Effect of IRSL-BLSL-TSL reading modes combination on thermoluminescence (TL) response of BeO dosimeter.

The ultimate goal of this work is the study of the effect of luminescence stimulations and signals reading modes combinations on the thermoluminescence intensity and glow curve behaviour for the same X-ray irradiation dose. Three interesting stimulating and reading modes are considered, namely, infrared stimulated luminescence (IRSL), blue light-emitting diode stimulated luminescence (BLSL) and thermally stimulated luminescence (TSL). The studied stimulation and reading modes combination protocols are (Protocol 1) IRSL-TSL, (Protocol 2) IRSL-BLSL-TSL and (Protocol 3) BLSL-IRSL-TSL. Experiments are performed on beryllium oxide (BeO) dosimeter. Results demonstrate well that the combination of reading modes have direct impact on the TL signal in terms of intensity and glow curve shape. It was also found that when reading modes are correctly combined, particularly when IRSL is applied first, then BLSL and TL, it is possible to collect two or more exploitable signals of different stimulation types for the same irradiation that can be used for different purposes and final applications.

The Na+,K+-ATPase in complex with beryllium fluoride mimics an ATPase phosphorylated state.

The Na+,K+-ATPase generates electrochemical gradients of Na+ and K+ across the plasma membrane via a functional cycle that includes various phosphoenzyme intermediates. However, the structure and function of these intermediates and how metal fluorides mimick them require further investigation. Here, we describe a 4.0 Å resolution crystal structure and functional properties of the pig kidney Na+,K+-ATPase stabilized by the inhibitor beryllium fluoride (denoted E2-BeFx). E2-BeFx is expected to mimic properties of the E2P phosphoenzyme, yet with unknown characteristics of ion and ligand binding. The structure resembles the E2P form obtained by phosphorylation from inorganic phosphate (Pi) and stabilized by cardiotonic steroids, including a low-affinity Mg2+ site near ion binding site II. Our anomalous Fourier analysis of the crystals soaked in Rb+ (a K+ congener) followed by a low-resolution rigid-body refinement (6.9-7.5 Å) revealed preocclusion transitions leading to activation of the dephosphorylation reaction. We show that the Mg2+ location indicates a site of initial K+ recognition and acceptance upon binding to the outward-open E2P state after Na+ release. Furthermore, using binding and activity studies, we find that the BeFx-inhibited enzyme is also able to bind ADP/ATP and Na+. These results relate the E2-BeFx complex to a transient K+- and ADP-sensitive E∗P intermediate of the functional cycle of the Na+,K+-ATPase, prior to E2P.

Disrupting bonding in azoles through beryllium bonds: Unexpected coordination patterns and acidity enhancement.

Although triazoles and tetrazole are amphoteric and may behave as weak acids, the latter property can be hugely enhanced by beryllium bonds. To explain this phenomenon, the structure and bonding characteristics of the complexes between triazoles and tetrazoles with one and two molecules of BeF2 have been investigated through the use of high-level G4 ab initio calculations. The formation of the complexes between the N basic sites of the azoles and the Be center of the BeF2 molecule and the (BeF2)2 dimer leads to a significant bonding perturbation of both interacting subunits. The main consequence of these electron density rearrangements is the above-mentioned increase in the intrinsic acidity of the azole subunit, evolving from a typical nitrogen base to a very strong nitrogenous acid. This effect is particularly dramatic when the interaction involves the (BeF2)2 dimer, that is, a Lewis acid much stronger than the monomer. Although the azoles investigated have neighboring N-basic sites, their interaction with the (BeF2)2 dimer yields a monodentate complex. However, the deprotonated species becomes extra-stabilized because a second N-Be bond is formed, leading to a new five-membered ring, with the result that the azole-(BeF2)2 complexes investigated become stronger nitrogenous acids than oxyacids such as perchloric acid.

Activation mechanism of a small prototypic Rec-GGDEF diguanylate cyclase.

Diguanylate cyclases synthesising the bacterial second messenger c-di-GMP are found to be regulated by a variety of sensory input domains that control the activity of their catalytical GGDEF domain, but how activation proceeds mechanistically is, apart from a few examples, still largely unknown. As part of two-component systems, they are activated by cognate histidine kinases that phosphorylate their Rec input domains. DgcR from Leptospira biflexa is a constitutively dimeric prototype of this class of diguanylate cyclases. Full-length crystal structures reveal that BeF3- pseudo-phosphorylation induces a relative rotation of two rigid halves in the Rec domain. This is coupled to a reorganisation of the dimeric structure with concomitant switching of the coiled-coil linker to an alternative heptad register. Finally, the activated register allows the two substrate-loaded GGDEF domains, which are linked to the end of the coiled-coil via a localised hinge, to move into a catalytically competent dimeric arrangement. Bioinformatic analyses suggest that the binary register switch mechanism is utilised by many diguanylate cyclases with N-terminal coiled-coil linkers.

The Importance of Strain (Preorganization) in Beryllium Bonds.

In order to explore the angular strain role on the ability of Be to form strong beryllium bonds, a theoretical study of the complexes of four beryllium derivatives of orthocloso-carboranes with eight molecules (CO, N2, NCH, CNH, OH2, SH2, NH3, and PH3) acting as Lewis bases has been carried out at the G4 computational level. The results for these complexes, which contain besides Be other electron-deficient elements, such as B, have been compared with the analogous ones formed by three beryllium salts (BeCl2, CO3Be and SO4Be) with the same set of Lewis bases. The results show the presence of large and positive values of the electrostatic potential associated to the beryllium atoms in the isolated four beryllium derivatives of ortho-carboranes, evidencing an intrinsically strong acidic nature. In addition, the LUMO orbital in these systems is also associated to the beryllium atom. These features led to short intermolecular distances and large dissociation energies in the complexes of the beryllium derivatives of ortho-carboranes with the Lewis bases. Notably, as a consequence of the special framework provided by the ortho-carboranes, some of these dissociation energies are larger than the corresponding beryllium bonds in the already strongly bound SO4Be complexes, in particular for N2 and CO bases. The localized molecular orbital energy decomposition analysis (LMOEDA) shows that among the attractive terms associated with the dissociation energy, the electrostatic term is the most important one, except for the complexes with the two previously mentioned weakest bases (N2 and CO), where the polarization term dominates. Hence, these results contribute to further confirm the importance of bending on the beryllium environment leading to strong interactions through the formation of beryllium bonds.

A simulation study on beam property of 124Sb-Be isotope-based neutron for BNCT.

The 9Be(γ,n) neutrons with the energies at 21-24 keV generated by 1.691 MeV photons from 124Sb was investigated as a source of epithermal neutrons for BNCT, using PHITS code. A beam shaping assembly composed of 13 mm thick Be target, a gamma ray shield made of 30 cm thick Bi, and a reflector of 30 cm thick Pb satisfied the beam requirements of IAEA-TECDOC-1223. The needed 124Sb activity was estimated in the order of 1016-1017 Bq. Feasibility of BNCT using 124Sb-Be neutrons would be influenced by the capability of periodic supply of short-lived 124Sb (half-life: 60 days) with such high activity.

Design of a BNCT irradiation room based on proton accelerator and beryllium target.

Preliminary studies for the design of an accelerator-based BNCT clinical facility are presented. The Beam Shaping Assembly neutron activation was evaluated experimentally and with Monte Carlo simulations. The activations of patient, air and walls in the room, the absorbed doses by the patient and the in-air dose distributions were evaluated. Based on these calculations, different walls compositions were tested to optimize the environmental conditions. Borated concrete, advantageously reducing the thermal flux in the room, was proven the best choice.

Beryllium coordination chemistry and its implications on the understanding of metal induced immune responses.

The inhalation of beryllium and its compounds can cause the development of chronic beryllium disease in susceptible individuals. This is caused by a distinct autoimmune process. Here, beryllium coordination compounds with biomimetic ligands are discussed, which are used to understand the coordination of Be2+ in the body and its effect on biomolecules. The advances in the development of precursors for the directed synthesis of these coordination complexes are presented as well as the potential use of non-aqueous solvents for these investigations.

Structural insights into G domain dimerization and pathogenic mutation of OPA1.

The fusion of mammalian inner mitochondrial membranes (IMMs) is mediated by dynamin-like GTPase OPA1. Mutations in human OPA1 cause optic atrophy, but the molecular basis for membrane fusion and pathogenesis is not clear. Here, we determined the crystal structure of the minimal GTPase domain (MGD) of human OPA1. A three-helix bundle (HB) domain including two helices extending from the GTPase (G) domain and the last helix of OPA1 tightly associates with the G domain. In the presence of GDP and BeF3-, OPA1-MGD forms a dimer, the interface of which is critical for the maintenance of mitochondrial morphology. The catalytic core of OPA1 possesses unique features that are not present in other dynamin-like proteins. Biochemical experiments revealed that OPA1-MGD forms nucleotide-dependent dimers, which is important for membrane-stimulated GTP hydrolysis, and an N-terminal extension mediates nucleotide-independent dimerization that facilitates efficient membrane association. Our results suggest a multifaceted assembly of OPA1 and explain the effect of most OPA1 mutations on optic atrophy.

Boron-Based Chiral Helix Be6 B10 2- and Be6 B11 - Clusters: Structures, Chemical Bonding, and Formation Mechanism.

Boron forms a rich variety of low-dimensional nanosystems, including the newly discovered helix Be6 B10 2- (1) and Be6 B11 - (2) clusters. We report herein on the elucidation of chemical bonding in clusters 1/2, using the modern quantum chemistry tools of canonical molecular orbital analyses and adaptive natural density partitioning (AdNDP). It is shown that clusters 1/2 contain a chiral helix Be2 B10 Be2 or Be2 B11 Be2 skeleton with a total of 11 and 12 segments, respectively, which effectively curve into "helical pseudo rings" and chemically consist of two "quasicircles" as defined by their anchoring Be centers. The helix skeleton is connected via Lewis-type B-B and Be-B-Be σ bonds, being further stabilized by island π/σ bonds and a loose π bond at the junction. The Be6 component in 1/2 assumes a distorted prism shape only physically, and it is fragmented into four parts: two terminal Be2 dimers and two isolated Be centers. A Be2 dimer at the far end manages to bend over and cap a quasicircle from one side of B plane. Consequently, each quasicircle of a helical pseudo ring is capped from opposite sides by two Be2 /Be units, facilitating intramolecular charge-transfers of 5 electrons from Be to B. Overall, the folding of B helix involves as many as 10 electrons. The enormous electrostatics offers the ultimate driving forces for B helix formation.

Aqueous solubility of beryllium(II) at physiological pH: effects of buffer composition and counterions.

Beryllium ion elicits p53-mediated cell cycle arrest in some types of human cancer cells, and it is a potent inhibitor of GSK3 kinase activity. Paradoxically, Be2+ is regarded to have almost negligible aqueous solubility at physiological pH, due to precipitation as Be(OH)2. This study demonstrates that the interaction of Be2+ with serum proteins greatly increases its effective solubility. In typical serum-supplemented mammalian cell culture medium, Be2+ was soluble up to about 0.5 mM, which greatly exceeds the concentration needed for biological activity. Some biochemical studies require protein-free Be2+ solutions. In such cases, the inclusion of a specific inorganic counterion, sulfate, increased solubility considerably. The role of sulfate as a solubility-enhancing factor became evident during preparation of buffered solutions, as the apparent solubility of Be2+ depended on whether H2SO4 or a different strong acid was used for pH adjustment. The binding behavior of Be2+ observed via isothermal titration calorimetry was affected by the inclusion of sodium sulfate. The data reflect a "Diverse Ion Effect" consistent with ion pair formation between solvated Be2+ and sulfate. These insights into the solubility behavior of Be2+ at physiological and near-physiological pH will provide guidance to assist sample preparation for biochemical studies.

Molecular mechanism of Be2+-ion binding to HLA-DP2: tetrahedral coordination, conformational changes and multi-ion binding.

The chemistry of beryllium is rather unusual, however, less explored as compared to other main group elements. This is mainly attributed to the high toxicity of beryllium, leading to chronic granulomatous pneumonitis, called chronic beryllium disease (CBD). It has been reported that Be2+-ion binding to the human leukocyte antigen protein (HLA-DP2) and peptide (M2) results in favorable interaction with the T-cell receptor protein (TCR), which initiates immune-mediated toxicity. We have carried out molecular dynamics (MD) simulations combined with quantum mechanical/molecular mechanical (QM/MM) studies to explore the binding nature of Be2+ with a HLA-DP2 protein and M2 peptide. The interaction between the negatively charged M2 peptide and the negatively charged binding cleft of HLA-DP2 is unfavorable. However, this interaction is stabilized by one Be2+ and two Na+-ions bridged by negatively charged carboxyl groups of glutamate residues (ß26E and ß69E) of the ß-chain of HLA-DP2 and one glutamate (p7E) and one aspartate residue (p4D) of the M2 peptide. This multi-ion cavity consists of tetrahedrally coordinated static Be2+ and Na+-ions, as well as one dynamically exchangeable Na+-ion. The smaller size and higher charge of the Be2+-ion as compared to the Na+-ion reduce the distance between the M2 peptide and the ß-chain of HLA-DP2, which results in conformational change suitable for TCR binding. However, the replacement of the Be2+ by the Na+-ion could not generate a suitable binding site for TCR.

Understanding the Localization of Berylliosis: Interaction of Be2+ with Carbohydrates and Related Biomimetic Ligands.

The interplay of metal ions with polysaccharides is important for the immune recognition in the lung. Due to the localization of beryllium associated diseases to the lung, it is likely that beryllium carbohydrate complexes play a vital role for the development of berylliosis. Herein, we present a detailed study on the interaction of Be2+ ions with fructose and glucose as well as simpler biomimetic ligands, which emulate binding motives of saccharides. Through NMR and IR spectroscopy as well as single-crystal X-ray diffraction, complemented by competition reactions we were able to determine a distinctive trend in the binding affinity of these ligands. This suggests that under physiological conditions beryllium ions are only bound irreversibly in glycoproteins or polysaccharides if a quasi ideal tetrahedral environment and κ4 -coordination is provided by the respective biomolecule. Furthermore, Lewis acid induced conversions of the ligands and an extreme increase in the Brønstedt acidity of the present OH-groups imply that upon enclosure of Be2+ , alterations may be induced by the metal ion in glycoproteins or polysaccharides. In addition the frequent formation of Be-O-heterocycles indicates that multinuclear beryllium compounds might be the actual trigger of berylliosis. This investigation on beryllium coordination chemistry was supplemented by binding studies of selected biomimetic ligands with Al3+ , Zn2+ , Mg2+ , and Li+ , which revealed that none of these beryllium related ions was tetrahedrally coordinated under the give conditions. Therefore, studies on the metabolization of beryllium compounds cannot be performed with other hard cations as a substitute for the hazardous Be2+ .

Synthesis and characterization of modified sulfonated chitosan for beryllium recovery.

A new adsorbent, sulfated crosslinked chitosan (SGCH), has been synthesized for the effective extraction of beryllium ions from their aqueous solutions. In recent times, beryllium extraction has been of great importance because beryllium can be used in many applications such as in nuclear reactor, heat shields, high-technology ceramics, alloys and electronic heat sinks. SGCH has been synthesized by two successive phases. The first is the conversion of chitosan (CH) into non-soluble cross-linked chitosan (GCH) through the interaction between chitosan and glutaraldehyde. The second step is the formation of functional sulfonate groups onto the adsorbent material through the interaction of GCH with chlorosulfonic acid (sulfating agent). The role played by the sulfonate groups in the adsorption process was analyzed using FT-IR and SEM. Also, the role played by the solution pH, time, beryllium concentration and temperature on the batch adsorption process was investigated. Our results point to the successful preparation of SGCH adsorbent with high affinity for beryllium ions. The maximum sorption values of beryllium ions on the investigated biosorbent is 40.6 mg/g. The desorption of the loaded beryllium ions from the SGCH was achieved by using 1.5 M urea acidified by 0.6 M H2SO4.

New insight in beryllium toxicity excluding exposure to beryllium-containing dust: accumulation patterns, target organs, and elimination.

There is much contradiction between different experimental studies on beryllium (Be) toxicity. The majority of studies focus on occupational pathologies, caused by the exposure to Be dust. However, Be pollution may affect wide population groups through other exposure routes. The discrepancies between experimental studies may be attributed to the lack of adequate Be toxicity model since conventional administration routes are hampered by high acidity and low solubility of Be compounds. This study was aimed to develop a novel way to implement Be toxicity avoiding side effects, related to high acidity or low solubility of Be salts. Intraperitoneal injection of Be-glycine composition (containing BeSO4, glycine, purified water, pH adjusted to 5.5 with NaOH) was tested in the dose range 238-7622 µmol Be kg-1 (body weight, b/w) in full-grown Wistar male rats. The model provided reliable uptake of Be from the peritoneum into general circulation for at least 48 h. LD50 was found to be 687 µmol Be kg-1 (b/w). The established LD50 value differed from previous data on gastrointestinal, intramuscular or intravenous administration of Be compounds. The liver was found to act as a primary elimination route for Be and related to the highest Be content in the animal. However, it had no signs of morphological damage, which was observed only in the testes (deterioration of germinal epithelium). At the same time, the lungs, stated as a primary target tissue for Be in the models of chronic beryllium disease, did not show strong Be accumulation nor morphological changes. Survived animals showed behavioral changes, including increased motor activity and aggressive reactions in some cases, and complete spasticity in other. The obtained data show the applicability of the established modeling protocol and testified for the independence of chronic beryllium disease on Be2+ ion toxicity per se.

Density-dependent Energy Loss of Protons in Pb and Be Targets and Percent Mass-Stopping Power from Bethe-Bloch Formula and Bichsel-Sternheimer Data Within 1-12 MeV Energy Range: A Comparative Study Based on Bland-Altman Analysis.

BACKGROUND: This comparative study calculated Bethe-Bloch results with Bichsel-Sternheimer values, employing the Bland-Altman analysis within 95% limit of agreement for the first time. The Bethe-Bloch formula was employed for the physical realization of the density-dependent energy loss of protons in lead (208Pb) and beryllium (9Be) targets in the energy range 1-12 MeV. METHODS: The mass-stopping power of protons for the given elements was calculated and the corresponding normalized difference and standard deviation was also calculated. The obtained theoretical results were compared with the Bichsel-Sternheimer values for the same targets within the same energy range of the projectile protons in terms of stopping-power percent difference. RESULTS: As a general trend, as the energy of proton increases the percent normalized difference decreases. For elements having a high atomic number like lead, the percent difference is large. This may mean that calculated values of percent difference for heavy elements like lead are not in agreement with experimental results. CONCLUSION: The calculated mass-stopping power in view of the normalized percent difference is consistent with the Bichsel-Sternheimer results for the same projectile of higher energy in Pb and Be targets. However, results deviate from the Bichsel-Sternheimer results for high atomic number materials for the same projectile of lower energy. The difference may be attributed to the adjusted parameters in the Bethe-Bloch formula.

ENERGY RESPONSE FACTOR of BeO DOSEMETER CHIPS: A MONTE CARLO SIMULATION AND GENERAL CAVITY THEORY STUDY.

The objective of this study is to determine the energy response factors for BeO optically simulated dosemeter (OSLD) using general cavity theory and Monte Carlo (MC) simulations. A virtual phantom is constructed in EGSnrc MC program and energy response of BeO OSLDs were simulated at 5 cm depth for x-ray beams ranging from 1.25 to 25 MV and at 2 cm for beams with <250 kV including ISO 4037 narrow beam energies in a virtual water phantom. The energy response factor for a given radiation quality relative to 60Co was determined for BeO and compared to the Al2O3:C and LiF:Mg,Ti dosemeters. Burlin cavity theory calculations were done using mean photon energy (MPE) of the beam spectra, while EGSnrc software package was used to carry out MC simulation of full spectra. The cavity theory and MC methods agreed well within the 0.7%. Energy response of x-ray beams at MV range showed a maximum of 1.5% under-response. At energies higher than 150 kV (105 keV MPE) showed no significant difference while a significant under-response were observed at 100 kV (53 keV MPE) and 50 kV (29 keV MPE), ~8 and ~12%, respectively. BeO, Al2O3:C and LiF:Mg,Ti dosemeters exhibited very similar energy response at higher energies mainly in the MeV range. At 50 kV (29 keV MPE), however, BeO dosemeter under responded by a factor of 0.878, while Al2O3:C and LiF:Mg,Ti dosemeters over responded by a factor of 3.2 and 1.44, respectively. Furthermore, at low energies, BeO energy response showed dependence on photon spectra. For instance, at 100 kV, the difference was ~8, ~6 and 2% for 53, 60 and 83 keV MPE (ISO 4037N-100), respectively. Furthermore, calibration with 137Cs instead of 60Co resulted up to 1.8% differences in energy response. Both energy spectrum and calibration methods make considerable differences in energy response of OSLDs. This study concludes that BeO chips are nearly energy independent at energies higher than 100 keV MPE, while Al2O3:C dosemeters show an extremely enhanced energy-response ranging between 1.44 and 3.2 at energies between 170 and 29 keV MPE mainly due to dominance of photoelectric effect.

Isothermal Titration Calorimetry of Be2+ with Phosphatidylserine Models Guides All-Atom Force-Field Development for Lipid-Ion Interactions.

Beryllium has multiple industrial applications but exposure to its dust during manufacturing is associated with developing chronic inflammation in lungs known as berylliosis. Besides binding to specific alleles of MHC-II, Be2+ was recently found to compete with Ca2+ for binding sites on phosphatidylserine-containing membranes and inhibit recognition of this lipid by phagocytes. Computational studies of possible molecular targets for this small toxic dication are impeded by the absence of a reliable force field. This study introduces parameters for Be2+ for the CHARMM36 additive force field that represent interactions with water, including free energy of hydration and ion-monohydrate interaction energy and separation distance; and interaction parameters describing Be2+ affinity for divalent ion binding sites on lipids, namely phosphoryl and carboxylate oxygens. Results from isothermal titration calorimetry experiments for the binding affinities of Be2+ to dimethyl phosphate and acetate ions reveal that Be2+ strongly binds to phosphoryl groups. Revised interaction parameters for Be2+ with these types of oxygens reproduce experimental affinities in solution simulations. Surface tensions calculated from simulations of DOPS monolayers with varied concentrations of Be2+ are compared with prior results from Langmuir monolayer experiments, verifying the compacting effect that produces greater surface tensions (lower pressures) for Be2+-bound monolayers at the same surface area in comparison with K+. The new parameters will enable simulations that should reveal the mechanism of Be2+ interference with molecular recognition and signaling processes.

Beryllium Complexes with Bio-Relevant Functional Groups: Coordination Geometries and Binding Affinities.

The coordination mode around beryllium in proteins and the binding affinity towards the peptide are unknown because there have been no coordination compounds of beryllium with ligands bearing bio-relevant functional groups. We report the first comprehensive study on Be complexes with monodentate carboxylic acids, esters, aldehydes, and alcohols. Through solution and solid-state techniques we determined that the binding affinities of Be2+ ions towards the functional groups are: carboxylate > alcohol > aldehyde > ester. Crystal structures of all the compounds have been determined including the unprecedented dodeca-nuclear macrocyclic ring structure of non-basic beryllium benzoate, which is the first example of those beryllium carboxylates. These findings enable the evaluation of potential beryllium binding sites inside proteins and is required to understand the mechanism of metal-triggered immune responses.