proposed that the data are classified on the basis of a set of parameters that take into account the underlying diffraction physics and specific relations between the real-space structure of a particle and its reciprocal-space intensity distribution. The approach is demonstrated by applying principal component analysis and support vector machine algorithms to the simulated and measured X-ray data sets.

Disruption of the colonization resistance syndrome in humans in altered habitats and its prevention.

Exposure of human subjects to environments with modified parameters is associated with reduced colonization resistance of the intestine and epithelial tissue, which leads to dysbiotic changes. Probiotics - preparations based on protective microflora - are used to correct dysbacteriosis of different etiologies and localizations. However, the effectiveness of probiotics largely depends on the adhesive ability of a probiotic strain and lack of competitive relations with the indigenous microflora, which can be achieved by individual selection of a preparation. We propose to use autochtonous microflora as a probiotic drug to optimize the prevention and treatment results. A personalized approach to probiotic selection will improve therapy efficiency and reduce the risk of adverse effects in each individual patient.

Use of Corynebacterium pseudodiphtheriticum for elimination of Staphylococcus aureus from the nasal cavity in volunteers exposed to abnormal microclimate and altered gaseous environment.

Effectiveness of saline suspension of Corynebacterium pseudodiphtheriticum containing spray was assessed in a 30-days chamber experiment modeling the effects of hyperthermia and polluted air on humans. Spray was targeted at eliminating Staphylococcus aureus from the nasal cavity of human subjects. Three of four volunteers became S. aureus carriers in the course of the experiment, and one was a chronic carrier of methicillin-resistant S. aureus (MRSA). Spray application eradicated S. aureus in three subjects and reduced its presence in the MRSA carrier. Results of the study suggest that C. pseudodiphtheriticum can be used for control of S. aureus in the nasal environment. However, further investigations are required.

The association of gene polymorphisms with athlete status in ukrainians.

UNLABELLED: Athletic performance is a polygenic trait influenced by both environmental and genetic factors. OBJECTIVE: To investigate individually and in combination the association of common gene polymorphisms with athlete status in Ukrainians. METHODS: A total of 210 elite Ukrainian athletes (100 endurance-oriented and 110 power-orientated athletes) and 326 controls were genotyped for ACE I/D, HIF1A Pro582Ser, NOS3 -786 T/C, PPARA intron 7 G/C, PPARG Pro12Ala and PPARGC1B Ala203Pro gene polymorphisms, most of which were previously reported to be associated with athlete status or related intermediate phenotypes in different populations. RESULTS: Power-oriented athletes exhibited an increased frequency of the HIF1A Ser (16.1 vs. 9.4%, P = 0.034) and NOS3 T alleles (78.3 vs. 66.2%, P = 0.0019) in comparison with controls. Additionally, we found that the frequency of the PPARG Ala allele was significantly higher in power-oriented athletes compared with the endurance-oriented athletes (24.7 vs. 13.5%; P = 0.0076). Next, we determined the total genotype score (TGS, from the accumulated combination of the three polymorphisms, with a maximum value of 100 for the theoretically optimal polygenic score) in athletes and controls. The mean TGS was significantly higher in power-oriented athletes (39.1 ± 2.3 vs. 32.6 ± 1.5; P = 0.0142) than in controls. CONCLUSIONS: We found that the HIF1A Ser, NOS3 T and PPARG Ala alleles were associated with power athlete status in Ukrainians.

Resonant addressing and manipulation of silicon vacancy qubits in silicon carbide.

Several systems in the solid state have been suggested as promising candidates for spin-based quantum information processing. In spite of significant progress during the last decade, there is a search for new systems with higher potential [D. DiVincenzo, Nat. Mater. 9, 468 (2010)]. We report that silicon vacancy defects in silicon carbide comprise the technological advantages of semiconductor quantum dots and the unique spin properties of the nitrogen-vacancy defects in diamond. Similar to atoms, the silicon vacancy qubits can be controlled under the double radio-optical resonance conditions, allowing for their selective addressing and manipulation. Furthermore, we reveal their long spin memory using pulsed magnetic resonance technique. All these results make silicon vacancy defects in silicon carbide very attractive for quantum applications.

Microbiological status of cosmonauts during orbital spaceflights on Salyut and Mir orbital stations.

The main feature of the human-microorganism eco-system forming in the environment of manned space vehicles is the periodic accumulation of the potential for pathogenicity. This process is characterized by the activation of opportunistic pathogens, representatives of which grow in large number within the system, settle in various niches, and demonstrate expansion, intruding into microbiocenoses of open biotopes of humans who, until contamination, have been clean of these microorganisms. Clones (similar to hospital strains) arising out of these populations exhibit the ability to spread "epidemically" within isolated teams.

Study of methanogenesis during bioutilization of plant residuals.

The waste management strategy for the future should meet the benefits of human safety, respect principles of planet ecology, and compatibility with other habitability systems. For these purposes waste management technologies relevant to application of the biodegradation properties of bacteria are of great value. Biological treatment method is based on the biodegradation of organic substances by various microorganisms.The objectives of our study were: to evaluate the effectiveness of microbial biodegradation of vegetable non-edible residual, using artificial inoculum, and to study the peculiarities of biogas, and possibilities of optimizing or reducing the share of methane. The diminution rate of organic gained 76% from initial mass within 9 days of fermentation. The biogas production achieved 46 l/kg of substrate. The microbial studies of biodegradation process revealed the following peculiarities: (i) gradual quantitative increase of Lactobacillus sp. (from 10(3) to 10(5) colony-forming units (CFU) per ml); (ii) activation of Clostridia sp. (from 10(2) to 10(4) CFU/ml); and (iii) elimination of aerobic conventional pathogens (Enterobacteriaceae, Protea sp., Staphylococci). Chromatography analysis revealed the constant presence of carbon dioxide (up to 90.9%). The methane content measures revealed traces 0.1-0.4%. However, when we optimized the methane production in "boiling layer" using methanogenic granules, the amount of methane in biogas reached 80-90%. Based on the results obtained the artificial inoculum was created which was capable of initiating biodegradation of vegetable wastes. This inoculum consisted of active sludge adapted to wastes mixed with excretea of insects which consume plant wastes. Using this inoculum the biodegradation process takes less time than that using active sludge. Regulation of methane concentration from traces to 90% may be achieved by adding methane reactor to the plant digester.

Microbial utilisation of natural organic wastes.

The waste management strategy for the future should meet the benefits of humanity safety, respect principals of planet ecology, and compatibility with other habitability systems. For these purpose the waste management technologies, relevant to application of the biodegradation properties of bacteria are of great value. The biological treatment method is based upon the biodegradation of organic substances by various microorganisms. The advantage of the biodegradation waste management in general: it allows to diminish the volume of organic wastes, the biological hazard of the wastes is controlled, and this system may be compatible with the other systems. The objectives of our study were: to evaluate effectiveness of microbial biodegradation of non-pretreated substrate, to construct phneumoautomatic digester for organic wastes biodegradation, and to study microbial characteristics of active sludge samples used as inoculi in biodegradation experiment. The technology of vegetable wastes treatment was elaborated in IBMP and BMSTU. For this purpose the special unit was created where the degradation process is activated by enforced reinvention of portions of elaborated biogas into digester. This technology allows to save energy normally used for electromechanical agitation and to create optimal environment for anaerobic bacteria growth. The investigations were performed on waste simulator, which imitates physical and chemical content of food wastes calculated basing on the data on food wastes of moderate Russian city. The volume of created experimental sample of digester is 40 l. The basic system elements of device are digesters, gas receiver, remover of drops and valve monitoring and thermal control system. In our testing we used natural food wastes to measure basic parameters and time of biodegradation process. The diminution rate of organic gained 76% from initial mass taking part within 9 days of fermentation. The biogas production achieved 46 l per 1 kg of substrate. The microbial studies of biodegradation process revealed following peculiarities: (i) gradual quantitative increasing of Lactobacillus sp. (from 10(3) to 10(5) colony forming units (CFU) per ml), (ii) activation of Clostridia sp. (from 10(2) to 10(4)CFU/ml), (iii) elimination of aerobic conventional pathogens (Enterobacteriaceae sp., Protea sp., staphylococci). The obtained results allow to evaluate effectiveness of proposed technology and to determine the leading role of lactobacilli and clostridia in process of natural wastes biodegradation. Our further investigations shall further be concentrated on creation of artificial inoculi for launching of food wastes biodegradation. These inoculi will include active and adapted strains of clostridia and lactobacilli.

Structural genomics of enzymes involved in sterol/isoprenoid biosynthesis.

X-ray structures of two enzymes in the sterol/isoprenoid biosynthesis pathway have been determined in a structural genomics pilot study. Mevalonate-5-diphosphate decarboxylase (MDD) is a single-domain alpha/beta protein that catalyzes the last of three sequential ATP-dependent reactions which convert mevalonate to isopentenyl diphosphate. Isopentenyl disphosphate isomerase (IDI) is an alpha/beta metalloenzyme that catalyzes interconversion of isopentenyl diphosphate and dimethylallyl diphosphate, which condense in the next step toward synthesis of sterols and a host of natural products. Homology modeling of related proteins and comparisons of the MDD and IDI structures with two other experimentally determined structures have shown that MDD is a member of the GHMP superfamily of small-molecule kinases and IDI is similar to the nudix hydrolases, which act on nucleotide diphosphatecontaining substrates. Structural models were produced for 379 proteins, encompassing a substantial fraction of both protein superfamilies. All three enzymes responsible for synthesis of isopentenyl diphosphate from mevalonate (mevalonate kinase, phosphomevalonate kinase, and MDD) share the same fold, catalyze phosphorylation of chemically similar substrates (MDD decarboxylation involves phosphorylation of mevalonate diphosphate), and seem to have evolved from a common ancestor. These structures and the structural models derived from them provide a framework for interpreting biochemical function and evolutionary relationships.

DBAli: a database of protein structure alignments.

SUMMARY: The DBAli database includes approximately 35000 alignments of pairs of protein structures from SCOP (Lo Conte et al., Nucleic Acids Res., 28, 257-259, 2000) and CE (Shindyalov and Bourne, Protein Eng., 11, 739-747, 1998). DBAli is linked to several resources, including Compare3D (Shindyalov and Bourne, http://www.sdsc.edu/pb/software.htm, 1999) and ModView (Ilyin and Sali, http://guitar.rockefeller.edu/ModView/, 2001) for visualizing sequence alignments and structure superpositions. A flexible search of DBAli by protein sequence and structure properties allows construction of subsets of alignments suitable for a number of applications, such as benchmarking of sequence-sequence and sequence-structure alignment methods under a variety of conditions. AVAILABILITY: http://guitar.rockefeller.edu/DBAli/

Geriatric men at altitude: hypoxic ventilatory sensitivity and blood dopamine changes.

BACKGROUND: Short-term exposure to high-altitude hypoxia increases hypoxic ventilatory sensitivity (HVS) in healthy humans. Dopamine (DA) is the implicated neurotransmitter in carotid body (CB) chemoreceptor response, and the microenvironmental conditions in CB tissue are comparable to blood. Continuous DA infusion affected ventilation in animals and humans. Age-related oscillations in blood DA levels may influence peripheral chemoreflexes. OBJECTIVE: Hypoxic ventilatory responses (HVR) relative to blood DA concentration and its precursor, dihydroxyphenylalanine (DOPA) was measured in young and elderly men during short-term altitude adaptation. METHODS: Nine elderly climbers (group 1:61+/-1.4 years) and 7 young healthy subjects (group 2: 23+/-2 years) were tested at sea level on day 0, on day 3 after passive transport to 2,200 m, and on day 14 after climbing to 4,200 and 5,642 m. RESULTS: Sea level HVR in group 1 was 47% lower than in group 2, accompanied by higher blood DOPA (300%) and DA (37%) content. Initial DA and DOPA concentrations showed a negative correlation with initial HVR but a positive correlation with age. Passive transport to middle altitude (2,200 m) increased HVS, doubling HVR slopes in groups 1 and 2 and producing increased maximum expired minute ventilation during isocapnic rebreathing (29 and 28%, respectively). Day 3 2,200-meter blood DOPA content decreased by 22% in group 1 and increased by 300% in group 2. DA increased in both groups. CONCLUSION: The relationship between HVR and the reciprocal DA and DOPA values seen in both groups is associated with age, producing decreased DA receptor sensitivity and enhanced DA reuptake during adaptation to high altitude.

2.9 A crystal structure of ligand-free tryptophanyl-tRNA synthetase: domain movements fragment the adenine nucleotide binding site.

The crystal structure of ligand-free tryptophanyl-tRNA synthetase (TrpRS) was solved at 2.9 A using a combination of molecular replacement and maximum-entropy map/phase improvement. The dimeric structure (R = 23.7, Rfree = 26.2) is asymmetric, unlike that of the TrpRS tryptophanyl-5'AMP complex (TAM; Doublié S, Bricogne G, Gilmore CJ, Carter CW Jr, 1995, Structure 3:17-31). In agreement with small-angle solution X-ray scattering experiments, unliganded TrpRS has a conformation in which both monomers open, leaving only the tryptophan-binding regions of their active sites intact. The amino terminal alphaA-helix, TIGN, and KMSKS signature sequences, and the distal helical domain rotate as a single rigid body away from the dinucleotide-binding fold domain, opening the AMP binding site, seen in the TAM complex, into two halves. Comparison of side-chain packing in ligand-free TrpRS and the TAM complex, using identification of nonpolar nuclei (Ilyin VA, 1994, Protein Eng 7:1189-1195), shows that significant repacking occurs between three relatively stable core regions, one of which acts as a bearing between the other two. These domain rearrangements provide a new structural paradigm that is consistent in detail with the "induced-fit" mechanism proposed for TyrRS by Fersht et al. (Fersht AR, Knill-Jones JW, Beduelle H, Winter G, 1988, Biochemistry 27:1581-1587). Coupling of ATP binding determinants associated with the two catalytic signature sequences to the helical domain containing the presumptive anticodon-binding site provides a mechanism to coordinate active-site chemistry with relocation of the major tRNA binding determinants.

Synthesis of 7,8-(methylenedioxy)-1-phenyl-3,5-dihydro-4H-2, 3-benzodiazepin-4-ones as novel and potent noncompetitive AMPA receptor antagonists.

A group of 7,8-(methylenedioxy)-1-phenyl-3,5-dihydro-4H-2, 3-benzodiazepin-4-ones was synthesized and assayed for antagonism of rat brain alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors expressed in Xenopus oocytes. The benzodiazepinones inhibited AMPA-activated membrane current responses in a manner consistent with noncompetitive, allosteric inhibition of the receptor-channel complex. The most potent compound in the series was 1-(4-aminophenyl)-7,8-(methylenedioxy)-3,5-dihydro-4H-2, 3-benzodiazepin-4-one (6), which had an IC50 of 2.7 microM. For comparison, the reference compound GYKI 52466 (2) had an IC50 of 6.9 microM. Compound 6 also had potent anticonvulsant activity in a mouse maximum electroshock-induced seizure (MES) assay: the ED50 was 2.8 mg/kg iv, whereas the ED50 for GYKI 52466 was 4.6 mg/kg iv. In contrast to a previous report, the 7,8-dimethoxy analogue of 6 was a low-potency AMPA antagonist (IC50 >100 microM) and weak anticonvulsant (ED50 >10 mg/kg iv). The benzodiazepinones described herein are potent noncompetitive AMPA receptor antagonists that could have therapeutic potential as anticonvulsants and neuroprotectants.

Compression stimuli increase the efficacy of breast pump function.

OBJECTIVE: The dynamics of milk ejection and also prolactin concentration in the blood during milk expression by means of a breast pump were studied in 82 lactating women. STUDY DESIGN: The design of the breast pump used in this study is new. It is based on the correlation with the amplitude, duration and frequency of vacuum and compression stimuli formed by the baby's mouth apparatus during the suckling process. RESULTS: It was found that during continuous co-action of the vacuum and compression stimuli at a frequency of 1 cycle per second, the rate of milk ejection from the breast changed periodically. The highest rates of milk ejection coincided with the greatest rises in intramammary pressure. When the compression stimulus was turned off, leaving only the vacuum, the period of the first rise in pressure increased 1.5-2 fold, with a 1.5-2 fold reduction in the milk ejection rate as compared with the normal function of the breast pump. The basal prolactin level on day 3 and 5 post delivery in women who used a breast pump was not significantly different from that of puerperal women who only breast-fed their babies. Prolactin concentration in the blood of puerperal women did not change within the 5-6 min of expression and stimulation with the breast pump. The prolactin level began to increase by the 10th minute, whereas by the 25th minute it exceeded the initial concentration 1.3-1.5-fold. CONCLUSION: It is suggested that by introducing a tactile component to the mechanism of the breast pump, milk secretion is enhanced, as well as stimulating the breast milk flow. This directly improves the dynamics of breast milk expression.

5-(N-oxyaza)-7-substituted-1,4-dihydroquinoxaline-2,3-diones: novel, systemically active and broad spectrum antagonists for NMDA/glycine, AMPA, and kainate receptors.

A group of 5-aza-7-substituted-1,4-dihydroquinoxaline-2,3-diones (QXs) and the corresponding 5-(N-oxyaza)-7-substituted QXs were prepared and evaluated as antagonists of ionotropic glutamate receptors. The in vitro potency of these QXs was determined by inhibition of [3H]-5,7-dichlorokynurenic acid ([3H]DCKA) binding to N-methyl-D-aspartate (NMDA)/glycine receptors, [3H]-(S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid ([3H]AMPA) binding to AMPA receptors, and [3H]kainate ([3H]KA) binding to KA receptors in rat brain membranes. 5-(N-Oxyaza)-QXs 12a-e all have low micromolar or submicromolar potency for NMDA/glycine receptors and low micromolar potencies for AMPA and KA receptors. QXs 12a-e display 2-12-fold selectivity for NMDA/glycine receptors compared to AMPA receptors, and approximately 2-fold difference between AMPA and KA potency. In contrast to other QXs that either show high selectivity for NMDA (such as ACEA 1021) or AMPA (such as NBQX) receptors, these molecules are broad spectrum antagonists of ionotropic glutamate receptors. 7-Nitro-5-(N-oxyaza)-QX (12e) is the most potent inhibitor among 12a-e, having IC50 values of 0.69, 1.3, and 2.4 microM at NMDA, AMPA, and KA receptors, respectively. In functional assays on glutamate receptors expressed in oocytes by rat cerebral cortex poly(A+) RNA, 7-chloro-5-(N-oxyaza)-QX (12a) and 7-nitro-5-(N-oxyaza)-QX (12e) have Kb values of 0.63 and 0.31 microM for NMDA/glycine receptors, and are 6- and 4-fold selective for NMDA over AMPA receptors, respectively. 5-(N-Oxyaza)-7-substituted-QXs 12a-e all have surprisingly high in vivo potency as anticonvulsants in a mouse maximal electroshock-induced seizure (MES) model. 7-Chloro-5-(N-oxyaza)-QX (12a), 7-bromo-5-(N-oxyaza)-QX (12b), and 7-methyl-5-(N-oxyaza)-QX (12c) have ED50 values of 0.82, 0.87, and 0.97 mg/kg i.v., respectively. The high in vivo potency of QXs 12a-e is particularly surprising given their low log P values (approximately -2.7). Separate studies indicate that QXs 12a and 12e are also active in vivo as neuroprotectants and also have antinociceptive activity in animal pain models. In terms of in vivo activity, these 5-(N-oxyaza)-7-substituted-QXs are among the most potent broad spectrum ionotropic glutamate antagonists reported.