Identifying medically relevant xenon protein targets by in silico screening of the structural proteome.

In a previous study, in silico screening of the binding of almost all proteins in the Protein Data Bank to each of the five noble gases xenon, krypton, argon, neon, and helium was reported. This massive and rich data set requires analysis to identify the gas-protein interactions that have the best binding strengths, those where the binding of the noble gas occurs at a site that can modulate the function of the protein, and where this modulation might generate clinically relevant effects. Here, we report a preliminary analysis of this data set using a rational, heuristic score based on binding strength and location. We report a partial prioritized list of xenon protein targets and describe how these data can be analyzed, using arginase and carbonic anhydrase as examples. Our aim is to make the scientific community aware of this massive, rich data set and how it can be analyzed to accelerate future discoveries of xenon-induced biological activity and, ultimately, the development of new "atomic" drugs.

Synergistic effect of 222-nm krypton-chlorine excilamp and mild heating combined treatment on inactivation of Escherichia coli O157:H7 and Salmonella Typhimurium in apple juice.

Simultaneous treatment with 222-nm KrCl excilamp and mild heating (EX-MH) at 45, 50 and 55 °C showed synergistic bactericidal effects on non-acid and acid adapted cells of Escherichia coli O157:H7 and Salmonella Typhimurium in apple juice. In particular, acid-adapted pathogens exhibited increased resistance to EX-MH compared to pathogenic bacteria that were not acid-adapted. Also, elucidation of the synergistic bactericidal mechanism of EX-MH was performed through several assays and this mechanism was described as follows: (i) when KrCl excilamp (EX) and mild heating (MH) are applied simultaneously, MH reversibly inactivates the antioxidant enzyme, superoxide dismutase (SOD), thereby increasing accumulation of reactive oxygen species (ROS) generated by EX and thus inducing synergistic ROS generation, (ii) ROS production induces lipid peroxidation occurrence in the cell membrane, (iii) this lipid peroxidation occurrence in the cell membrane induces synergistic destruction of cell membrane, resulting in synergistic cell death. While EX-MH of 45, 50, or 55 °C reduced E. coli O157:H7 (the pathogen most resistant to EX-MH) in apple juice by 5-log, the qualities such as color (L*, a*, and b*), total phenolic compounds (TPC), and DPPH free radical scavenging activity of apple juice did not change significantly (P > 0.05). This study not only suggests the applicability of EX-MH to the apple juice industry, but also can be used as baseline data for future relevant research.

Neuroprotection of dopamine neurons by xenon against low-level excitotoxic insults is not reproduced by other noble gases.

Using midbrain cultures, we previously demonstrated that the noble gas xenon is robustly protective for dopamine (DA) neurons exposed to L-trans-pyrrolidine-2,4-dicarboxylate (PDC), an inhibitor of glutamate uptake used to generate sustained, low-level excitotoxic insults. DA cell rescue was observed in conditions where the control atmosphere for cell culture was substituted with a gas mix, comprising the same amount of oxygen (20%) and carbon dioxide (5%) but 75% of xenon instead of nitrogen. In the present study, we first aimed to determine whether DA cell rescue against PDC remains detectable when concentrations of xenon are progressively reduced in the cell culture atmosphere. Besides, we also sought to compare the effect of xenon to that of other noble gases, including helium, neon and krypton. Our results show that the protective effect of xenon for DA neurons was concentration-dependent with an IC50 estimated at about 44%. We also established that none of the other noble gases tested in this study protected DA neurons from PDC-mediated insults. Xenon's effectiveness was most probably due to its unique capacity to block NMDA glutamate receptors. Besides, mathematical modeling of gas diffusion in the culture medium revealed that the concentration reached by xenon at the cell layer level is the highest of all noble gases when neurodegeneration is underway. Altogether, our data suggest that xenon may be of potential therapeutic value in Parkinson disease, a chronic neurodegenerative condition where DA neurons appear vulnerable to slow excitotoxicity.

Decontamination Effect of the Spindle and 222-Nanometer Krypton-Chlorine Excimer Lamp Combination against Pathogens on Apples (Malus domestica Borkh.) and Bell Peppers (Capsicum annuum L.).

In this study, we developed a washing system capable of decontaminating fresh produce by combining the Spindle apparatus, which detaches microorganisms on sample surfaces, and a 222-nm krypton-chlorine excimer lamp (KrCl excilamp) (Sp-Ex) and investigated their decontamination effect against Escherichia coli O157:H7, Salmonella enterica serovar Typhimurium, and Listeria monocytogenes on apple (Malus domestica Borkh.) and bell pepper (Capsicum annuum L.) surfaces. Initial levels of the three pathogens were approximately 108 CFU/sample. Both E. coli O157:H7 and S. Typhimurium were reduced to below the detection limit (2.0 log CFU/sample) after 5 and 7 min of treatment on apple and bell pepper surfaces, respectively. The amounts of L. monocytogenes on apple and bell pepper surfaces were reduced by 4.26 and 5.48 logs, respectively, after 7 min of treatment. The decontamination effect of the Sp-Ex was influenced by the hydrophobicity of the sample surface as well as the microbial cell surface, and the decontamination effect decreased as the two hydrophobicity values increased. To improve the decontamination effect of the Sp-Ex, Tween 20, a surfactant that weakens the hydrophobic interaction between the sample surface and pathogenic bacteria, was incorporated into Sp-Ex processing. It was found that its decontamination effect was significantly (P < 0.05) increased by the addition of 0.1% Tween 20. Sp-Ex did not cause significant quality changes in apple or bell pepper surfaces during 7 days storage following treatment (P > 0.05). Our results suggest that Sp-Ex could be applied as a system to control pathogens in place of chemical sanitizer washing by the fresh-produce industry.IMPORTANCE Although most fresh-produce processing currently controls pathogens by means of washing with sanitizers, there are still problems such as the generation of harmful substances and changes in product quality. A combination system composed of the Spindle and a 222-nm KrCl excilamp (Sp-Ex) developed in this study reduced pathogens on apple and bell pepper surfaces using sanitizer-free water without altering produce color and texture. This study demonstrates the potential of the Sp-Ex to replace conventional washing with sanitizers, and it can be used as baseline data for practical application by industry. In addition, implementation of the Sp-Ex developed in this study is expected not only to meet consumer preference for fresh, minimally processed produce but also to reduce human exposure to harmful chemicals while being beneficial to the environment.

Increased Resistance of Salmonella enterica Serovar Typhimurium and Escherichia coli O157:H7 to 222-Nanometer Krypton-Chlorine Excilamp Treatment by Acid Adaptation.

In this study, we examined the change in resistance of Salmonella enterica serovar Typhimurium and Escherichia coli O157:H7 to 222-nm krypton-chlorine (KrCl) excilamp treatment as influenced by acid adaptation and identified a mechanism of resistance change. In addition, we measured changes in apple juice quality indicators, such as color, total phenols, and 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging activity, during treatment. Non-acid-adapted and acid-adapted pathogens were induced by growing the cells in tryptic soy broth without dextrose (TSB w/o D) at pH 7.3 and in TSB w/o D at pH 5.0 (adjusted with HCl), respectively. For the KrCl excilamp treatment, acid-adapted pathogens exhibited significantly (P < 0.05) higher D5d values, which indicate dosages required to achieve a 5-log reduction, than those for non-acid-adapted pathogens in both commercially clarified apple juice and phosphate-buffered saline (PBS), and the pathogens in the juice showed significantly (P < 0.05) higher D5d values than those for pathogens in PBS because of the UV-absorbing characteristics of apple juice. Through mechanism identification, it was found that the generation of lipid peroxidation in the cell membrane, inducing cell membrane destruction, was significantly (P < 0.05) lower in acid-adapted cells than in non-acid-adapted cells for the same amount of reactive oxygen species (ROS) generated at the same dose because the ratio of unsaturated to saturated fatty acids (USFA/SFA) in the cell membrane was significantly (P < 0.05) decreased as a result of acid adaptation. Treated apple juice showed no significant (P > 0.05) difference in quality indicators compared to those of untreated controls during treatment at 1,773 mJ/cm2IMPORTANCE There is a need for novel, mercury-free UV lamp technology to replace germicidal lamps containing harmful mercury, which are routinely utilized for UV pasteurization of apple juice. In addition, consideration of the changes in response to antimicrobial treatments that may occur when pathogens are adapted to the acid in an apple juice matrix is critical to the practical application of this technology. Based on this, an investigation using 222-nm KrCl excilamp technology, an attractive alternative to mercury lamps, was conducted. Our study demonstrated increased resistance to 222-nm KrCl excilamp treatment as pathogens adapted to acids, and this was due to changes in reactivity to ROS with changes in the fatty acid composition of the cell membrane. Despite increased resistance, the 222-nm KrCl excilamp achieved pathogen reductions of 5 log or more at laboratory scale without affecting apple juice quality. These results provide valuable baseline data for application of 222-nm KrCl excilamps in the apple juice industry.

Hyperpolarized 83Kr magnetic resonance imaging of alveolar degradation in a rat model of emphysema.

Hyperpolarized (83)Kr surface quadrupolar relaxation (SQUARE) generates MRI contrast that was previously shown to correlate with surface-to-volume ratios in porous model surface systems. The underlying physics of SQUARE contrast is conceptually different from any other current MRI methodology as the method uses the nuclear electric properties of the spin I = 9/2 isotope (83)Kr. To explore the usage of this non-radioactive isotope for pulmonary pathophysiology, MRI SQUARE contrast was acquired in excised rat lungs obtained from an elastase-induced model of emphysema. A significant (83)Kr T1 relaxation time increase in the SQUARE contrast was found in the elastase-treated lungs compared with the baseline data from control lungs. The SQUARE contrast suggests a reduction in pulmonary surface-to-volume ratio in the emphysema model that was validated by histology. The finding supports usage of (83)Kr SQUARE as a new biomarker for surface-to-volume ratio changes in emphysema.

Planar images reprojected from SPECT V/Q data perform similarly to traditional planar V/Q scans in the diagnosis of pulmonary embolism.

OBJECTIVE: To compare the diagnostic interpretation of traditional ventilation/perfusion (V/Q) planar images with that of planar-like images reprojected from single-photon emission computed tomography (SPECT) data sets. METHODS: Retrospective data from patients who had undergone both planar and SPECT imaging were used to generate anonymized reprojected planar images, which were compared with traditional planar V/Q images. Two consultants interpreted both sets of images for 81 patients following a proforma. We assessed the agreement in the final diagnosis between the two imaging methods and between the two clinicians. We also compared the number, nature, and localization of defects, as well as image quality. Finally, we compared the diagnosis made using planar methods with the original diagnosis made using SPECT. RESULTS: There was excellent agreement in diagnosis both between the two planar methods (κ=0.93) and between the two consultants (κ=0.91). Similar numbers of defects were detected, with fewer matched defects being reported in the reprojected group by one of the clinicians. Localization of defects and image quality were similar for the two imaging methods. Six additional pulmonary embolisms were diagnosed using SPECT data. CONCLUSION: We have shown that the performance of reprojected planars from SPECT V/Q was similar to that of traditional planars. These results have potential important implications for patient workflow in busy nuclear medicine departments, as well as for patient comfort.

Effect of noble gases on oxygen and glucose deprived injury in human tubular kidney cells.

The noble gas xenon has been shown to be protective in preconditioning settings against renal ischemic injury. The aims of this study were to determine the protective effects of the other noble gases, helium, neon, argon, krypton and xenon, on human tubular kidney HK2 cells in vitro. Cultured human renal tubular cells (HK2) were exposed to noble gas preconditioning (75% noble gas; 20% O(2); 5% CO(2)) for three hours or mock preconditioning. Twenty-four hours after gas exposure, cell injury was provoked with oxygen-glucose deprived (OGD) culture medium for three hours. Cell viability was assessed 24 h post-OGD by a 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay. Other cohorts of cultured cells were incubated in the absence of OGD in 75% noble gas, 20% O(2) and 5% CO(2) and cellular signals phospho-Akt (p-Akt), hypoxia-inducible factor-1alpha (HIF-1alpha) and Bcl-2 were assessed by Western blotting. OGD caused a reduction in cell viability to 0.382 +/- 0.1 from 1.0 +/- 0.15 at control (P < 0.01). Neon, argon and krypton showed no protection from injury (0.404 +/- 0.03; 0.428 +/- 0.02; 0.452 +/- 0.02; P > 0.05). Helium by comparison significantly enhanced cell injury (0.191 +/- 0.05; P < 0.01). Xenon alone exerted a protective effect (0.678 +/- 0.07; P < 0.001). In the absence of OGD, helium was also detrimental (0.909 +/- 0.07; P < 0.01). Xenon caused an increased expression of p-Akt, HIF-1alpha and Bcl-2, while the other noble gases did not modify protein expression. These results suggest that unlike other noble gases, preconditioning with the anesthetic noble gas xenon may have a role in protection against renal ischemic injury.

Neuroprotection (and lack of neuroprotection) afforded by a series of noble gases in an in vitro model of neuronal injury.

Xenon-induced neuroprotection has been well studied both in vivo and in vitro. In this study, the neuroprotective properties of the other noble gases, namely, krypton, argon, neon and helium, were explored in an in vitro model of neuronal injury. Pure neuronal cultures, derived from foetal BALB/c mice cortices, were provoked into injury by oxygen and glucose deprivation (OGD). Cultures were exposed to either nitrogen hypoxia or noble gas hypoxia in balanced salt solution devoid of glucose for 90min. The cultures were allowed to recover in normal culture medium for a further 24h in nitrogen or noble gas. The effect of noble gases on cell reducing ability in the absence of OGD was also investigated. Cell reducing ability was quantified via an MTT assay and expressed as a ratio of the control. The OGD caused a reduction in cell reducing ability to 0.56+/-0.04 of the control in the absence of noble gas (p<0.001). Like xenon (0.92+/-0.10; p<0.001), neuroprotection was afforded by argon (0.71+/-0.05; p<0.01). Neon and krypton did not have a protective effect under our experimental conditions. Helium had a detrimental effect on the cells. In the absence of OGD, krypton reduced the reducing ability of uninjured cells to 0.84+/-0.09 (p<0.01), but argon showed an improvement in reducing ability to 1.15+/-0.11 (p<0.05). Our data suggest that the cheap and widely available noble gas argon may have potential as a neuroprotectant for the future.

[Effect of krypton-containing gas mixture on Japanese quail embryo development].

Investigated were effects of gas mixture with up to 3.0 kgs/cm2 of krypton on the embryonic development of domesticated Japanese quail (Coturnix coturnix japonica dom.). Results demonstrated absence of a serious krypton effect on Japanese quail embryos. Development of embryos proceeded in due course; morphometrically the experimental embryos were essentially similar to controls. It should be noted that despite exposure to acute hypoxic hypoxia during the initial 12 hours of development in the krypton-containing gas mixture, viability of quail embryos was high enough which can be ascribed to the krypton protective action. Besides, an additional experiment showed that krypton partial pressure of 5-5.5 kgs/cm2 produces the narcotic effect on adult Japanese quails.

Effect of high-pressure gas on yeast growth.

Microcalorimetry is a useful tool for monitoring the growth behavior of microorganisms. In this study, microcalorimetry was used to investigate the effects of nitrogen, air, oxygen, nitrous oxide, argon, and krypton at high pressure on the growth of the yeast Saccharomyces cerevisiae. Growth thermograms (metabolic heat vs. incubation time) were generated to estimate metabolic activity under compressed gases and to determine the 50% inhibitory pressure (IP(50)) and minimum inhibitory pressure (MIP), which are regarded as indices of the toxicity of compressed gases. Based on MIP values, the most toxic to the least toxic gases were found to be: O(2) > N(2)O > air > Kr > N(2) > Ar.

Effect of pressure of helium, argon, krypton, and xenon on the porosity, microstructure, and mechanical properties of commercially pure titanium castings.

STATEMENT OF PROBLEM: Porosity is a frequently observed casting defect in dental titanium alloys. PURPOSE: This study evaluated the effect of pressure of helium, argon, krypton, and xenon on the porosity, microstructure, and mechanical properties of commercially pure titanium (cp Ti) castings. MATERIAL AND METHODS: Eight groups (A-H) of 16 rectangular wax patterns each (30 mm in length, 3 mm in width, and 1 mm in depth) were prepared. The wax patterns were invested with a magnesia-based material and cast with cp Ti (grade II). Groups A, C, E, and G were cast under a pressure of 1 atm, and groups B, D, F, and H were cast under a pressure of 0.5 atm of He, Ar, Kr, and Xe, respectively. The extent of the porosity of the cast specimens was determined radiographically and quantified by image analysis. Three specimens of each group and 3 cylinders of the as-received cp Ti used as a reference were embedded in resin and studied metallographically after grinding, polishing, and chemical etching. These surfaces were used for determination of the Vickers hardness (VHN) as well. Eight specimens from each group were fractured in the tensile mode, and the 0.2% yield strength, fracture stress, and percentage elongation were calculated. Porosity was analyzed with 2-way ANOVA and the Newman-Keuls multiple range test. VHN measurements and tensile properties for specimen groups were compared with 1-way ANOVA and the Newman-Keuls multiple range test (95% significance level). RESULTS: The porosity levels per group were (%): A = 5.50 +/- 4.34, B = 0.77 +/- 1.27, C = 2.44 +/- 3.68, D = 0.06 +/- 0.12, E-H = 0. Two-way ANOVA showed that there was no detectable interaction (P<.05) between gas type and applied pressure. Metallographic examination revealed no differences in microstructure among the groups studied. A finer grain size was observed in all cast groups compared with the original cp Ti. The VHN of the as-received cp Ti was significantly greater than all the cast groups tested. Groups cast under He showed the highest VHN, yield strength, and fracture stress. No significant differences were found in percentage elongation values among the groups. CONCLUSION: Porosity and mechanical properties of cp Ti castings are dependent on the gas type and pressure, whereas the microstructure remains unaffected.

Effects of xenon and krypton on regional cerebral blood flow in the rat.

The effects of high inspired concentrations of xenon and krypton on regional CBF (rCBF) were assessed in the rat using [14C]iodoantipyrine and quantitative autoradiography. Inhalation of 80% xenon for 1 or 2 min and inhalation of 40% xenon for 2 min were found to have significant effects on rCBF, including average increases of 75-96% in cerebral neocortical regions. Inhalation of 40% xenon for 1 min and of 80% krypton for 2 min had no significant effect on rCBF in most brain regions studied. If xenon inhalation produces effects on rCBF in humans similar to those observed in the rat, such effects could be an important source of error in xenon computed tomography rCBF studies.

Effects of helium and other inert gases on Echinosphaerium nucleofilium (protozoa, heliozoa).

The effects of helium, nitrogen, argon and krypton on Echinosphaerium nucleofilum (Heliozoa) have been studied at partial pressures of 10-130 atm. Additional experiments have been carried out with hydrostatic pressure alone. Helium causes shortening of the axopods over the whole range of pressures, and damage to the cell body at pressures of 60-90 atm, both with a maximum at 80 atm. These effects cannot be explained in terms of hydrostatic pressure alone; a 'pressure reversal' effect may be operating, causing the peak at 80 atm. Nitrogen also causes both cell damage and axopod shortening, the severity increasing with increasing pressure. Argon and krypton cause cell damage but no shortening. The order of potency for cell damage is krypton greater than argon greater than nitrogen greater than helium. It is suggested that there may be tuo sites of action, possibly the microtubules (for axopod shortening) and the cell membrane (for cell damage). In appropriate mixtures of helium and argon, both the cell damage usually caused by argon, and the axopod shortening usually caused by helium, are prevented. Possible mechanisms include the effects of hydrostatic pressure on gas solubility coefficients, reversal of the effects of the gases by the increase in total pressure, and competition for sites of action.