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1.  Nanopore sculpting with noble gas ions 
Journal of applied physics  2006;100(2):024914-024914-6.
We demonstrate that 3 keV ion beams, formed from the common noble gasses, He, Ne, Ar, Kr, and Xe, can controllably “sculpt” nanometer scale pores in silicon nitride films. Single nanometer control of structural dimensions in nanopores can be achieved with all ion species despite a very wide range of sputtering yields and surface energy depositions. Heavy ions shrink pores more efficiently and make thinner pores than lighter ions. The dynamics of nanopore closing is reported for each ion species and the results are fitted to an adatom diffusion model with excellent success. We also present an experimental method for profiling the thickness of the local membrane around the nanopore based on low temperature sputtering and data is presented that provides quantitative measurements of the thickness and its dependence on ion beam species.
doi:10.1063/1.2216880
PMCID: PMC3039599  PMID: 21331305
2.  Surface Morphology Evolution of GaAs by Low Energy Ion Sputtering 
Nanoscale Research Letters  2007;2(10):504-508.
Low energy Ar+ion sputtering, typically below 1,200 eV, of GaAs at normal beam incident angle is investigated. Surface morphology development with respect to varying energy is analyzed and discussed. Dot-like patterns in the nanometer scale are obtained above 600 eV. As the energy approaches upper eV range regular dots have evolved. The energy dependent dot evolution is evaluated based on solutions of the isotropic Kuramoto-Sivashinsky equation. The results are in agreement with the theoretical model which describes a power law dependency of the characteristic wavelength on ion energy in the ion-induced diffusion regime.
doi:10.1007/s11671-007-9090-4
PMCID: PMC3246606
Low energy; Ion sputtering; Surface morphology; GaAs quantum dot
3.  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  PMID: 24586011
heavy ion beam; clustered DNA damage; LET; RBE
4.  Misrepair of DNA double-strand breaks after exposure to heavy-ion beams causes a peak in the LET–RBE relationship with respect to cell killing in DT40 cells 
Journal of Radiation Research  2013;54(6):1029-1035.
To determine the radiobiological mechanisms underlying relative biological effectiveness (RBE) and the repair efficiencies of DNA double-strand breaks (DSBs) as a function of linear energy transfer (LET), we exposed cells of the chicken B-lymphocyte cell line DT40 and its DSB repair pathway-deficient derivatives to heavy-ion beams produced at the Heavy-Ion Medical Accelerator in Chiba (HIMAC) at the National Institute of Radiological Sciences (NIRS), Chiba, Japan. The relationship between LET and cell lethality was investigated in the DNA DSB repair gene knockouts Ku70−/−, Rad54−/−, and Ku70−/−Rad54−/−, and in the wild-type cells. We found that cell-cycle stage and activity of the DNA DSB repair pathways influence LET-mediated biological effects. An expected LET–RBE relationship was observed in the cells capable of DNA repair, but no peak was found in the RBE with respect to cell survival in the Ku70−/−Rad54−/− cells or in Ku70−/− cells in the G1 and early S cell-cycle phases (when no sister chromatids were present and homologous recombination could not occur). These findings suggest that the peak in RBE is caused by deficient repair of the DNA DSBs.
doi:10.1093/jrr/rrt064
PMCID: PMC3823785  PMID: 23722078
linear energy transfer; relative biological effectiveness; sensitivity; misrepair; heavy ion
5.  Radioactivity and lung cancer-mathematical models of radionuclide deposition in the human lungs 
Journal of Thoracic Disease  2011;3(4):231-243.
The human respiratory tract is regarded as pathway for radionuclides and other hazardous airborne materials to enter the body. Radioactive particles inhaled and deposited in the lungs cause an irradiation of bronchial/alveolar tissues. At the worst, this results in a malignant cellular transformation and, as a consequence of that, the development of lung cancer. In general, naturally occurring radionuclides (e.g., 222Rn, 40K) are attached to so-called carrier aerosols. The aerodynamic diameters of such radioactively labeled particles generally vary between several nanometers (ultrafine particles) and few micrometers, whereby highest particle fractions adopt sizes around 100 nm. Theoretical simulations of radioactive particle deposition in the human lungs were based on a stochastic lung geometry and a particle transport/deposition model using the random-walk algorithm. Further a polydisperse carrier aerosol (diameter: 1 nm–10 µm, ρ ≈ 1 g cm−3) with irregularly shaped particles and the effect of breathing characteristics and certain respiratory parameters on the transport of radioactive particles to bronchial/alveolar tissues were considered. As clearly shown by the results of deposition modeling, distribution patterns of radiation doses mainly depend on the size of the carrier aerosol. Ultrafine (< 10 nm) and large (> 2 µm) aerosol particles are preferentially deposited in the extrathoracic and upper bronchial region, whereas aerosol particles with intermediate size (10 nm–2 µm) may penetrate to deeper lung regions, causing an enhanced damage of the alveolar tissue by the attached radionuclides.
doi:10.3978/j.issn.2072-1439.2011.04.01
PMCID: PMC3256534  PMID: 22263097
Radionuclides; Carrier aerosol; Monte Carlo model; Stochastic lung geometry
6.  Modeling the biological response of normal human cells, including repair processes, to fractionated carbon beam irradiation 
Journal of Radiation Research  2013;54(5):798-807.
To understand the biological response of normal cells to fractionated carbon beam irradiation, the effects of potentially lethal damage repair (PLDR) and sublethal damage repair (SLDR) were both taken into account in a linear-quadratic (LQ) model. The model was verified by the results of a fractionated cell survival experiment with normal human fibroblast cells. Cells were irradiated with 200-kV X-rays and monoenergetic carbon ion beams (290 MeV/u) at two irradiation depths, corresponding to linear energy transfers (LETs) of approximately 13 keV/μm and 75 keV/μm, respectively, at the Heavy Ion Medical Accelerator in Chiba of the National Institute of Radiological Sciences. When we only took into account the repair factor of PLDR, γ, which was derived from the delayed assay, the cell survival response to fractionated carbon ion irradiation was not fully explained in some cases. When both the effects of SLDR and PLDR were taken into account in the LQ model, the cell survival response was well reproduced. The model analysis suggested that PLDR occurs in any type of radiation. The γ factors ranged from 0.36–0.93. In addition, SLD was perfectly repaired during the fraction interval for the lower LET irradiations but remained at about 30% for the high-LET irradiation.
doi:10.1093/jrr/rrt012
PMCID: PMC3766285  PMID: 23449640
modeling; SLDR; PLDR; fractionated carbon beam irradiation
7.  Differences in Phosphorylated Histone H2AX Foci Formation and Removal of Cells Exposed to Low and High Linear Energy Transfer Radiation 
Current Genomics  2012;13(6):418-425.
The use of particle ion beams in cancer radiotherapy has a long history. Today, beams of protons or heavy ions, predominantly carbon ions, can be accelerated to precisely calculated energies which can be accurately targeted to tumors. This particle therapy works by damaging the DNA of tissue cells, ultimately causing their death. Among the different types of DNA lesions, the formation of DNA double strand breaks is considered to be the most relevant of deleterious damages of ionizing radiation in cells. It is well-known that the extremely large localized energy deposition can lead to complex types of DNA double strand breaks. These effects can lead to cell death, mutations, genomic instability, or carcinogenesis. Complex double strand breaks can increase the probability of mis-rejoining by NHEJ. As a consequence differences in the repair kinetics following high and low LET irradiation qualities are attributed mainly to quantitative differences in their contributions of the fast and slow repair component. In general, there is a higher contribution of the slow component of DNA double strand repair after exposure to high LET radiation, which is thought to reflect the increased amount of complex DNA double strand breaks. These can be accurately measured by the γ-H2AX assay, because the number of phosphorylated H2AX foci correlates well with the number of double strand breaks induced by low or / and high LET radiation.
doi:10.2174/138920212802510501
PMCID: PMC3426775  PMID: 23450137
DNA double strand breaks; Linear energy transfer; Radiation; γ-H2AX foci.
8.  Multifactorial Resistance of Bacillus subtilis Spores to High-Energy Proton Radiation: Role of Spore Structural Components and the Homologous Recombination and Non-Homologous End Joining DNA Repair Pathways 
Astrobiology  2012;12(11):1069-1077.
Abstract
The space environment contains high-energy charged particles (e.g., protons, neutrons, electrons, α-particles, heavy ions) emitted by the Sun and galactic sources or trapped in the radiation belts. Protons constitute the majority (87%) of high-energy charged particles. Spores of Bacillus species are one of the model systems used for astro- and radiobiological studies. In this study, spores of different Bacillus subtilis strains were used to study the effects of high energetic proton irradiation on spore survival. Spores of the wild-type B. subtilis strain [mutants deficient in the homologous recombination (HR) and non-homologous end joining (NHEJ) DNA repair pathways and mutants deficient in various spore structural components such as dipicolinic acid (DPA), α/β-type small, acid-soluble spore protein (SASP) formation, spore coats, pigmentation, or spore core water content] were irradiated as air-dried multilayers on spacecraft-qualified aluminum coupons with 218 MeV protons [with a linear energy transfer (LET) of 0.4 keV/μm] to various final doses up to 2500 Gy. Spores deficient in NHEJ- and HR-mediated DNA repair were significantly more sensitive to proton radiation than wild-type spores, indicating that both HR and NHEJ DNA repair pathways are needed for spore survival. Spores lacking DPA, α/β-type SASP, or with increased core water content were also significantly more sensitive to proton radiation, whereas the resistance of spores lacking pigmentation or spore coats was essentially identical to that of the wild-type spores. Our results indicate that α/β-type SASP, core water content, and DPA play an important role in spore resistance to high-energy proton irradiation, suggesting their essential function as radioprotectants of the spore interior. Key Words: Bacillus—Spores—DNA repair—Protection—High-energy proton radiation. Astrobiology 12, 1069–1077.
doi:10.1089/ast.2012.0890
PMCID: PMC3491616  PMID: 23088412
9.  Characterization of highly efficient heavy-ion mutagenesis in Arabidopsis thaliana 
BMC Plant Biology  2011;11:161.
Background
Heavy-ion mutagenesis is recognised as a powerful technology to generate new mutants, especially in higher plants. Heavy-ion beams show high linear energy transfer (LET) and thus more effectively induce DNA double-strand breaks than other mutagenic techniques. Previously, we determined the most effective heavy-ion LET (LETmax: 30.0 keV μm-1) for Arabidopsis mutagenesis by analysing the effect of LET on mutation induction. However, the molecular structure of mutated DNA induced by heavy ions with LETmax remains unclear. Knowledge of the structure of mutated DNA will contribute to the effective exploitation of heavy-ion beam mutagenesis.
Results
Dry Arabidopsis thaliana seeds were irradiated with carbon (C) ions with LETmax at a dose of 400 Gy and with LET of 22.5 keV μm-1 at doses of 250 Gy or 450 Gy. The effects on mutation frequency and alteration of DNA structure were compared. To characterise the structure of mutated DNA, we screened the well-characterised mutants elongated hypocotyls (hy) and glabrous (gl) and identified mutated DNA among the resulting mutants by high-resolution melting curve, PCR and sequencing analyses. The mutation frequency induced by C ions with LETmax was two-fold higher than that with 22.5 keV μm-1 and similar to the mutation frequency previously induced by ethyl methane sulfonate. We identified the structure of 22 mutated DNAs. Over 80% of the mutations caused by C ions with both LETs were base substitutions or deletions/insertions of less than 100 bp. The other mutations involved large rearrangements.
Conclusions
The C ions with LETmax showed high mutation efficiency and predominantly induced base substitutions or small deletions/insertions, most of which were null mutations. These small alterations can be determined by single-nucleotide polymorphism (SNP) detection systems. Therefore, C ions with LETmax might be useful as a highly efficient reverse genetic system in conjunction with SNP detection systems, and will be beneficial for forward genetics and plant breeding.
doi:10.1186/1471-2229-11-161
PMCID: PMC3261129  PMID: 22085561
10.  Field Emission and Radial Distribution Function Studies of Fractal-like Amorphous Carbon Nanotips 
Nanoscale Research Letters  2009;4(5):431-436.
The short-range order of individual fractal-like amorphous carbon nanotips was investigated by means of energy-filtered electron diffraction in a transmission electron microscope (TEM). The nanostructures were grown in porous silicon substrates in situ within the TEM by the electron beam-induced deposition method. The structure factor S(k) and the reduced radial distribution function G(r) were calculated. From these calculations a bond angle of 124° was obtained which suggests a distorted graphitic structure. Field emission was obtained from individual nanostructures using two micromanipulators with sub-nanometer positioning resolution. A theoretical three-stage model that accounts for the geometry of the nanostructures provides a value for the field enhancement factor close to the one obtained experimentally from the Fowler-Nordheim law.
doi:10.1007/s11671-009-9270-5
PMCID: PMC2894329  PMID: 20596340
Carbon nanotips; Graphite-like a-C; EELS; EFED; Field emission
11.  Field Emission and Radial Distribution Function Studies of Fractal-like Amorphous Carbon Nanotips 
Nanoscale Research Letters  2009;4(5):431-436.
The short-range order of individual fractal-like amorphous carbon nanotips was investigated by means of energy-filtered electron diffraction in a transmission electron microscope (TEM). The nanostructures were grown in porous silicon substrates in situ within the TEM by the electron beam-induced deposition method. The structure factorS(k) and the reduced radial distribution functionG(r) were calculated. From these calculations a bond angle of 124° was obtained which suggests a distorted graphitic structure. Field emission was obtained from individual nanostructures using two micromanipulators with sub-nanometer positioning resolution. A theoretical three-stage model that accounts for the geometry of the nanostructures provides a value for the field enhancement factor close to the one obtained experimentally from the Fowler-Nordheim law.
doi:10.1007/s11671-009-9270-5
PMCID: PMC2894329  PMID: 20596340
Carbon nanotips; Graphite-like a-C; EELS; EFED; Field emission
12.  Drying nano particles solution on an oscillating tip at an air liquid interface: what we can learn, what we can do 
Nanoscale Research Letters  2007;2(7):309-318.
Evaporation of fluid at micro and nanometer scale may be used to self-assemble nanometre-sized particles in suspension. Evaporating process can be used to gently control flow in micro and nanofluidics, thus providing a potential mean to design a fine pattern onto a surface or to functionalize a nanoprobe tip. In this paper, we present an original experimental approach to explore this open and rather virgin domain. We use an oscillating tip at an air liquid interface with a controlled dipping depth of the tip within the range of the micrometer. Also, very small dipping depths of a few ten nanometers were achieved with multi walls carbon nanotubes glued at the tip apex. The liquid is an aqueous solution of functionalized nanoparticles diluted in water. Evaporation of water is the driving force determining the arrangement of nanoparticles on the tip. The results show various nanoparticles deposition patterns, from which the deposits can be classified in two categories. The type of deposit is shown to be strongly dependent on whether or not the triple line is pinned and of the peptide coating of the gold nanoparticle. In order to assess the classification, companion dynamical studies of nanomeniscus and related dissipation processes involved with thinning effects are presented.
doi:10.1007/s11671-007-9065-5
PMCID: PMC3246374
Nanofluidics; Nanoparticles; Micromeniscus; Nanomeniscus; Dynamical mode of atomic force microcopy
13.  Molecular Threading: Mechanical Extraction, Stretching and Placement of DNA Molecules from a Liquid-Air Interface 
PLoS ONE  2013;8(7):e69058.
We present “molecular threading”, a surface independent tip-based method for stretching and depositing single and double-stranded DNA molecules. DNA is stretched into air at a liquid-air interface, and can be subsequently deposited onto a dry substrate isolated from solution. The design of an apparatus used for molecular threading is presented, and fluorescence and electron microscopies are used to characterize the angular distribution, straightness, and reproducibility of stretched DNA deposited in arrays onto elastomeric surfaces and thin membranes. Molecular threading demonstrates high straightness and uniformity over length scales from nanometers to micrometers, and represents an alternative to existing DNA deposition and linearization methods. These results point towards scalable and high-throughput precision manipulation of single-molecule polymers.
doi:10.1371/journal.pone.0069058
PMCID: PMC3729692  PMID: 23935923
14.  Biological consequences of nanoscale energy deposition near irradiated heavy atom nanoparticles 
Scientific Reports  2011;1:18.
Gold nanoparticles (GNPs) are being proposed as contrast agents to enhance X-ray imaging and radiotherapy, seeking to take advantage of the increased X-ray absorption of gold compared to soft tissue. However, there is a great discrepancy between physically predicted increases in X-ray energy deposition and experimentally observed increases in cell killing. In this work, we present the first calculations which take into account the structure of energy deposition in the nanoscale vicinity of GNPs and relate this to biological outcomes, and show for the first time good agreement with experimentally observed cell killing by the combination of X-rays and GNPs. These results are not only relevant to radiotherapy, but also have implications for applications of heavy atom nanoparticles in biological settings or where human exposure is possible because the localised energy deposition high-lighted by these results may cause complex DNA damage, leading to mutation and carcinogenesis.
doi:10.1038/srep00018
PMCID: PMC3216506  PMID: 22355537
15.  Nanopore Fabrication by Controlled Dielectric Breakdown 
PLoS ONE  2014;9(3):e92880.
Nanofabrication techniques for achieving dimensional control at the nanometer scale are generally equipment-intensive and time-consuming. The use of energetic beams of electrons or ions has placed the fabrication of nanopores in thin solid-state membranes within reach of some academic laboratories, yet these tools are not accessible to many researchers and are poorly suited for mass-production. Here we describe a fast and simple approach for fabricating a single nanopore down to 2-nm in size with sub-nm precision, directly in solution, by controlling dielectric breakdown at the nanoscale. The method relies on applying a voltage across an insulating membrane to generate a high electric field, while monitoring the induced leakage current. We show that nanopores fabricated by this method produce clear electrical signals from translocating DNA molecules. Considering the tremendous reduction in complexity and cost, we envision this fabrication strategy would not only benefit researchers from the physical and life sciences interested in gaining reliable access to solid-state nanopores, but may provide a path towards manufacturing of nanopore-based biotechnologies.
doi:10.1371/journal.pone.0092880
PMCID: PMC3962464  PMID: 24658537
16.  The contribution of phosphate–phosphate repulsions to the free energy of DNA bending 
Nucleic Acids Research  2005;33(4):1257-1268.
DNA bending is important for the packaging of genetic material, regulation of gene expression and interaction of nucleic acids with proteins. Consequently, it is of considerable interest to quantify the energetic factors that must be overcome to induce bending of DNA, such as base stacking and phosphate–phosphate repulsions. In the present work, the electrostatic contribution of phosphate–phosphate repulsions to the free energy of bending DNA is examined for 71 bp linear and bent-form model structures. The bent DNA model was based on the crystallographic structure of a full turn of DNA in a nucleosome core particle. A Green's function approach based on a linear-scaling smooth conductor-like screening model was applied to ascertain the contribution of individual phosphate–phosphate repulsions and overall electrostatic stabilization in aqueous solution. The effect of charge neutralization by site-bound ions was considered using Monte Carlo simulation to characterize the distribution of ion occupations and contribution of phosphate repulsions to the free energy of bending as a function of counterion load. The calculations predict that the phosphate–phosphate repulsions account for ∼30% of the total free energy required to bend DNA from canonical linear B-form into the conformation found in the nucleosome core particle.
doi:10.1093/nar/gki272
PMCID: PMC552960  PMID: 15741179
17.  Absolute cross section for low-energy-electron damage to condensed macromolecules: A case study of DNA 
Cross sections (CSs) for the interaction of low-energy electrons (LEE) with condensed macromolecules are essential parameters for accurate modeling of radiation-induced molecular decomposition and chemical synthesis. Electron irradiation of dry nanometer-scale macromolecular solid films has often been employed to measure CSs and other quantitative parameters for LEE interactions. Since such films have thicknesses comparable with electron thermalization distances, energy deposition varies throughout the film. Moreover, charge accumulation occurring inside the films shields a proportion of the macromolecules from electron irradiation. Such effects complicate the quantitative comparison of the CSs obtained in films of different thicknesses and limit the applicability of such measurements. Here, we develop a simple mathematical model, termed the molecular survival model, that employs a CS for a particular damage process together with an attenuation length related to the total CS, to investigate how a measured CS might be expected to vary with experimental conditions. As a case study, we measure the absolute CS for the formation of DNA strand breaks (SBs) by electron irradiation at 10 and 100 eV of lyophilized plasmid DNA films with thicknesses between 10 and 30 nm. The measurements are shown to depend strongly on the thickness and charging condition of the nanometer-scale films. Such behaviors are in accord with the model and support its validity. Via this analysis, the CS obtained for SB damage is nearly independent of film thickness and charging effects. In principle, this model can be adapted to provide absolute CSs for electron-induced damage or reactions occurring in other molecular solids across a wider range of experimental conditions.
PMCID: PMC3815646  PMID: 23030950 CAMSID: cams3603
18.  Protein-membrane interactions: Blood clotting on nanoscale bilayers 
Summary
The clotting cascade requires the assembly of protease-cofactor complexes on membranes with exposed anionic phospholipids. Despite their importance, protein-membrane interactions in clotting remain relatively poorly understood. Calcium ions are known to induce anionic phospholipids to cluster, and we propose that clotting proteins assemble preferentially on such anionic lipid-rich microdomains. Until recently, there was no way to control the partitioning of clotting proteins into or out of specific membrane microdomains, so experimenters only knew the average contributions of phospholipids to blood clotting. The development of nanoscale membrane bilayers (Nanodiscs) has now allowed us to probe, with nanometer resolution, how local variations in phospholipid composition regulate the activity of key protease-cofactor complexes in blood clotting. Furthermore, exciting new progress in solid-state NMR and large-scale molecular dynamics simulations are allowing structural insights into interactions between proteins and membrane surfaces with atomic resolution.
doi:10.1111/j.1538-7836.2009.03390.x
PMCID: PMC2839880  PMID: 19630793
membranes; phospholipids; microdomains; GLA-domains; cofactors
19.  Metal site occupancy and allosteric switching in bacterial metal sensor proteins 
All prokaryotes encode a panel of metal sensor or metalloregulatory proteins that govern the expression of genes that allows an organism to quickly adapt to toxicity or deprivation of both biologically essential transition metal ions, e.g., Zn, Cu, Fe, and heavy metal pollutants. As such, metal sensor proteins can be considered arbiters of intracellular transition metal bioavailability and thus potentially control the metallation state of the metalloproteins in the cell. Metal sensor proteins are specialized allosteric proteins that regulate transcription as a result direct binding of one or two cognate metal ions, to the exclusion of all others. In most cases, the binding of the cognate metal ion induces a structural change in a protein oligomer that either activates or inhibits operator DNA binding. A quantitative measure of the degree to which a particular metal drives metalloregulation of operator DNA-binding is the allosteric coupling free energy, ΔGc. In this review, we summarize recent work directed toward understanding metal occupancy and metal selectivity of these allosteric switches in selected families of metal sensor proteins and examine the structural origins of ΔGc in the functional context a thermodynamic “set-point” model of intracellular metal homeostasis.
doi:10.1016/j.abb.2011.11.021
PMCID: PMC3312040  PMID: 22178748
metalloregulation; metal sensor protein; transition metal ions; allosteric coupling free energy; protein-DNA interactions; linkage
20.  Large-scale automated histology in the pursuit of connectomes 
How does the brain compute? Answering this question necessitates neuronal connectomes, annotated graphs of all synaptic connections within defined brain areas. Further, understanding the energetics of the brain’s computations requires vascular graphs. The assembly of a connectome requires sensitive hardware tools to measure neuronal and neurovascular features in all three dimensions, as well as software and machine learning for data analysis and visualization. We present the state-of-the-art on the reconstruction of circuits and vasculature that link brain anatomy and function. Analysis at the scale of tens of nanometers yields connections between identified neurons, while analysis at the micrometer scale yields probabilistic rules of connection between neurons and exact vascular connectivity.
doi:10.1523/JNEUROSCI.4077-11.2011
PMCID: PMC3758571  PMID: 22072665
21.  Large-Scale Automated Histology in the Pursuit of Connectomes 
The Journal of Neuroscience  2011;31(45):16125-16138.
How does the brain compute? Answering this question necessitates neuronal connectomes, annotated graphs of all synaptic connections within defined brain areas. Further, understanding the energetics of the brain's computations requires vascular graphs. The assembly of a connectome requires sensitive hardware tools to measure neuronal and neurovascular features in all three dimensions, as well as software and machine learning for data analysis and visualization. We present the state of the art on the reconstruction of circuits and vasculature that link brain anatomy and function. Analysis at the scale of tens of nanometers yields connections between identified neurons, while analysis at the micrometer scale yields probabilistic rules of connection between neurons and exact vascular connectivity.
doi:10.1523/JNEUROSCI.4077-11.2011
PMCID: PMC3758571  PMID: 22072665
22.  Three-dimensional imaging of chemical phase transformations at the nanoscale with full-field transmission X-ray microscopy 
Journal of Synchrotron Radiation  2011;18(Pt 5):773-781.
Two-dimensional and three-dimensional single-pixel and single-voxel speciation of Ni in Li-ion battery electrodes is accomplished combining full-field hard X-ray transmission microscopy and XANES imaging at tens of nanometers resolution.
The ability to probe morphology and phase distribution in complex systems at multiple length scales unravels the interplay of nano- and micrometer-scale factors at the origin of macroscopic behavior. While different electron- and X-ray-based imaging techniques can be combined with spectroscopy at high resolutions, owing to experimental time limitations the resulting fields of view are too small to be representative of a composite sample. Here a new X-ray imaging set-up is proposed, combining full-field transmission X-ray microscopy (TXM) with X-ray absorption near-edge structure (XANES) spectroscopy to follow two-dimensional and three-dimensional morphological and chemical changes in large volumes at high resolution (tens of nanometers). TXM XANES imaging offers chemical speciation at the nanoscale in thick samples (>20 µm) with minimal preparation requirements. Further, its high throughput allows the analysis of large areas (up to millimeters) in minutes to a few hours. Proof of concept is provided using battery electrodes, although its versatility will lead to impact in a number of diverse research fields.
doi:10.1107/S0909049511019364
PMCID: PMC3161818  PMID: 21862859
X-ray microscopy; synchrotron X-ray imaging; Li-ion battery; XANES
23.  Synthesis and Electrochemical Sensing Toward Heavy Metals of Bunch-like Bismuth Nanostructures 
Nanoscale Research Letters  2009;5(2):398-402.
Large-scale bunch-like bismuth (Bi) nanostructures were the first time to be synthesized via two-step electrochemical deposition. The growth mechanism of the nanostructures was discussed. Such a designed bunch-like Bi electrode has high sensitivity to detect the heavy metal ions due to its unique three-dimensional structures and strong ability of adsorbing the heavy metal ions. The bunch-like Bi electrode’s detection of heavy metals was statically performed using anodic stripping voltammetry (ASV). The detection in the Pb(II) concentration range of 2.5–50 μg/l was also performed. Based on the experimental results, this bunch-like Bi electrode can be considered as an interesting alternative to common mercury electrodes and bismuth film electrodes for possible use in electrochemical studies and electroanalytical applications.
doi:10.1007/s11671-009-9495-3
PMCID: PMC2894205  PMID: 20672072
Bismuth; Nanostructure; Electrochemical deposition
24.  Synthesis and Electrochemical Sensing Toward Heavy Metals of Bunch-like Bismuth Nanostructures 
Nanoscale Research Letters  2009;5(2):398-402.
Large-scale bunch-like bismuth (Bi) nanostructures were the first time to be synthesized via two-step electrochemical deposition. The growth mechanism of the nanostructures was discussed. Such a designed bunch-like Bi electrode has high sensitivity to detect the heavy metal ions due to its unique three-dimensional structures and strong ability of adsorbing the heavy metal ions. The bunch-like Bi electrode’s detection of heavy metals was statically performed using anodic stripping voltammetry (ASV). The detection in the Pb(II) concentration range of 2.5–50 μg/l was also performed. Based on the experimental results, this bunch-like Bi electrode can be considered as an interesting alternative to common mercury electrodes and bismuth film electrodes for possible use in electrochemical studies and electroanalytical applications.
doi:10.1007/s11671-009-9495-3
PMCID: PMC2894205  PMID: 20672072
Bismuth; Nanostructure; Electrochemical deposition
25.  DNA–DNA Interactions in Tight Supercoils Are Described by a Small Effective Charge Density 
Physical review letters  2010;105(15):158101.
DNA-DNA interactions are important for the assembly of DNA nanostructures and during biological processes such as genome compaction and transcription regulation. In studies of these complex processes, DNA is commonly modeled as a homogeneously charged cylinder and its electrostatic interactions are calculated within the framework of the Poisson-Boltzmann equation. Commonly, a charge adaptation factor is used to address limitations of this theoretical approach. Despite considerable theoretical and experimental efforts, a rigorous quantitative assessment of this parameter is lacking. Here, we comprehensively characterized DNA-DNA interactions in the presence of monovalent ions by analyzing the supercoiling behavior of single DNA molecules held under constant tension. Both a theoretical model and coarse-grained simulations of this process revealed a surprisingly small effective DNA charge of 40% of the nominal charge density. These findings were directly supported by atomic-scale molecular dynamics simulations that determined the effective force between two DNA molecules. Our new parameterization has direct impact on many physical models involving DNA-DNA interactions.
PMCID: PMC3170404  PMID: 21230940
DNA; self-assembly; electrostatics; single-molecule; molecular dynamics; super-coiling

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