Nuclear Track Emulsion Research Articles

Age, dose, and binding to TfR on blood cells influence brain delivery of a TfR-transported antibody

BackgroundTransferrin receptor 1 (TfR1) mediated brain delivery of antibodies could become important for increasing the efficacy of emerging immunotherapies in Alzheimer's disease (AD). However, age, dose, binding to TfR1 on blood cells, and pathology could influence the TfR1-mediated transcytosis of TfR1-binders across the blood–brain barrier (BBB). The aim of the study was, therefore, to investigate the impact of these factors on the brain delivery of a bispecific TfR1-transported Aβ-antibody, mAb3D6-scFv8D3, in comparison with the conventional antibody mAb3D6.MethodsYoung (3–5 months) and aged (17–20 months) WT and tg-ArcSwe mice (AD model) were injected with 125I-labeled mAb3D6-scFv8D3 or mAb3D6. Three different doses were used in the study, 0.05 mg/kg (low dose), 1 mg/kg (high dose), and 10 mg/kg (therapeutic dose), with equimolar doses for mAb3D6. The dose-corrected antibody concentrations in whole blood, blood cells, plasma, spleen, and brain were evaluated at 2 h post-administration. Furthermore, isolated brains were studied by autoradiography, nuclear track emulsion, and capillary depletion to investigate the intrabrain distribution of the antibodies, while binding to blood cells was studied in vitro using blood isolated from young and aged mice.ResultsThe aged WT and tg-ArcSwe mice showed significantly lower brain concentrations of TfR-binding [125I]mAb3D6-scFv8D3 and higher concentrations in the blood cell fraction compared to young mice. For [125I]mAb3D6, no significant differences in blood or brain delivery were observed between young and aged mice or between genotypes. A low dose of [125I]mAb3D6-scFv8D3 was associated with increased relative parenchymal delivery, as well as increased blood cell distribution. Brain concentrations and relative parenchymal distribution of [125I]mAb3D6-scFv8D6 did not differ between tg-ArcSwe and WT mice at this early time point but were considerably increased compared to those observed for [125I]mAb3D6.ConclusionAge-dependent differences in blood and brain concentrations were observed for the bispecific antibody mAb3D6-scFv8D3 but not for the conventional Aβ antibody mAb3D6, indicating an age-related effect on TfR1-mediated brain delivery. The lowest dose of [125I]mAb3D6-scFv8D3 was associated with higher relative BBB penetration but, at the same time, a higher distribution to blood cells. Overall, Aβ-pathology did not influence the early brain distribution of the bispecific antibody. In summary, age and bispecific antibody dose were important factors determining brain delivery, while genotype was not.

Studies of angular distribution of the grey particles in 16O-emulsion collision at 3.7A GeV

By means of [Formula: see text] emulsion track detectors, we report the characteristics of the experimental angular distributions of the fast target protons (grey particles) emitted in interactions of [Formula: see text]O with emulsion nuclei at 3.7A[Formula: see text]GeV. Grey tracks in nuclear emulsion corresponding protons with kinetic energy in the ranges [Formula: see text][Formula: see text]MeV. The angular distributions are compared with those resulting from interactions of other projectiles ([Formula: see text]C, [Formula: see text]Ne and [Formula: see text]Si) at nearly the same incident energy. These angular distributions are studied at different target sizes ([Formula: see text]-values) and at various projectile spectator charges ([Formula: see text]-values) in the framework of the modified Maxwell– Boltzmann statistical model. The nuclear limiting fragmentation hypothesis is shown to be fulfilled for these target protons angular distributions which are found to be independent of the target size and centrality of collisions. Also, the size of the projectile is found to be ineffective at Dubna energies. The angular distributions of all groups of events possess peaks positioned at [Formula: see text]. The calculated statistical moments of the distributions along with skewness and kurtosis are investigated in addition to the forward-backward asymmetry ratio [Formula: see text] for the different groups of events.

Transferrin Receptor Binding BBB-Shuttle Facilitates Brain Delivery of Anti-Aβ-Affibodies

Affibodies targeting amyloid-beta (Aβ) could potentially be used as therapeutic and diagnostic agents in Alzheimer’s disease (AD). Affibodies display suitable characteristics for imaging applications such as high stability and a short biological half-life. The aim of this study was to explore brain delivery and retention of Aβ protofibril-targeted affibodies in wild-type (WT) and AD transgenic mice and to evaluate their potential as imaging agents. Two affibodies, Z5 and Z1, were fused with the blood–brain barrier (BBB) shuttle single-chain variable fragment scFv8D3. In vitro binding of 125I-labeled affibodies with and without scFv8D3 was evaluated by ELISA and autoradiography. Brain uptake and retention of the affibodies at 2 h and 24 h post injection was studied ex vivo in WT and transgenic (tg-Swe and tg-ArcSwe) mice. At 2 h post injection, [125I]I-Z5 and [125I]I-Z1 displayed brain concentrations of 0.37 ± 0.09% and 0.46 ± 0.08% ID/g brain, respectively. [125I]I-scFv8D3-Z5 and [125I]I-scFv8D3-Z1 showed increased brain concentrations of 0.53 ± 0.16% and 1.20 ± 0.35%ID/g brain. At 24 h post injection, brain retention of [125I]I-Z1 and [125I]I-Z5 was low, while [125I]I-scFv8D3-Z1 and [125I]I-scFv8D3-Z5 showed moderate brain retention, with a tendency towards higher retention of [125I]I-scFv8D3-Z5 in AD transgenic mice. Nuclear track emulsion autoradiography showed greater parenchymal distribution of [125I]I-scFv8D3-Z5 and [125I]I-scFv8D3-Z1 compared with the affibodies without scFv8D3, but could not confirm specific affibody accumulation around Aβ deposits. Affibody-scFv8D3 fusions displayed increased brain and parenchymal delivery compared with the non-fused affibodies. However, fast brain washout and a suboptimal balance between Aβ and mTfR1 affinity resulted in low intrabrain retention around Aβ deposits.

Design and performance of a scintillation tracker for track matching in nuclear-emulsion-based neutrino interaction measurement

Precise measurement of neutrino–nucleus interactions with an accelerator neutrino beam is highly important for current and future neutrino oscillation experiments. To measure muon-neutrino charged-current interactions with nuclear-emulsion-based hybrid detector, muon track matching among the detectors are essential. We describe the design and performance of a newly developed scintillation tracker for the muon track matching in the neutrino–nucleus interaction measurement with nuclear emulsion detectors. The muon tracks are reconstructed using the scintillation tracker and another detector called Baby MIND, then, they are matched with the tracks in nuclear emulsion detectors.The scintillation tracker consists of four layers of horizontally and vertically aligned scintillator bars, covering an area of 1m×1m. In the layer, 24mm-wide plastic scintillator bars are specially arranged with deliberate gaps between each other. By recognizing the hit pattern of the four layers, a precise positional resolution of 2.5mm is achieved while keeping the number of readout channels as small as 256. The efficiency of the track matching is evaluated to be more than 97% for forward-going muons, and the positional and angular resolutions of the scintillation tracker are 2.5mm and 20–40mrad respectively. The results demonstrate the usefulness of the design of the scintillation tracker for the muon track matching in the nuclear-emulsion-based neutrino–nucleus interaction measurements.

Search for Decays of the 9B Nucleus and Hoyle State in 14N Nucleus Dissociation

First results of an analysis to determine contribution of decays of the unstable $^{8}$Be and $^{9}$B nuclei and the Hoyle 3$\alpha$-state to dissociation of $^{14}$N $\to$ 3He (+H) are presented. As the research material, layers of nuclear track emulsion longitudinally exposed to 2.9 $A$ GeV/$c$ $^{14}$N nuclei with at the JINR Nuclotron. Under the assumption that the He and H fragments retain momentum per nucleon of the primary nucleus, these unstable states are identified by the invariant mass calculated from the emission angles of the fragments.

Directional Observation of Particles of Cold Dark Matter (WIMPs) in Experiments with Nuclear Track Emulsions and Other Tracking Detectors

Directional Observation of Particles of Cold Dark Matter (WIMPs) in Experiments with Nuclear Track Emulsions and Other Tracking Detectors

An Enhancement of Formation of Unstable 8Be Nucleus with the Growth of α-Particle Multiplicity in Fragmentation of Relativistic Nuclei

In this paper, the correlation between the formation of the unstable $^{8}$Be nucleus and accompanying $\alpha$ particles in the fragmentation of relativistic $^{16}$O, $^{22}$Ne, $^{28}$Si, and $^{197}$Au nuclei in a nuclear track emulsion is investigated. The $^{8}$Be decays are identified in a wide energy range by invariant masses calculated from 2$\alpha$-pair opening angles. The adopted approximations are verified by data on fragmentation of $^{16}$O nuclei in a hydrogen bubble chamber in a magnetic field. An increase in the $^{8}$Be contribution to the dissociation with the growth of $\alpha$-particle multiplicity is found.

Correlation in formation of 8Be nuclei and α-particles in fragmentation of relativistic nuclei

In the events of peripheral dissociation of relativistic nuclei in the nuclear track emulsion, it is possible to study the emerging ensembles of He and H nuclei, including those from decays of unstable 8Be and 9B nuclei, as well as the Hoyle state. These extremely short-lived states are identified by invariant masses calculated from the angles in 2α-pairs, 2αp- and 3α-triplets in the approximation of conservation of momentum per nucleon of the primary nucleus. In the same approach, it is possible to search for more complex states. This paper explores the correlation between the formation of 8Be nuclei and the multiplicity of accompanying α-particles in the dissociation of relativistic 16O, 22Ne, 28Si, and 197Au nuclei. On the above basis, estimates of this correlation are presented for the unstable 9B nucleus and the Hoyle state. The enhancement in the 8Be contribution to dissociation with the α-particle multiplicity has been found. Decays of 9B nuclei and Hoyle states follow the same trend.

Brain pharmacokinetics of two BBB penetrating bispecific antibodies of different size

BackgroundTransferrin receptor (TfR1) mediated enhanced brain delivery of antibodies have been studied extensively in preclinical settings. However, the brain pharmacokinetics, i.e. brain entry, distribution and elimination are still not fully understood for this class of antibodies. The overall aim of the study was to compare the brain pharmacokinetics of two BBB-penetrating bispecific antibodies of different size (210 vs 58 kDa). Specifically, we wanted to investigate if the faster systemic clearance of the smaller non-IgG antibody di-scFv3D6-8D3, in comparison with the IgG-based bispecific antibody mAb3D6-scFv8D3, was also reflected in the brain.MethodsWild-type (C57/Bl6) mice were injected with 125I-iodinated ([125I]) mAb3D6-scFv8D3 (n = 46) or [125I]di-scFv3D6-8D3 (n = 32) and euthanized 2, 4, 6, 8, 10, 12, 16, or 24 h post injection. Ex vivo radioactivity in whole blood, peripheral organs and brain was measured by γ-counting. Ex vivo autoradiography and nuclear track emulsion were performed on brain sections to investigate brain and parenchymal distribution. Capillary depletion was carried out at 2, 6, and 24 h after injection of [125I]mAb3D6-scFv8D3 (n = 12) or [125I]di-scFv3D6-8D3 (n = 12), to estimate the relative levels of radiolabelled antibody in brain capillaries versus brain parenchyma. In vitro binding kinetics for [125I]mAb3D6-scFv8D3 or [125I]di-scFv3D6-8D3 to murine TfR were determined by LigandTracer.Results[125I]di-scFv3D6-8D3 showed faster elimination from blood, lower brain Cmax, and Tmax, a larger parenchymal-to-capillary concentration ratio, and a net elimination from brain at an earlier time point after injection compared with the larger [125I]mAb3D6-scFv8D3. However, the elimination rate from brain did not differ between the antibodies. The study also indicated that [125I]di-scFv3D6-8D3 displayed lower avidity than [125I]mAb3D6-scFv8D3 towards TfR1 in vitro and potentially in vivo, at least at the BBB.ConclusionA smaller size and lower TfR1 avidity are likely important for fast parenchymal delivery, while elimination of brain-associated bispecific antibodies may not be dependent on these characteristics.

Multiplicity characteristics of the produced shower particles in backward direction-target and projectile dependence

In the present paper a detailed investigation of the multiplicity distribution of the produced shower particles in the backward hemisphere ( $$\theta _{\mathrm {Lab}} \ge 90^{\circ }$$ ) in nuclear emulsion track detector has been carried out. The present study involves interactions of $$^{\mathrm {16}}\hbox {O}$$ and $$^{\mathrm {32}}\hbox {S}$$ projectiles with CNO, AgBr and composite emulsion target at 4.5 AGeV/c. We have compared our results with the results obtained from the analysis of modified Fritiof model. Present study reveals that the production of single shower particle is the most dominant production mode of shower particles in the backward direction. This probability increases with the increase of target mass. The percentage of events having backward shower particles remains almost independent of the projectile beam. But it increases with the increase of target size. Average multiplicity of the shower particles in the backward direction reflects a weaker dependence on the mass number of the projectile beam. Multiplicity distribution of backward shower particles for both experimental and modified Fritiof model can be described by an expression $$\mathrm {P}_{\mathrm {N}} = {\mathrm {P}_{\mathrm {s}}\mathrm {N}_{\mathrm {B}}}^{-{\uplambda }_{\mathrm {B}}}$$ . The fitting parameter $${\uplambda }_{\mathrm {B}}$$ decreases as the target size increases. The decay constant has lower value for the heavier projectile. Higher order multiplicity moments and scaled variance of multiplicity distribution for the backward shower particles showed strong target dependence. Multiplicity distributions of the backward shower particles violate KNO scaling law. Modified Fritiof model failed to reproduce the various features of the multiplicity distribution.

Backward shower particle production in high energy nucleus–nucleus collisions — an outlook to centrality dependence

A detailed study on the centrality dependence of the different aspects multiplicity distribution of the shower particles produced in the backward direction ([Formula: see text] in nuclear emulsion track detector has been carried out for [Formula: see text]Ne-emulsion interactions at 4.1 AGeV/c. Depending on the values of the total charges or sum of the charges of noninteracting projectile fragments, event samples were classified into four centrality classes. From the analysis presented in this paper, qualitative information about the assembly of shower particles in the backward direction has been extracted.

Devendra Lal. 14 February 1929—1 December 2012

Devendra Lal was an Indian nuclear physicist who began his career studying particle physics while a student at the Tata Institute of Fundamental Research (TIFR) in Bombay, using tracks in nuclear emulsions to study cosmic ray particles and their interactions. He soon moved on to the search for radionuclides produced in the atmosphere by cosmic ray bombardment, independently (with colleagues) discovering radioisotopes of Be, P and Si and using them as geophysical tracers for atmospheric, meteorological and oceanographic processes. His career revolved principally around multiple aspects of cosmic rays, employing theory and experiment to examine their flux, chemical composition and energy spectrum, both at present and in the past through (for example) studies of particle tracks in the minerals of meteorites and lunar samples. He played a major role in developing approaches for the use of terrestrial cosmic-ray-produced isotopes as dating tools and tracers for a wide range of Earth processes, from biological cycles in the ocean to landscape evolution and ice ablation in the Antarctic. At various stages of his career Lal was professor at TIFR and led the geophysics group there, was professor and director of the Physical Research Laboratory in Ahmedabad, India, and was professor at the Scripps Institution of Oceanography, University of California San Diego. He was elected fellow of numerous scientific organizations and academies internationally, and was the recipient of many scientific awards and prizes.

Optical shape analysis based on discrete Fourier transform and second-order moment analysis of the brightness distribution for the detection of sub-micron range tracks in nuclear emulsion

Abstract To recognize sub-micron-range low-energy tracks recorded in a super-fine-grained nuclear emulsion (Nano Imaging Tracker), an elliptical fitting method was devised to analyze anisotropic images taken by an optical microscope. We report on this newly developed method using a discrete Fourier transform and second-order moment analysis of the brightness distribution. We succeeded in lowering the ellipticity threshold, thereby improving the selection efficiency and angular resolution. Notably, the success of detecting carbon 30 keV tracks is the first such achievement in the world, where the incident direction of carbon 30 keV ions was determined with an accuracy of 41$^\circ$ and an efficiency of $1.7 \pm 0.1\%$.

Unstable states in dissociation of relativistic nuclei

The invariant mass method is used to identify the $^8$Be and $^9$B nuclei and Hoyle state formed in dissociation of relativistic nuclei in a nuclear track emulsion. It is shown that to identify these extremely short-lived states in the case of the isotopes $^9$Be, $^{10}$B, $^{10}$C, $^{11}$C, $^{12}$C, and $^{16}$O, it is sufficient to determine the invariant mass as a function of the angles in pairs and triples of He and H fragments in the approximation of the conservation of momentum per nucleon of the parent nucleus. According to the criteria established in this way, the contribution of these three unstable states was evaluated in the relativistic fragmentation of the $^{28}$Si and $^{197}$Au nuclei.

Prospects of nuclear clustering studies via dissociation of relativistic nuclei in nuclear track emulsion

Status and prospects of nuclear clustering studies by dissociation of relativistic nuclei in nuclear track emulsion are presented. The unstable 8Be and 9B nuclei are identified in dissociation of the isotopes 9Be, 10B, 10C and nC, and the Hoyle state in the cases 12C and 16O. On this ground searching for the Hoyle state and more complex α-particle states in the dissociation of the heavier nuclei is suggested. A detailed study of a low-density baryonic matter arising in dissociation of the heaviest nuclei is forthcoming long-term problem. An analysis of nuclear fragmentation induced by relativistic muons is proposed to examine the mechanism dissociation.

Centrality dependence of pseudo-rapidity distribution in nucleus–nucleus collisions at (4.1–4.5) AGeV/c

A detailed study of the centrality dependence of pseudo-rapidity distribution has been carried out for [Formula: see text]O-emulsion interactions at 4.5[Formula: see text]AGeV/c and [Formula: see text]Ne-emulsion interactions at 4.1[Formula: see text]AGeV/c using nuclear emulsion track detector. Depending on the values of the total charges or sum of the charges of noninteracting projectile fragments, event samples were classified into four centrality classes. Maximum pseudo-rapidity density, average pseudo-rapidity values, moments of pseudo-rapidity distribution along with skewness and kurtosis of the distributions have been investigated for different centrality classes.

An investigation of projectile helium fragments in high-energy nucleus–nucleus interactions

A detailed study on the multiplicity distribution of helium (He) fragments emitted in projectile fragmentation of 22Ne, 28Si, and 32S projectiles on interactions with H, CNO, and AgBr targets in a nuclear emulsion track detector has been presented at an incident momentum of (4.1–4.5) AGeV/c. The percentage of events with He fragments increases with increase in projectile mass for all three targets. Studies of multiplicity moments, dispersion of multiplicity distribution, and the investigation of dynamical fluctuations of the projectile He fragments have also been carried out.

Application of Nuclear Track Emulsion in Search for the Hoyle State in Dissociation of Relativistic 12C Nuclei

In dissociation in nuclear track emulsion of 4.5 and 1 A GeV/c12C nuclei, the formation of triplets of α particles in the Hoyle state (the second excited state 0+) is observed. This state is identified by the invariant mass, calculated from pair angles in the α triples in approximation of conservation of momentum per nucleon of the parent nucleus. An estimate of the contribution of the Hoyle state to the dissociation of 12C→ 3α is 10–15%.

Nuclear track emulsion in search for the Hoyle-state in dissociation of relativistic 12C nuclei

• Nuclear track emulsion is applied to identify the Hoyle’s state in dissociation of relativistic 12 C nuclei. • The Hoyle's state events are identified by invariant mass values calculated on a basis of most prices measurements of α-particle emission angles in approximation of conservation of momentum per nucleon of the parent nucleus. • An estimate of the Hoyle's state contribution to the relativistic dissociation 12 C → 3α is 10–15%.

Nuclear Track Emulsion in Search for the Hoyle’s State in Dissociation of Relativistic 12C Nuclei

Study of production of ensembles of alpha-particle triples associated with the Hoyle state (the second excited state 0+ 2 of the 12 C nucleus) in peripheral dissociation of relativistic 12C nuclei is started. Stacks of pellicles of nuclear track emulsion exposed to 12C of energy from hundreds MeV to few GeV per nucleon serve as the material of the study. The Hoyle state decays are reconstructed via measurements of emission angles of α-particles with accuracy that allows one to identify the unstable 8Be nucleus. A role in the Hoyle state of alpha-particle bonds corresponding to 8Be is determined.