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The structure, energetic, and spectroscopy properties of the ionic system K 2 + (X 2 Σ + g ) interacting with the noble gas atoms Argon, Krypton and Xenon are studied. The computations are done by an accurate ab initio approach based on the pseudo-potential technique, Gaussian basis sets, parameterized l-dependent polarization potentials and an analytic potential form for the K + Ar, K + Kr and K + Xe interactions. These interactions are added via the CCSD(T) potential taken from literature and fitted applying the analytical expression of Tang and Toennies. The application of the pseudo-potential approach reduces the number of active electrons of each complex to only one electron. The potential energy surfaces are analyzed on a large range of the Jacobi coordinates, R and θ. By the general interpolation outline based on the RKHS (Reproducing Kernel Hilbert Space) procedure, we have reproduced for each complex from our ab initio results the two-dimensional contour plots of an analytical potential. To evaluate the stability of each complex, we have determined from the potential energy surfaces the equilibrium distance (R e ), the well depth (D e ), the quantum energy (D 0 ), the zero-point-energy (ZPE) and the ZPE%. The results showed that the linear configurations, where the noble gas atom connected to the K 2 + (X 2 Σ + g ) system, are the more stable., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

In this work we examine how small hydrophobic molecules such as inert gases interact with membrane proteins (MPs) at a molecular level. High pressure atmospheres of argon and krypton were used to produce noble gas derivatives of crystals of three well studied MPs (two different proton pumps and a sodium light-driven ion pump). The structures obtained using X-ray crystallography showed that the vast majority of argon and krypton binding sites were located on the outer hydrophobic surface of the MPs - a surface usually accommodating hydrophobic chains of annular lipids (which are known structural and functional determinants for MPs). In conformity with these results, supplementary in silico molecular dynamics (MD) analysis predicted even greater numbers of argon and krypton binding positions on MP surface within the bilayer. These results indicate a potential importance of such interactions, particularly as related to the phenomenon of noble gas-induced anaesthesia., (© 2022. The Author(s).)

F420H2-oxidase (FprA) catalyses the four-electron reduction of O2 to 2H2O using the reduced form of F420 as electron donor. The hydrophobic O2-channel detected by Kr-derivatization and the concerted movement of a gating loop could contribute to prevent unwanted side-reaction between the catalytic intermediates and solvents, therefore preventing reactive oxygen species formation.

Neuroglobin (Ngb) is a hexacoordinate globin expressed in the brain of vertebrates. Ferrous Ngb binds dioxygen with high affinity and the O(2) adduct is able to scavenge NO. Convincing in vitro and in vivo data indicate that Ngb is involved in neuroprotection during hypoxia and ischemia. The 3D structure of Ngb reveals the presence of a wide internal cavity connecting its heme active site with the bulk. To explore the role of this "tunnel" in the control of ligand binding, we determined the structure of metNgb and NgbCO equilibrated with Xe or Kr. We show four docking sites for Xe (only two for Kr); two of the four Xe sites are within the large cavity. They are only partially conserved in globins, since the two proximal Xe sites identified in myoglobin (Xe1 and Xe2) are absent in Ngb, as well as in cytoglobin. The Xe docking sites in Ngb map a pathway within the protein matrix, leading to the heme, which becomes more accessible in the ligand-bound species. This may be of significance in connection with the redox chemistry that may be the primary function of this hexacoordinate globin.

To understand the functional role of apolar cavities in bacteriorhodopsin, a light-driven proton pump found in Halobacterium salinarum, we investigated the crystal structure in pressurized xenon or krypton. Diffraction data from the P622 crystal showed that one Xe or Kr atom binds to a preexisting hydrophobic cavity buried between helices C and D, located at the same depth from the membrane surface as Asp96, a key residue in the proton uptake pathway. The occupation fraction of Xe or Kr was calculated as approximately 0.32 at a pressure of 1 MPa. In the unphotolyzed state, the binding of Xe or Kr caused no large deformation of the cavity. However, the proton pumping cycle was greatly perturbed when an aqueous suspension of purple membrane was pressurized with xenon gas; that is, the decay of the M state was accelerated significantly (~5 times at full occupancy), while the decay of an equilibrium state of N and O was slightly decelerated. A similar but much smaller perturbation in the reaction kinetics was observed upon pressurization with krypton gas. In a glycerol/water mixture, xenon-induced acceleration of M decay became less significant in proportion to the water activity. Together with the structure of the xenon-bound protein, these observations suggest that xenon binding helps water molecules permeate into apolar cavities in the proton uptake pathway, thereby accelerating the water-mediated proton transfer from Asp96 to the Schiff base.

In recent years, the use of noble-gas complexes for the de novo phasing of protein structures has proven to be a useful alternative to selenomethionine and more traditional derivatives, largely owing to improvements in methods for incorporating noble gases within protein crystals. Advantages of noble-gas derivatives include a high degree of isomorphism when using xenon for multiple isomorphous replacement (MIR) and an easily accessible absorption edge when using krypton for multiwavelength anomalous dispersion (MAD) phasing. One problem with this approach is that not all proteins contain cavities which bind noble gases. Even in proteins which do bind noble gases, the resulting derivative may not be sufficient for phasing. Using T4 lysozyme as an example, it is illustrated how this limitation might be overcome by using 'large-to-small' mutations to introduce potential noble-gas binding sites. Wild-type T4 lysozyme contains a single xenon-binding site. By truncating leucine and phenylalanine residues to alanine, it is possible to generate additional noble-gas binding sites within the core of the protein. Combining rotating-anode data from xenon complexes of wild-type and mutant lysozymes yields MIR phases which compare favorably with those determined from a selenomethionine MAD experiment conducted at a synchrotron. Experience with T4 lysozyme suggests that a leucine-to-alanine substitution made at random in a protein of unknown structure has about a 30% chance of providing a useful derivative. This procedure holds promise for the determination of unknown protein structures, especially when selenomethionine-containing protein is not available or when access to a synchrotron is limited.

Background: As a class effect, potent I(Kr)-blockers have been shown to induce stage-specific external malformations. The aim of this study was to investigate whether I(Kr)-blockers also induce stage-specific visceral and skeletal defects and to further elucidate a proposed arrhythmia-hypoxia hypothesis., Methods: Single oral doses of the selective I(Kr)-blocker almokalant (ALM) 25-150 micromol/kg, 7-14 dams/group, were given to Sprague-Dawley rats on gestation days (GD) 10-14, and the fetuses were examined for malformations on GD 21. One group was pretreated with the spin-trapping agent, alpha-phenyl-N-t-butylnitrone (PBN), given intraperitoneally 1 hr before ALM on GD 11., Results: Cardiac ventricular septum defects and vascular malformations were observed after dosing on GD 10-11 and, to a lesser degree, on GD 12-13. Urogenital defects, absence/malposition of the postcaval lung lobe, and attenuated diaphragm were observed mainly on GD 10-11. Skeletal examination showed a high incidence of vertebral abnormalities on thoracic level on GD 10, on lower thoracic to caudal level on GD 11, and sternebral defects were observed all days. On GD 13 brachy-, oligo-, and syndactyly of the forepaw were induced, and of the hindpaw on GD 14. PBN reduced the incidence of both visceral and skeletal defects., Conclusions: The stage specificity of observed visceral and skeletal defects correlates well with what has been reported in the literature after temporary interruption of oxygen supply during the same stages of development. The protective effect by PBN present further evidence that the teratogenicity of potent I(Kr)-blockers is related to induction of hypoxia- reoxygenation injury due to embryonic cardiac arrhythmia., (Copyright 2001 Wiley-Liss, Inc.)

The complexes of phage T4 lysozyme L99A with noble gases have been studied by molecular dynamics simulation. In a long simulation of the complex with one Xe atom, the structure was found to undergo global conformation change involving a reversible opening and closing of the entrance to the substrate-binding site, during which the conformations of the N and C-terminal domains varied little. The distributions of Xe positions sampled in dynamics simulations were refined in terms of anisotropic Gaussian distributions via least-squares minimization of the difference between Fourier transforms. In addition, molecular transformation simulations have been applied in order to calculate the binding free energies of Xe, Kr and Ar relative to a standard state at a pressure of 1 bar. A single bound Xe is found to assume an equilibrium distribution over three adjacent preferred sites, while in a two-Xe complex, the two Xe atoms preferentially occupy two of these. The positions of the three sites agree closely with the positions of bound Xe determined in the refined crystal structure of a complex formed at a pressure of 8 bar Xe, and the calculated affinities agree well with the observed partial occupancies. At a pressure of 8 bar, a mixture of one-Xe and two-Xe complexes is present, and similarly for complexes with Kr and Ar, with single occupancy relatively more prevalent with Kr and Ar. (Binding of a third Xe atom is found to be quite unfavorable.) A comparison with simulation results for the binding of benzene to the same site leads to the conclusion that binding of Xe within cavities in proteins is common because of several favorable factors: (1) Xe has a large atomic polarizability; (2) Xe can be applied at a relatively high pressure, i.e. high chemical potential; (3) an unfavorable entropic term related to the need to orient the ligand in the binding site is absent. Finally, it is found that the model's binding energy of a water molecule in the cavity is insufficient to overcome the unfavorable binding entropy., (Copyright 2000 Academic Press.)

To investigate the relative importance of size and polarizability in ligand binding within proteins, we have determined the crystal structures of pseudo wild-type and cavity-containing mutant phage T4 lysozymes in the presence of argon, krypton, and xenon. These proteins provide a representative sample of predominantly apolar cavities of varying size and shape. Even though the volumes of these cavities range up to the equivalent of five xenon atoms, the noble gases bind preferentially at highly localized sites that appear to be defined by constrictions in the walls of the cavities, coupled with the relatively large radii of the noble gases. The cavities within pseudo wild-type and L121A lysozymes each bind only a single atom of noble gas, while the cavities within mutants L133A and F153A have two independent binding sites, and the L99A cavity has three interacting sites. The binding of noble gases within two double mutants was studied to characterize the additivity of binding at such sites. In general, when a cavity in a protein is created by a "large-to-small" substitution, the surrounding residues relax somewhat to reduce the volume of the cavity. The binding of xenon and, to a lesser degree, krypton and argon, tend to expand the volume of the cavity and to return it closer to what it would have been had no relaxation occurred. In nearly all cases, the extent of binding of the noble gases follows the trend xenon>krypton>argon. Pressure titrations of the L99A mutant have confirmed that the crystallographic occupancies accurately reflect fractional saturation of the binding sites. The trend in noble gas affinity can be understood in terms of the effects of size and polarizability on the intermolecular potential. The plasticity of the protein matrix permits repulsion due to increased ligand size to be more than compensated for by attraction due to increased ligand polarizability. These results have implications for the mechanism of general anesthesia, the migration of small ligands within proteins, the detection of water molecules within apolar cavities and the determination of crystallographic phases., (Copyright 2000 Academic Press.)

Because tracer techniques are gaining an increasing importance for imaging flow (and metabolism) in the heart, experimental evidence is needed on the role of convection and diffusion in the transcoronary transport of solutes. In the present work, the transport of four different inert gases through the coronary system is studied in five closed-chest dog experiments and is compared with a digital multicapillary convection-diffusion model. Transport may be defined as flow dependent, as judged by the gross similarity of shape of the time-normalized dilution curves. However, the results show that the transcoronary transport of helium and xenon is more dispersed than that of argon and krypton, probably because of differences in diffusibility and solubility. A comparison of the animal and model experiments emphasizes the importance of diffusive transport of the gases. It is suggested that there is a diffusion shunt that is mainly located within the capillary network itself rather than between conduit vessels. Only for helium (which has the highest diffusivity) was a small arteriovenous shunt fraction seen that is thought to bypass the capillary exchange region. The conclusion is that although there is evidence of diffusional shunting at a capillary level, the inert gas kinetics in the heart are compatible with a basically flow-limited transport.

A method for quantifying esophageal transit by means of 81mKr is described. The principal advantage of 81mKr compared with 99mTc is its ultra-short half-life with its consequences on radiation dose and counting statistics. Factors which may influence the esophageal transit time such as body posture, volume of the tracer, and the nature of the tracer were studied. The reproducibility of the technique is quite good and its capacity to detect minor esophageal transit disorders is demonstrated.

The rate of 85Kr absorption from the feline gut was studied at varying intestinal blood flows induced by i.a. infusions of a vasodilator drug or by lowering arterial inflow pressure. The effects on rate of absorption of distending the intestine by increasing intraluminal pressure from 0-1 to 5-7 cm H2O as well as of augmenting the rate of luminal perfusion of the 85Kr solution were also investigated. Distending the small bowel increased rate of 85Kr absorption at all levels of intestinal blood flow except at the very low and the very high blood flow rates. Decreasing blood flow by lowering of arterial perfusion pressure decreased the rate of absorption from the distended gut while it had no effect in the collapsed small intestine. Increasing the rate of luminal perfusion enhanced the rate of 85Kr absorption at all blood flow levels except at the lowest ones. The results are discussed with regard to villous hemodynamics, intestinal countercurrent exchange and intraluminal concentration gradients in the lumen. It is concluded that the countercurrent exchanger represents, under physiological conditions, the major limiting factor for the absorption of lipophilic solutes such as 85Kr.

1. Testicular blood flow (ml. 100 g(-1).min(-1); mean +/- S.E. of the mean) measured in monkeys by (133)Xe clearance was 15.9 +/- 1.2 (twenty-six estimations on three monkeys; six testes) within 15 min of anaesthesia and 7.5 +/- 0.8 (twelve estimates; four monkeys, eight testes), after 1-2 hr of anaesthesia; and, when measured by (85)Kr clearance in the second hour of anaesthesia was 9.1 +/- 3.7 (seven estimates; four monkeys, four testes). Testicular temperature was 32.9 +/- 0.2 degrees C (mean +/- S.E. of mean) when deep body temperature was 37.2 +/- 0.2 degrees C.2. Blood flow in the caput epididymidis was 27.4 +/- 2.1 ml. 100 g(-1).min(-1) (mean +/- S.E. of mean; four estimates).3. Radioactivity accumulated in the ipsilateral testis and epididymis but not in the contralateral tissues, during the infusion of (85)Kr saline into the testicular veins.4. During [(3)H]testosterone infusions into the testicular veins, radioactivity was consistently higher in ipsilateral testicular arterial plasma than in plasma withdrawn simultaneously from the aorta in four of five experiments with no difference in one. After two such infusions, the radioactivity was up to 5 times greater in the ipsilateral testis and epididymis than in the contralateral tissues.5. During one infusion of [(125)I]bovine serum albumin into the testicular veins, there was no accumulation of radioactivity in the ipsilateral tissues.6. Testosterone concentrations (ng.ml(-1); mean +/- S.E. of mean) in plasma from seven anaesthetized monkeys which were sexually experienced were: testicular vein 53.22 +/- 8.03 (eight estimates); testicular artery, 4.58 +/- 0.94 (14); saphenous vein, 3.81 +/- 0.68 (14). The corresponding values from four sexually inexperienced monkeys were 25.27 +/- 2.11 (12); 2.89 +/- 1.99 (12); aorta 2.76 +/- 0.57 (12).7. The results are discussed as evidence for vascular exchange of molecules between the testicular veins and artery in the spermatic cord.

Carbon monoxide (CO) uptake from the feline small intestine was measured to investigate if it could be used to determine blood flow in the superficial parts of the intestinal mucosa. Several observations were made that substantiated this proposal: 1) Lowering PCO in the intestinal lumen from 100 to 70 kPa did not influence the rate of CO absorption during "resting" blood flow conditions, while the same reduction of lumen PCO resulted in a decreased rate of CO uptake during isoprenaline induced vasodilatation. These observations suggest that CO uptake was flow limited during "rest" and diffusion limited during vasodilation. 2) Lowering perfusion pressure or totally occluding the intestinal vascular supply markedly reduced the rate of CO uptake. 3) The diffusion distance for CO into the tissue was calculated to be 75-225 micron, i.e. CO mainly diffused into the villous tissue. 4) The flow values calculated from the CO measurements were of the same order of magnitude as earlier reported with other techniques (microspheres, indicator dilution method). It was concluded that CO absorption mainly reflected villous blood flow during "resting" and low intestinal blood flow. Total blood flow (venous drop recorder) and muscle layer blood flow (85Kr elimination) were measured simultaneously to CO uptake. From these determinations "resting" blood flow distribution in the small intestine was calculated.

Wistar rats were exposed to 85Kr gas atmospheres to determine saturation/desaturation kinetics in major tissues. Tissue partition coefficients [concentration 85Kr in tissue (muCi/g)/concentration of 85Kr in the atmosphere (muCi/cc)] were determined following equilibration with 85Kr gas. Tissue partition coefficients were highest for adrenals and fat; lowest for bone, heart and brain. Tissue partition coefficients for immature rats, 1-12 days of age, and for adults, were not significantly different. The highest concentrations of 85Kr were found in fatty tissues and in gas pockets in the intestinal lumen.

The in vivo measurements of 127Xe and 79Kr clearance from the whole body indicate five components, with biologic half-times ranging from 13 sec to 17.04 h. The slowest component correlated highly with percent total-body fat, the half-time varying between 7.59 and 17.04 for xenon and between 4.20 and 9.62 h for krypton. The long-term retention was localized to regions of high fat content as determined by the coincidence mode of the whole-body counter and images obtained with the scintillation camera. The estimated dose based on the retention data of this study would indicate increased doses to body fat and gonads as compared with those previously calculated. These increased doses are due to the longer retention of noble gases in fat. After 10-min inhalations of a mixture of 127Xe and air and 79Kr and air, approximately one third of the total 127Xe and one fifth of the total 79Kr were transferred to the body tissues, extrapolated back to the start of gas washout. Of this amount, approximately 13% of the 127Xe and approximately 9% of the 79Kr were associated with the slowest component.

To permit utilization of the Kety-Schmidt technique for measuring cerebral blood flow during hypothermia, the brain-blood partition coefficients for 85krypton at 37 C and 29.5 C were determined in a series of cats. At 37 C the partition coefficient for 85krypton was 1.092 +/- 0.009; it was 0.931 +/- 0.007 (SE) at 29.5 C. These values were significantly different from each other (P less than .001).

A miniature Geiger-Müller probe was inserted into one ovary of 8 women undergoing hysterectomy. A control probe was inserted into the other ovary of 2 of the women. Krypton-85 in 0.15 M-NaCl was infused into the adjacent utero-ovarian vein and the radioactivity was registered for 5--14 min after the infusion. An increase of radioactivity was recorded in the ovary in 5 cases. In one of the women with 2 probes, no increase in radioactivity was observed in the control ovary. The results show a local transfer of gas from the ovarian branch of the uterine vein into the adjacent ovary, which may be due to a countercurrent exchange mechanism between the vessels of the human uterine adnexa.

Continuous carotid infusion of short-lived krypton-81m (t1/2 13 sec) yields an assessment of regional cerebral perfusion. This assessment can be obtained in three dimensions if activity is recorded with a rotating gamma camera and a computer to reconstruct krypton-81m distribution in tomographic sections. These showed several advantages over conventional views: (a) visualization of blood-flow distribution within brain structures (gray and white matter, basal ganglia); (b) more accurate location and evaluation of areas of relatively reduced or increased perfusion; (c) better definition of patterns of collateral circulation; (d) greater sensitivity and specificity in detecting and defining blood-flow changes during physiological activation studies. A limitation of the krypton-81m technique is its invasiveness. However, this study shows that the combination of new advances in radiochemistry with single-photon emission computed tomography may result in accessible methods for assessing, noninvasively and in three dimensions, the behavior of cerebral function in man.

A miniature Geiger-Müller probe was inserted into the corpus luteum in five anesthetized ewes. A similar probe was inserted into either the lumen of the adjacent fallopian tube or the opposite ovary. Overall, 17 infusions of 85Krypton-saline into the uterine vein were carried out in the five subjects. After each two minute infusion into the uterine vein, an increase in radioactivity was registered in the adjacent corpus luteum within 30 - 60 seconds. Maximum radioactivity was registered 1 - 3 minutes after the start of the infusion and within 10 minutes radioactivity had dropped to background [corrected] levels. In two out of three sheep a similar kpattern of 85Krypton transfer was registered in the adjacent fallopian tube. Only a negligible amount of radioactivity above background level was registered in the contralateral control ovary, a result in keeping with the known rapid clearance of 85Krypton from the circulation. There was no indication of any change in pattern of the counter current transfer of 85Krypton during the infusion of PGF2alpha (10 microng/hr) into the ovarian pedicle. These results suggest that the previously observed slow transfer of PGF2alpha itself in the ovarian pedicle may be due to physical rather than pharmacological properties of this prostaglandin.

Pregnant rats were housed in 85Kr atmospheres at 10, 15, or 20 days of gestation (dg) and killed after 4 hr of exposure to 37-40 nCi/ml. The 85Kr was present in the components of the fetoplacental unit (FPU) at concentrations (nCi/g) equivalent to approximately 2% of the concentration (nCi/ml) in the exposure atmosphere. Tissue distribution of 85Kr and the distribution of radiation dose did not suggest any unusual hazard to the fetus associated with exposure of pregnant animals. This conclusion was tested using 5-day exposures to a 1000-fold increased concentration: 40 muCi/ml. The main effects observed in pregnant rats exposed to 85Kr from 7-12 or 12-17 dg (estimated radiation dose of 5 X 10(3) rad to maternal lung and 5 X 10(5) rad to maternal skin surface) were deaths, impaired weight gain and skin lesions. Secondarily, the maternal toxicity led to indications of embryotoxicity, although the incidence of malformations was not increased by the estimated 50-rad dose to the FPU.

Detailed estimates of radiation absorbed dose based on solubility data and the distribution of body water and fat are presented for 19Ne and 77Kr, useful PET rCBF imaging agents. The steady-state inhalation of 75 mCi of 19Ne and the bolus inhalation of 18 mCi of 77Kr should result in comparable imaging statistics for typical protocols and lung radiation absorbed doses less than approx. 0.5 rad. A model for both steady-state and bolus inhalation techniques for soluble gases used for these radiation absorbed dose calculations is also presented.

Quantitative measurements of blood flow using xenon-133 to measure cerebral blood flow and krypton-85 to measure choroidal blood flow were made in 12 anesthetized baboons (Papio anubis). Analysis of the clearance curves of krypton from the eye and studies of the diffusion of krypton in the eye show that the inert gas-clearance method measures choroidal blood flow only. The mean choroidal blood flow at normocapnia in this group of baboons is 463 +/- 44 ml./100 mg./min., and the mean cerebral blood flow is 46 +/- 5 ml./100 mg./min. (mean +/- 1 S.D.).

Krypton 81m has many advantages for paediatric lung imaging, although the proper interpretation of ventilation and perfusion lung scans requires the quantitative analysis of the steady state images and clearance curves. Both the theory and practice are described and illustrated by means of 11 paediatric cases aged from 18 days to 14 years. It was possible to calculate the regional distributions of ventilation and perfusion and the normalized ventilation-perfusion (V/Q) ratios. Of greater functional significance was the detection of differences between the clearance rates of inhaled and infused 81Krm within single regions, since such differences reflected the dispersion of V/Q ratios amongst lung units within individual regions.