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1.  Digging gold: keV He+ ion interaction with Au 
Summary
Helium ion microscopy (HIM) was used to investigate the interaction of a focused He+ ion beam with energies of several tens of kiloelectronvolts with metals. HIM is usually applied for the visualization of materials with extreme surface sensitivity and resolution. However, the use of high ion fluences can lead to significant sample modifications. We have characterized the changes caused by a focused He+ ion beam at normal incidence to the Au{111} surface as a function of ion fluence and energy. Under the influence of the beam a periodic surface nanopattern develops. The periodicity of the pattern shows a power-law dependence on the ion fluence. Simultaneously, helium implantation occurs. Depending on the fluence and primary energy, porous nanostructures or large blisters form on the sample surface. The growth of the helium bubbles responsible for this effect is discussed.
doi:10.3762/bjnano.4.53
PMCID: PMC3740815  PMID: 23946914
formation and healing of defects in crystals; helium ion microscopy; ion beam/solid interactions; vacancies in crystals
2.  Channeling in helium ion microscopy: Mapping of crystal orientation 
Summary
Background: The unique surface sensitivity and the high resolution that can be achieved with helium ion microscopy make it a competitive technique for modern materials characterization. As in other techniques that make use of a charged particle beam, channeling through the crystal structure of the bulk of the material can occur.
Results: Here, we demonstrate how this bulk phenomenon affects secondary electron images that predominantly contain surface information. In addition, we will show how it can be used to obtain crystallographic information. We will discuss the origin of channeling contrast in secondary electron images, illustrate this with experiments, and develop a simple geometric model to predict channeling maxima.
Conclusion: Channeling plays an important role in helium ion microscopy and has to be taken into account when trying to achieve maximum image quality in backscattered helium images as well as secondary electron images. Secondary electron images can be used to extract crystallographic information from bulk samples as well as from thin surface layers, in a straightforward manner.
doi:10.3762/bjnano.3.57
PMCID: PMC3458594  PMID: 23019544
channeling; crystallography; helium ion microscopy; ion scattering
3.  High Resolution Helium Ion Scanning Microscopy of the Rat Kidney 
PLoS ONE  2013;8(3):e57051.
Helium ion scanning microscopy is a novel imaging technology with the potential to provide sub-nanometer resolution images of uncoated biological tissues. So far, however, it has been used mainly in materials science applications. Here, we took advantage of helium ion microscopy to explore the epithelium of the rat kidney with unsurpassed image quality and detail. In addition, we evaluated different tissue preparation methods for their ability to preserve tissue architecture. We found that high contrast, high resolution imaging of the renal tubule surface is possible with a relatively simple processing procedure that consists of transcardial perfusion with aldehyde fixatives, vibratome tissue sectioning, tissue dehydration with graded methanol solutions and careful critical point drying. Coupled with the helium ion system, fine details such as membrane texture and membranous nanoprojections on the glomerular podocytes were visualized, and pores within the filtration slit diaphragm could be seen in much greater detail than in previous scanning EM studies. In the collecting duct, the extensive and striking apical microplicae of the intercalated cells were imaged without the shrunken or distorted appearance that is typical with conventional sample processing and scanning electron microscopy. Membrane depressions visible on principal cells suggest possible endo- or exocytotic events, and central cilia on these cells were imaged with remarkable preservation and clarity. We also demonstrate the use of colloidal gold probes for highlighting specific cell-surface proteins and find that 15 nm gold labels are practical and easily distinguishable, indicating that external labels of various sizes can be used to detect multiple targets in the same tissue. We conclude that this technology represents a technical breakthrough in imaging the topographical ultrastructure of animal tissues. Its use in future studies should allow the study of fine cellular details and provide significant advances in our understanding of cell surface structures and membrane organization.
doi:10.1371/journal.pone.0057051
PMCID: PMC3591388  PMID: 23505418
4.  Acute effects of ionizing radiation on human endothelial barrier function 
Journal of Radiation Research  2014;55(Suppl 1):i97-i98.
The human vasculature is critical to healthy functioning of the tissues of the body and a major factor in maintaining homeostasis is the endothelial barrier. In the brain, the blood–brain barrier (BBB) is highly specialized in order to sustain the neural tissue.
Here, we have examined the effects of radiation on BBB models using a unique variety of endpoints to assess barrier function. These include trans-endothelial electrical resistance (TEER), morphological effects, localization of adhesion and cell junction proteins (in two-dimensional monolayers and in three-dimensional tissue models) and permeability of molecules through the endothelial barrier. Two culture conditions were used to represent conditions on the inside or the lumen of vessels and conditions on the outside or ablumenal side of vessels. For the lumen, cells were cultured in serum and growth factor containing media, and for the ablumenal side of vessels, cells were cultured in serum-free defined media.
Initial experiments with gamma rays in serum-free conditions revealed a previously unknown acute effect involving cell detachment and the loss of the clinically relevant cell adhesion molecule—cell platelet endothelial adhesion molecule (PECAM)-1 [ 1]. Gamma radiation (5 Gy) induced a rapid and transient decrease in TEER at 3 h, with effects also seen at the lower radiotherapy dose of 2 Gy. This dip in resistance correlated with the transient loss PECAM-1 in discrete areas where cells often detached from the monolayer leaving gaps. Loss in PECAM-1 occurred at least in part as detached microparticles. Redistribution of PECAM-1 microparticles was also seen in three-dimensional human tissue models. By 6 h, the remaining cells had migrated to reseal the barrier, coincident with TEER returning to control levels. Resealed monolayers contained fewer cells per unit area and their barrier function was weakened as corroborated by an increased permeability over 24 h. Because PECAM-1 is involved in barrier function and platelet aggregation, this effect is likely highly relevant to cancer radiotherapy using gamma rays.
These studies were extended to include low linear energy transfer (LET) photons of X-rays and ion particles present in the space environment—low LET ion particles including high energy (1 GeV) protons and helium ions. X-rays under serum-free conditions also showed an acute response involving a dip in TEER at 3 h and the loss of PECAM-1 between cells as microparticles. Ion particles, however, did not show these effects of photons under serum-free conditions. Both protons and helium ions at doses up to 5 Gy did not produce this transient change in TEER or PECAM-1, although some longer term effects in TEER were noted.
In the presence of serum and growth factors, however, all radiations tested showed short-term effects in TEER, that of a series of symmetrical peaks which diminished in size over several hours. For 1 GeV protons and helium ions, this effect could be fitted to an equation for under-damped oscillation, a pattern typical of a mechanism for timing of events in periodic processes. For gamma and X-rays, the underdamped oscillation was present but superimposed on a drop in resistance at 3 h similar to that seen in serum-free conditions.
In conclusion, we have shown two acute effects of low LET radiation on the human endothelial barrier. First, a short-term effect of photons but not ion particles involving a single dip in TEER and the loss of PECAM-1 at 3 h after irradiation, and second an underdamped oscillation of TEER induced by both photons and ion particles that to date does not appear to be associated with the loss of PECAM-1 or any other junction molecules.
doi:10.1093/jrr/rrt171
PMCID: PMC3941523
endothelial barrier; radiation; charged particles
5.  Long-term follow-up after uveal melanoma charged particle therapy. 
PURPOSE: To examine the results of helium ion irradiation in 218 uveal melanoma patients treated more than 10 years ago. METHODS: Retrospective review of 218 eyes treated with helium ion radiation for uveal melanoma between 1978 and 1984. Several parametric and non-parametric statistical analysis techniques were used. RESULTS: In 218 eyes treated with helium ion radiation for uveal melanoma, the mean dimension for largest basal diameter was 11.9 mm (range 5 mm to 24 mm). The mean tumor thickness was 6.7 mm (range 1.3 mm to 14.2 mm). Following helium ion radiation 208 (95.4%) of 218 eyes had local tumor control. At 10 years after radiation 46 (22.4%) of 218 eyes were enucleated; the majority (37 of 46) of enucleations were due to anterior ocular segment complications. At 10 years after radiation 102 (46.8%) of the 218 patients were dead; half had non-tumor related deaths and 51 died from metastatic melanoma. Best corrected visual acuity after radiation was > or = 20/40 in 21 of 93 eyes of patients that were alive and retained their eyes 10 or more years after treatment. In patients with tumors that were less than 6 mm in height and more than 3 mm away from the nerve or the fovea, 13 of 18 (72%) retained > or = 20/40. In contrast, only 11% of the patients with either thicker tumors or those close to the nerve or fovea retained that level of acuity. The actuarial enucleation rate at 5 years was 17.2% (2.7% S.E.) and at 10 years this was 22.4% (3.1% S.E). The recurrence tumor control rate at both 5 and 10 years was 5.3% (S.E 1.7%). CONCLUSIONS: Helium ion radiation of uveal melanoma is associated with good local tumor control and reasonable retention of the treated eye 10 years after treatment. In tumors that are less than 6 mm in thickness and greater than 3 mm from the optic nerve and fovea, many retain excellent vision. Approximately one-half of the deaths 10 years after treatment were due to non-tumor-related causes.
PMCID: PMC1298357  PMID: 9440169
6.  Quantitative characteristics of clustered DNA damage in irradiated cells by heavy ion beams 
Journal of Radiation Research  2014;55(Suppl 1):i89-i90.
Heavy ion beam as typical high linear energy transfer (LET) radiation produces more expanding ionization domain around their tracks than low LET radiation such as X-rays and gamma rays. Thus, heavy ion beam can cause more densely accumulated damage cluster in the target DNA, termed clustered DNA damage. This damage exhibits difficulty for repair and inhibition of DNA replication with its complex structure [ 1]. So, clustered DNA damage is thought to be strongly involved in the biological effectiveness of heavy ion beam. However, a lot of studies have presented no certain correlation between yields of clustered DNA damage and severity of radiation effect. We previously indicated that the yields of clustered DNA damage decreased with increasing LET in the DNA molecules irradiated in test tubes with gamma rays, and carbon and iron ion beams whose showed different LET, respectively [ 2]. In this study, we aimed to reveal correlation between clustered DNA damage and the LET of heavy ion beam in the irradiated cells.
In the experiments, Chinese hamster ovary AA8 cells growing exponentially were irradiated by carbon, silicon, argon and iron ion beams from Heavy Ion Medical Accelerator in Chiba (HIMAC) of the National Institute of Radiological Sciences, Japan. These LETs were 13, 55, 90 and 200 keV/µm, respectively. For comparison, we used gamma rays from 137Cs-gamma source, Gammacell 40 (Atomic Energy of Canada Ltd), at Saga University. The irradiated cells were subjected by static-field gel electrophoresis to quantify clustered DNA damage of the genomic DNA. For this analysis, we used Fpg and endonuclease III for clustered DNA damage including oxidative purine and pyrimidine lesions, respectively. We also analysed the corresponding isolated DNA damages by aldehyde reactive probe method [ 3], and the surviving fractions of the irradiated cells in this study.
The electrophoretic results indicated that total yields of clustered DNA damage in the irradiated cells decreased with increasing LET, including the double-strand break (DSB) and the respective clustered base damages (Fig. 1). This result conforms to our previous study with the irradiated DNA molecules [ 2]. The damage kinetics is thought to be mainly derived from two reasons: decreasing fluxes and increasing reaction with reactive oxygen species each other in increase in LET. In the clustered DNA damage induced by each radiation, the most decremental fraction was clustered base damage, but not DSB. The isolated DNA damages decreased with increasing LET like clustered DNA damage in this study (data not shown). These results make us realize the degree of contribution of direct and indirect effects of ionizing radiation. The certain amount of DSB were derived from the direct effect and showed less reactivity to LET. In contrast, oxidative base lesions were mainly generated by indirect effect with reactive oxygen species, which sensitively responded to LET change. We also found seemingly conflicted result of the relationship between LET and RBE (data not shown). We need further study to elucidate act of clustered DNA damage in radiobiological effect with heavy ion beams. Fig. 1.The yields of clustered DNA damages in the cells irradiated with respective ionizing radiations. Each clustered DNA damage consists of DSB (open bar) and clustered base damage (closed bar), and calculated from the strength of released band on electrophoretic gel.
Clinical trial registration number if required: None.
doi:10.1093/jrr/rrt173
PMCID: PMC3941507
heavy ion beam; clustered DNA damage; LET; RBE
7.  Membrane Thickness Dependence of Nanopore Formation with a Focused Helium Ion Beam 
Sensors (Basel, Switzerland)  2014;14(5):8150-8161.
Solid-state nanopores are emerging as a valuable tool for the detection and characterization of individual biomolecules. Central to their success is the realization of fabrication strategies that are both rapid and flexible in their ability to achieve diverse device dimensions. In this paper, we demonstrate the membrane thickness dependence of solid-state nanopore formation with a focused helium ion beam. We vary membrane thickness in situ and show that the rate of pore expansion follows a reproducible trend under all investigated membrane conditions. We show that this trend shifts to lower ion dose for thin membranes in a manner that can be described quantitatively, allowing devices of arbitrary dimension to be realized. Finally, we demonstrate that thin, small-diameter nanopores formed with our approach can be utilized for high signal-to-noise ratio resistive pulse sensing of DNA.
doi:10.3390/s140508150
PMCID: PMC4063082  PMID: 24806739
solid-state nanopores; ultrathin nanopores; helium ion microscopy; ion milling; DNA translocation
8.  Helium Ion Microscopy (HIM) for the imaging of biological samples at sub-nanometer resolution 
Scientific Reports  2013;3:3514.
Scanning Electron Microscopy (SEM) has long been the standard in imaging the sub-micrometer surface ultrastructure of both hard and soft materials. In the case of biological samples, it has provided great insights into their physical architecture. However, three of the fundamental challenges in the SEM imaging of soft materials are that of limited imaging resolution at high magnification, charging caused by the insulating properties of most biological samples and the loss of subtle surface features by heavy metal coating. These challenges have recently been overcome with the development of the Helium Ion Microscope (HIM), which boasts advances in charge reduction, minimized sample damage, high surface contrast without the need for metal coating, increased depth of field, and 5 angstrom imaging resolution. We demonstrate the advantages of HIM for imaging biological surfaces as well as compare and contrast the effects of sample preparation techniques and their consequences on sub-nanometer ultrastructure.
doi:10.1038/srep03514
PMCID: PMC3865489  PMID: 24343236
9.  Fabrication of carbon nanomembranes by helium ion beam lithography 
Summary
The irradiation-induced cross-linking of aromatic self-assembled monolayers (SAMs) is a universal method for the fabrication of ultrathin carbon nanomembranes (CNMs). Here we demonstrate the cross-linking of aromatic SAMs due to exposure to helium ions. The distinction of cross-linked from non-cross-linked regions in the SAM was facilitated by transferring the irradiated SAM to a new substrate, which allowed for an ex situ observation of the cross-linking process by helium ion microscopy (HIM). In this way, three growth regimes of cross-linked areas were identified: formation of nuclei, one-dimensional (1D) and two-dimensional (2D) growth. The evaluation of the corresponding HIM images revealed the dose-dependent coverage, i.e., the relative monolayer area, whose density of cross-links surpassed a certain threshold value, as a function of the exposure dose. A complete cross-linking of aromatic SAMs by He+ ion irradiation requires an exposure dose of about 850 µC/cm2, which is roughly 60 times smaller than the corresponding electron irradiation dose. Most likely, this is due to the energy distribution of secondary electrons shifted to lower energies, which results in a more efficient dissociative electron attachment (DEA) process.
doi:10.3762/bjnano.5.20
PMCID: PMC3943867  PMID: 24605285
carbon nanomembranes; dissociative electron attachment; helium ion microscopy; ion beam-organic molecules interactions; self-assembled monolayers
10.  Conformational Ordering of Biomolecules in the Gas Phase: Nitrogen Collision Cross Sections Measured on a Prototype High Resolution Drift Tube Ion Mobility-Mass Spectrometer 
Analytical Chemistry  2014;86(4):2107-2116.
Ion mobility-mass spectrometry measurements which describe the gas-phase scaling of molecular size and mass are of both fundamental and pragmatic utility. Fundamentally, such measurements expand our understanding of intrinsic intramolecular folding forces in the absence of solvent. Practically, reproducible transport properties, such as gas-phase collision cross-section (CCS), are analytically useful metrics for identification and characterization purposes. Here, we report 594 CCS values obtained in nitrogen drift gas on an electrostatic drift tube ion mobility-mass spectrometry (IM-MS) instrument. The instrument platform is a newly developed prototype incorporating a uniform-field drift tube bracketed by electrodynamic ion funnels and coupled to a high resolution quadrupole time-of-flight mass spectrometer. The CCS values reported here are of high experimental precision (±0.5% or better) and represent four chemically distinct classes of molecules (quaternary ammonium salts, lipids, peptides, and carbohydrates), which enables structural comparisons to be made between molecules of different chemical compositions for the rapid “omni-omic” characterization of complex biological samples. Comparisons made between helium and nitrogen-derived CCS measurements demonstrate that nitrogen CCS values are systematically larger than helium values; however, general separation trends between chemical classes are retained regardless of the drift gas. These results underscore that, for the highest CCS accuracy, care must be exercised when utilizing helium-derived CCS values to calibrate measurements obtained in nitrogen, as is the common practice in the field.
doi:10.1021/ac4038448
PMCID: PMC3931330  PMID: 24446877
11.  Influence of helium-ion bombardment on the optical properties of ZnO nanorods/p-GaN light-emitting diodes 
Nanoscale Research Letters  2011;6(1):628.
Light-emitting diodes (LEDs) based on zinc oxide (ZnO) nanorods grown by vapor-liquid-solid catalytic growth method were irradiated with 2-MeV helium (He+) ions. The fabricated LEDs were irradiated with fluencies of approximately 2 × 1013 ions/cm2 and approximately 4 × 1013 ions/cm2. Scanning electron microscopy images showed that the morphology of the irradiated samples is not changed. The as-grown and He+-irradiated LEDs showed rectifying behavior with the same I-V characteristics. Photoluminescence (PL) measurements showed that there is a blue shift of approximately 0.0347 and 0.082 eV in the near-band emission (free exciton) and green emission of the irradiated ZnO nanorods, respectively. It was also observed that the PL intensity of the near-band emission was decreased after irradiation of the samples. The electroluminescence (EL) measurements of the fabricated LEDs showed that there is a blue shift of 0.125 eV in the broad green emission after irradiation and the EL intensity of violet emission approximately centered at 398 nm nearly disappeared after irradiations. The color-rendering properties show a small decrease in the color-rendering indices of 3% after 2 MeV He+ ions irradiation.
doi:10.1186/1556-276X-6-628
PMCID: PMC3274553  PMID: 22152066
12.  High-Throughput Top-Down Fabrication of Uniform Magnetic Particles 
PLoS ONE  2012;7(5):e37440.
Ion Beam Aperture Array Lithography was applied to top-down fabrication of large dense (108–109 particles/cm2) arrays of uniform micron-scale particles at rates hundreds of times faster than electron beam lithography. In this process, a large array of helium ion beamlets is formed when a stencil mask containing an array of circular openings is illuminated by a broad beam of energetic (5–8 keV) ions, and is used to write arrays of specific repetitive patterns. A commercial 5-micrometer metal mesh was used as a stencil mask; the mesh size was adjusted by shrinking the stencil openings using conformal sputter-deposition of copper. Thermal evaporation from multiple sources was utilized to form magnetic particles of varied size and thickness, including alternating layers of gold and permalloy. Evaporation of permalloy layers in the presence of a magnetic field allowed creation of particles with uniform magnetic properties and pre-determined magnetization direction. The magnetic properties of the resulting particles were characterized by Vibrating Sample Magnetometry. Since the orientation of the particles on the substrate before release into suspension is known, the orientation-dependent magnetic properties of the particles could be determined.
doi:10.1371/journal.pone.0037440
PMCID: PMC3365077  PMID: 22693574
13.  Responses of the central nervous system to high linear energy transfer radiation: NSCOR project highlights 
Journal of Radiation Research  2014;55(Suppl 1):i22-i23.
Overview: The five-university NSCOR project investigates the responses of the central nervous system to space-like charged particle exposure by evaluating: synaptic function, in vitro and in vivo neurogenesis, behavior and behaviorally induced gene expression, and oxidative stress of the mouse hippocampus and cultured neural precursor cells. To test the role of reactive oxygen species in mediating the effects of radiation exposure, we compare responses in a catalase overexpressing transgenic mouse strain to wild type. We also use computational models of the hippocampus in three dimensions, informed by experimental measurements, to provide insight into network behavior.
Radiation exposure protocols include single, acute whole-body exposures to 1H, 28Si and 56Fe ions and mixed field exposures using 1H + 56Fe ions (24 h later). The animal models are 10-week-old C57BL/6J and MCATtg males which are evaluated at 30 and 90 days postirradiation. In vitro models are cultured murine and human neural stem cells irradiated with 1H, 16O, 28Si and 56Fe ions at multiple energies and are evaluated at times from days to weeks.
Highlights: Neural stem cells organized into neurospheres were irradiated with several ions at doses as low as 0.75 cGy. Data show that significant oxidative stress occurs that alters survival, proliferation and differentiation. Overall trends indicate that changes in oxidative stress (persisting for weeks) correlate with particle linear energy transfer (LET). 56Fe ions elicited the largest and most persistent changes in stress markers, including antioxidant enzyme expression levels.
The hippocampus-dependent contextual fear conditioning (CFC) and novel object recognition (NOR) paradigms were used to assess cognition and showed cognitive deficits after irradiation with the NOR paradigm more sensitive than CFC. Analysis of neurogenesis indicates that overall neurogenesis is inhibited at doses ≥1 Gy, but newly born activated microglia are significantly elevated at ≥0.1 Gy. High LET radiation affects all lineages of neural precursor cells and elicits a U-shaped dose–response for cells exhibiting the astrocyte marker GFAP. In a mixed field irradiation regimen (0.1 Gy 1H, then 0.5 Gy 56Fe 24 h later), NOR was impaired with 0.1 Gy 1H or 0.1 Gy 1H + 0.5 Gy 56Fe but not with 0.5 Gy 56Fe alone. A negative correlation between newly born activated microglia and NOR or behaviorally activated Arc gene expression was observed for exposures using protons and iron ions, suggesting that neuroinflammation contributes to the cognitive injury. A set of monocyte chemoattractant chemokines was reduced after the mixed beam exposure but not after the individual exposures suggesting compensatory or adaptive responses are elicited by the proton exposure.
Patch clamp recordings on principal neurons of the CA1 and DG hippocampus fields were conducted on mice irradiated with 1H, 28Si and 56Fe iron ions. Input resistance and resting membrane potential were modified by irradiation in CA1 and protons were found to be the most effective ion species. These parameters suggest that more miniature excitatory post synaptic potentials must be elicited simultaneously to initiate action potentials and therefore the neurons are less responsive post irradiation. Si- and Fe-irradiated animals showed only minor alterations in mEPSCs and mIPSCs. Granule neurons of the DG field showed no differences after 28Si irradiation, but with 56Fe significant increases in AMPA receptor-mediated mEPSC frequency were observed without affecting amplitude. This focuses attention on presynaptic glutamate release mechanisms.
Functional changes in the CA1 network triggered by whole-body irradiation with protons, iron and silicon radiation were assessed with microelectrode array field recordings. Deficits in input–output curves and long-term potentiation (LTP) are observed in proton irradiated mice. In the dentate gyrus field, radiation enhanced input–output curves and LTP which is opposite of the inhibition observed for the CA1 field. This suggests that in the DG the most sensitive targets may be GABA-ergic inhibitory neurons that regulate granular cell excitability. 28Si ion effects appear to be associated with dendro-somatic coupling expected to affect signaling of the hippocampal neurons to other brain structures and vary between rostral and ventral hippocampal regions. Observations on MCATtg mice show attenuation of radiation-elicited responses, which implicates reactive oxygen species as mediators of the biological responses.
Modeling activities using a high-fidelity three-dimensional model of the hippocampus have begun and allow simulation of network activities incorporating neuron structural and functional parameters measured experimentally to probe their individual and combined contributions to network behavior. Changes in firing statistics are observed after incorporating measured electrophysiological parameters into the model.
Clinical trial registration number: not applicable.
doi:10.1093/jrr/rrt214
PMCID: PMC3941509
Brain; High LET radiation; Electrophysiology; Behavior; Neurogenesis
14.  Three-dimensional micro/nano-scale structure fabricated by combination of non-volatile polymerizable RTIL and FIB irradiation 
Scientific Reports  2014;4:3722.
Room-temperature ionic liquid (RTIL) has been widely investigated as a nonvolatile solvent as well as a unique liquid material because of its interesting features, e.g., negligible vapor pressure and high thermal stability. Here we report that a non-volatile polymerizable RTIL is a useful starting material for the fabrication of micro/nano-scale polymer structures with a focused-ion-beam (FIB) system operated under high-vacuum condition. Gallium-ion beam irradiation to the polymerizable 1-allyl-3-ethylimidazolium bis((trifluoromethane)sulfonyl)amide RTIL layer spread on a Si wafer induced a polymerization reaction without difficulty. What is interesting to note is that we have succeeded in provoking the polymerization reaction anywhere on the Si wafer substrate by using FIB irradiation with a raster scanning mode. By this finding, two- and three-dimensional micro/nano-scale polymer structure fabrications were possible at the resolution of 500,000 dpi. Even intricate three-dimensional micro/nano-figures with overhang and hollow moieties could be constructed at the resolution of approximately 100 nm.
doi:10.1038/srep03722
PMCID: PMC3893655  PMID: 24430465
15.  Collision Energetics in a Tandem Time-of-Flight (TOF/TOF) Mass Spectrometer with a Curved-Field Reflectron 
Collisions of fullerene ions (C60+) with helium and neon were carried out over a range of laboratory energies (3–20 keV) on a unique tandem time-of-flight (TOF/TOF) mass spectrometer equipped with a curved-field reflectron (CFR). The CFR enables focusing of product ions over a wide kinetic energy range. Thus, ions extracted from a laser desorption/ionization (LDI) source are not decelerated prior to collision, and collision energies in the laboratory frame are determined by the source extraction voltages. Comparison of product ion mass spectra obtained following collisions with inert gases show a time (and apparent mass) shift for product ions relative to those observed in spectra obtained by metastable dissociation (unimolecular decay), consistent with impulse collision models, in which interactions of helium with fullerene in the high energy range are primarily with a single carbon atom. In addition, within a narrow range of kinetic energies an additional peak corresponding to the capture of helium is observed for fragment ions C50+, C52+, C54+, C56+ and C58+.
doi:10.1016/j.ijms.2007.06.006
PMCID: PMC3124870  PMID: 21731425
16.  Shrinking of Solid-state Nanopores by Direct Thermal Heating 
Nanoscale Research Letters  2011;6(1):372.
Solid-state nanopores have emerged as useful single-molecule sensors for DNA and proteins. A novel and simple technique for solid-state nanopore fabrication is reported here. The process involves direct thermal heating of 100 to 300 nm nanopores, made by focused ion beam (FIB) milling in free-standing membranes. Direct heating results in shrinking of the silicon dioxide nanopores. The free-standing silicon dioxide membrane is softened and adatoms diffuse to a lower surface free energy. The model predicts the dynamics of the shrinking process as validated by experiments. The method described herein, can process many samples at one time. The inbuilt stress in the oxide film is also reduced due to annealing. The surface composition of the pore walls remains the same during the shrinking process. The linear shrinkage rate gives a reproducible way to control the diameter of a pore with nanometer precision.
doi:10.1186/1556-276X-6-372
PMCID: PMC3211463  PMID: 21711885
17.  Water equivalent thickness values of materials used in beams of protons, helium, carbon and iron ions 
Physics in medicine and biology  2010;55(9):2481-2493.
Heavy charged particle beam radiotherapy for cancer is of increasing interest because it delivers a highly conformal radiation dose to the target volume. Accurate knowledge of the range of a heavy charged particle beam after it penetrates a patient’s body or other materials in the beam line is very important and is usually stated in terms of the water equivalent thickness (WET). However, methods of calculating WET for heavy charged particle beams are lacking. Our objective was to test several simple analytical formulas previously developed for proton beams for their ability to calculate WET values for materials exposed to beams of protons, helium, carbon and iron ions. Experimentally measured heavy charged particle beam ranges and WET values from an iterative numerical method were compared with the WET values calculated by the analytical formulas. Inmost cases, the deviations were within 1 mm. We conclude that the analytical formulas originally developed for proton beams can also be used to calculate WET values for helium, carbon and iron ion beams with good accuracy.
doi:10.1088/0031-9155/55/9/004
PMCID: PMC2977971  PMID: 20371908
18.  Kr-86 Ion-Beam Irradiation of Hydrated DNA: Free Radical and Unaltered Base Yields 
Radiation research  2012;178(6):524-537.
This work reports an ESR and product analysis investigation of Kr-86 ion-beam irradiation of hydrated DNA at 77 K. The irradiation results in the formation and trapping of both base radicals and sugar phosphate radicals (DNA backbone radicals). The absolute yields (G, μmol/J) of the base radicals are smaller than the yields found in similarly prepared γ-irradiated DNA samples, and the relative yields of backbone radicals relative to base radicals are much higher than that found in γ-irradiated samples. From these results, we have elaborated our radiation chemical model of the track structure for ion-beam irradiated DNA as it applies to krypton ion-beams. The base radicals, which are trapped as ion radicals or reversibly protonated or deprotonated ion radicals, are formed almost entirely in the track penumbra, a region in which radiation chemical effects are similar to those found in γ-irradiated samples. By comparing the yields of base radicals in ion-beam samples to the yields of the same radicals in γ-irradiated samples, the partition of energy between the low-LET region (penumbra) and the core is experimentally determined. The neutral sugar and other backbone radicals, which are not as susceptible to recombination as are ion radicals, are formed largely in the track core. The backbone radicals show a linear dose response up to very high doses. Unaltered base release yields in Kr-86 irradiated hydrated DNA are equal to sugar radical yields within experimental error limits, consistent with radiation-chemical processes in which all base release originates with sugar radicals. Two phosphorus-centered radicals from fragmentation of the DNA backbone are found in low yields.
doi:10.1667/RR3066.3
PMCID: PMC3541717  PMID: 23106211
19.  Energy deposition by heavy ions: Additivity of kinetic and potential energy contributions in hillock formation on CaF2 
Scientific Reports  2014;4:5742.
Modification of surface and bulk properties of solids by irradiation with ion beams is a widely used technique with many applications in material science. In this study, we show that nano-hillocks on CaF2 crystal surfaces can be formed by individual impact of medium energy (3 and 5 MeV) highly charged ions (Xe22+ to Xe30+) as well as swift (kinetic energies between 12 and 58 MeV) heavy xenon ions. For very slow highly charged ions the appearance of hillocks is known to be linked to a threshold in potential energy (Ep) while for swift heavy ions a minimum electronic energy loss per unit length (Se) is necessary. With our results we bridge the gap between these two extreme cases and demonstrate, that with increasing energy deposition via Se the Ep-threshold for hillock production can be lowered substantially. Surprisingly, both mechanisms of energy deposition in the target surface seem to contribute in an additive way, which can be visualized in a phase diagram. We show that the inelastic thermal spike model, originally developed to describe such material modifications for swift heavy ions, can be extended to the case where both kinetic and potential energies are deposited into the surface.
doi:10.1038/srep05742
PMCID: PMC4102904  PMID: 25034006
20.  Ion-Selective Permeability of Ultrathin Nanoporous Silicon Membrane as Probed by Scanning Electrochemical Microscopy Using Micropipet-Supported ITIES Tips 
Analytical chemistry  2010;82(17):7127-7134.
We report on the application of scanning electrochemical microscopy (SECM) for the measurement of the ion-selective permeability of porous nanocrystalline silicon membrane as a new type of nanoporous material with potential applications in analytical, biomedical, and biotechnology device development. The reliable measurement of high permeability in the molecularly thin nanoporous membrane to various ions is important for greater understanding of its structure–permeability relationship and also for its successful applications. In this work, this challenging measurement is enabled by introducing two novel features into amperometric SECM tips based on the micropipet-supported interface between two immiscible electrolyte solutions (ITIES) to reveal the important ion-transport properties of the ultrathin nanopore membrane. The tip of a conventional heat-pulled micropipet is milled using focused ion beam (FIB) technique to be smoother, better aligned, and subsequently, approach closer to the membrane surface, which allows for more precise and accurate permeability measurement. The high membrane permeability to small monovalent ions is determined using FIB-milled micropipet tips to establish a theoretical formula for the membrane permeability that is controlled by free ion diffusion across water-filled nanopores. Moreover, the ITIES tips are rendered selective for larger polyions with biomedical importance, i.e., polyanionic pentasaccharide Arixtra and polycationic peptide protamine, to yield the membrane permeability that is lower than the corresponding diffusion-limited permeability. The hindered transport of the respective polyions is unequivocally ascribed to electrostatic and steric repulsions from the wall of the nanopores, i.e., the charge and size effects.
doi:10.1021/ac1005052
PMCID: PMC2932823  PMID: 20690617
21.  The role of helium gas in medicine 
Medical Gas Research  2013;3:18.
The noble gas helium has many applications owing to its distinct physical and chemical characteristics, namely: its low density, low solubility, and high thermal conductivity. Chiefly, the abundance of studies in medicine relating to helium are concentrated in its possibility of being used as an adjunct therapy in a number of respiratory ailments such as asthma exacerbation, COPD, ARDS, croup, and bronchiolitis. Helium gas, once believed to be biologically inert, has been recently shown to be beneficial in protecting the myocardium from ischemia by various mechanisms. Though neuroprotection of brain tissue has been documented, the mechanism by which it does so has yet to be made clear. Surgeons are exploring using helium instead of carbon dioxide to insufflate the abdomen of patients undergoing laparoscopic abdominal procedures due to its superiority in preventing respiratory acidosis in patients with comorbid conditions that cause carbon dioxide retention. Newly discovered applications in Pulmonary MRI radiology and imaging of organs in very fine detail using Helium Ion Microscopy has opened exciting new possibilities for the use of helium gas in technologically advanced fields of medicine.
doi:10.1186/2045-9912-3-18
PMCID: PMC3751721  PMID: 23916029
Helium; Heliox; Inhalation therapy; Cardioprotection; Neuroprotection; Insufflation
22.  Induced in-source fragmentation pattern of certain novel (1Z,2E)-N-(aryl)propanehydrazonoyl chlorides by electrospray mass spectrometry (ESI-MS/MS) 
Background
Collision induced dissociation (CID) in the triple quadrupole mass spectrometer system (QQQ) typically yields more abundant fragment ions than those produced with resonance excitation in the presence of helium gas in the ion trap mass spectrometer system (IT). Detailed product ion spectra can be obtained from one stage MS2 scan using the QQQ. In contrast, generating the same number of fragment ions in the ion trap requires multiple stages of fragmentation (MSn) using CID via in-trap resonance excitation with the associated time penalties and drop in sensitivity.
Results
The use of in-source fragmentation with electrospray ionization (ESI) followed by product ion scan (MS2) in a triple quadrupole mass spectrometer system, was demonstrated. This process enhances the qualitative power of tandem mass spectrometry to simulate the MS3 of ion trap for a comprehensive study of fragmentation mechanisms. A five pharmacologically significant (1Z, 2E)-N-arylpropanehydrazonoyl chlorides (3a-e) were chosen as model compounds for this study. In this work, detailed fragmentation pathways were elucidated by further dissociation of each fragment ion in the ion spectrum, essentially, by incorporating fragmentor voltage induced dissociation (in-source fragmentation) and isolation of fragments in a quadrupole cell Q1. Subsequently, CID occurs in cell, Q2, and fragment ions are analyzed in Q3 operated in product ion mode this process can be referred to as pseudo-MS3 scan mode.
Conclusions
This approach allowed unambiguous assignment of all fragment ions using tandem mass spectrometer and provided adequate sensitivity and selectivity. It is beneficial for structure determination of unknown trace components. The data presented in this paper provide useful information on the effect of different substituents on the ionization/fragmentation processes and can be used in the characterization of this important class of compounds.
doi:10.1186/1752-153X-7-16
PMCID: PMC3582627  PMID: 23351484
In-source fragmentation; Hydrazones; Fragmentor voltage; Electrospray ionization
23.  Nonlinear optical effects of ultrahigh-Q silicon photonic nanocavities immersed in superfluid helium 
Scientific Reports  2013;3:1436.
Photonic nanocavities are a key component in many applications because of their capability of trapping and storing photons and enhancing interactions of light with various functional materials and structures. The maximal number of photons that can be stored in silicon photonic cavities is limited by the free-carrier and thermo-optic effects at room temperature. To reduce such effects, we performed the first experimental study of optical nonlinearities in ultrahigh-Q silicon disk nanocavities at cryogenic temperatures in a superfluid helium environment. At elevated input power, the cavity transmission spectra exhibit distinct blue-shifted bistability behavior when temperature crosses the liquid helium lambda point. At even lower temperatures, the spectra restore to symmetric Lorentzian shapes. Under this condition, we obtain a large intracavity photon number of about 40,000, which is limited ultimately by the local helium phase transition. These new discoveries are explained by theoretical calculations and numerical simulations.
doi:10.1038/srep01436
PMCID: PMC3595694  PMID: 23486445
24.  Long term visual outcome of radiated uveal melanomas in eyes eligible for randomisation to enucleation versus brachytherapy. 
AIMS: To determine the long term visual outcome of patients who were eligible for randomisation to enucleation versus brachytherapy in a US collaborative ocular melanoma study (COMS) but were treated with either helium ion or 125I radioactive plaque therapy. METHOD: A retrospective analysis was performed of 426 ciliochoroidal melanomas that met COMS inclusion criteria for randomisation to enucleation versus radioactive plaque but were treated with either helium ions or 125I brachytherapy. RESULTS: At 3 years 36.0% of eyes had 6/12 or better visual acuity. The length of visual retention was most dependent on tumour thickness, tumour location with respect to the optic nerve, fovea, or ciliary body, and patient age. In addition to these factors, the retention of 6/12 visual acuity and the time to 6/120 visual acuity were dependent on the preoperative visual acuity. The risk of visual loss was greatest immediately after treatment and decreased with time. The 5 year actuarial metastatic rate was approximately 13%. Patients at the greatest risk of post-radiation visual loss had significantly greater risk of tumour related mortality. CONCLUSIONS: Some patients who would have been eligible for randomisation to either enucleation or radioactive plaque therapy can be irradiated with retention of excellent vision.
PMCID: PMC505401  PMID: 8814740
25.  Reactive Oxygen Species and Mitochondrial KATP Channels Mediate Helium-Induced Preconditioning Against Myocardial Infarction In Vivo 
Objectives
Helium produces preconditioning by activating prosurvival kinases, but the roles of reactive oxygen species (ROS) or mitochondrial KATP channels in this process are unknown. We tested the hypothesis that ROS and mitochondrial KATP channels mediate helium-induced preconditioning in vivo.
Design
Randomized, prospective study.
Setting
University research laboratory.
Participants
Male New Zealand white rabbits.
Interventions
Rabbits (n=64) were instrumented for measurement of systemic hemodynamics and subjected to a 30 min left anterior descending coronary artery (LAD) occlusion and 3 h reperfusion. In separate experimental groups, rabbits (n=7 or 8 per group) were randomly assigned to receive 0.9% saline (control) or three cycles of 70% helium-30% oxygen administered for 5 min interspersed with 5 min of an air-oxygen mixture before LAD occlusion with or without the ROS scavengers N-acetylcysteine (NAC; 150 mg/kg) or N-2-mercaptoproprionyl glycine (2-MPG; 75 mg/kg), or the mitochondrial KATP antagonist 5-hydroxydecanoate (5-HD; 5 mg/kg). Statistical analysis of data was performed with analysis of variance for repeated measures followed by Bonferroni's modification of Student's t test.
Measurements and Main Results
Myocardial infarct size was determined using triphenyltetrazolium chloride staining and presented as a percentage of the left ventricular area at risk. Helium significantly (P<0.05) reduced infarct size (23±4% of the area at risk; mean±SD) compared with control (46±3%). NAC, 2-MPG, and 5-HD did not affect irreversible ischemic injury when administered alone (49±5, 45±6, and 45±3%), but these drugs blocked reductions in infarct size produced by helium (45±4, 45±2, and 44±3%).
Conclusions
The results suggest that ROS and mitochondrial KATP channels mediate helium-induced preconditioning in vivo.
doi:10.1053/j.jvca.2008.04.005
PMCID: PMC2568984  PMID: 18662630
myocardial ischemia; preconditioning; helium; reactive oxygen species; mitochondrial KATP channels

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