Microdosimetric Analysis for Boron Neutron Capture Therapy via Monte Carlo Track Structure Simulation with Modified Lithium Cross-sections.

Boron neutron capture therapy (BNCT) is a cellular-level hadron therapy achieving therapeutic effects via the synergistic action of multiple particles, including Lithium, alpha, proton, and photon. However, evaluating the relative biological effectiveness (RBE) in BNCT remains challenging. In this research, we performed a microdosimetric calculation for BNCT using the Monte Carlo track structure (MCTS) simulation toolkit, TOPAS-nBio. This paper reports the first attempt to derive the ionization cross-sections of low-energy (>0.025 MeV/u) Lithium for MCTS simulation based on the effective charge cross-section scalation method and phenomenological double-parameter modification. The fitting parameters λ1=1.101,λ2=3.486 were determined to reproduce the range and stopping power data from the ICRU report 73. Besides, the lineal energy spectra of charged particles in BNCT were calculated, and the influence of sensitive volume (SV) size was discussed. Condensed history simulation obtained similar results with MCTS when using Micron-SV while overestimating the lineal energy when using Nano-SV. Furthermore, we found that the microscopic boron distribution can significantly affect the lineal energy for Lithium, while the effect for alpha is minimal. Similar results to the published data by PHITS simulation were observed for the compound particles and monoenergetic protons when using micron-SV. Spectra with nano-SV reflected that the different track densities and absorbed doses in the nucleus together result in the dramatic difference in the macroscopic biological response of BPA and BSH. This work and the developed methodology could impact the research fields in BNCT where understanding radiation effects is crucial, such as the treatment planning system, source evaluation, and new boron drug development.

Resonance of vector vortex beams in a triangular optical cavity.

We experimentally demonstrate resonance of first-order vector vortex beams (VVB) with a triangular optical cavity. We also show that, due to their symmetry properties, the VVBs commonly known as radial and azimuthal beams do not resonate at the same cavity length, which could be explored to use the triangular resonator as a mode sorter. In addition, an intracavity Pancharatnam phase shifter (PPS) is implemented in order to compensate for any birefringent phase that the cavity mirrors may introduce.

An integrated Monte Carlo track-structure simulation framework for modeling inter and intra-track effects on homogenous chemistry.

Objective. The TOPAS-nBio Monte Carlo track structure simulation code, a wrapper of Geant4-DNA, was extended for its use in pulsed and longtime homogeneous chemistry simulations using the Gillespie algorithm.Approach. Three different tests were used to assess the reliability of the implementation and its ability to accurately reproduce published experimental results: (1) a simple model with a known analytical solution, (2) the temporal evolution of chemical yields during the homogeneous chemistry stage, and (3) radiolysis simulations conducted in pure water with dissolved oxygen at concentrations ranging from 10µM to 1 mM with [H2O2] yields calculated for 100 MeV protons at conventional and FLASH dose rates of 0.286 Gy s-1and 500 Gy s-1, respectively. Simulated chemical yield results were compared closely with data calculated using the Kinetiscope software which also employs the Gillespie algorithm.Main results. Validation results in the third test agreed with experimental data of similar dose rates and oxygen concentrations within one standard deviation, with a maximum of 1% difference for both conventional and FLASH dose rates. In conclusion, the new implementation of TOPAS-nBio for the homogeneous long time chemistry simulation was capable of recreating the chemical evolution of the reactive intermediates that follow water radiolysis.Significance. Thus, TOPAS-nBio provides a reliable all-in-one chemistry simulation of the physical, physico-chemical, non-homogeneous, and homogeneous chemistry and could be of use for the study of FLASH dose rate effects on radiation chemistry.

Simulation of alpha particle emitted by 222Rn from natural spring water in Puebla, México.

A computational simulation of alpha-particle expansion, emitted by 222Rn naturally diluted in the water of a spring located in the state of Puebla Mexico, is presented. This simulation provided information on the volume of expansion of the alpha particles in the vicinity of the spring and thus awareness if there was a radiological risk for the users or the population that lived near to it. Before performing the simulation, several measurements were made to water samples with a dynamic measurement system. This in order to know the level of radon concentration and compare the results obtained with the levels recommended by the United States Environmental Protection Agency (US-EPA) and the World Health Organization (WHO). In addition, to know if there was a radiological risk due to the presence of gamma emitting radionuclides, complementary water analyses were carried out using gamma-ray spectrometry techniques. The simulation was developed using the scientific software of particle interaction with matter, Geant4. The different variables declared for the software parameters are presented in this document. The results of the radon measurements in the water and the computational simulation, determined that there was no radiological risk due to alpha radiation. Furthermore, the results from the gamma-ray spectrometer showed that there was no presence of other hazardous radionuclides in the water.

Ubiquitin is a component of paired helical filaments in Alzheimer's disease.

Paired helical filaments (PHF), which constitute a distinct type of pathological neuronal fiber, are the principal constituent of neurofibrillary tangles that occur in the brain of patients with Alzheimer's disease. Their insolubility in sodium dodecyl sulfate and urea has prevented the analysis of their subunit composition by gel electrophoresis. A monoclonal antibody (DF2) was isolated that specifically labeled PHF at both the light and electron microscopic levels. It labeled a small polypeptide (5 kilodaltons) that was shown to be ubiquitin in immunoblots of the soluble fraction of brain homogenates. To obtain direct evidence that ubiquitin is a component of PHF, PHF were treated with concentrated formic acid and digested with lysylendopeptidase; ubiquitin-derived peptides were then identified by reversed-phase high-performance liquid chromatography. Two fragments in the PHF digest were identified as derived from ubiquitin by protein sequencing. This procedure should make possible definitive identification of other PHF components.

The carboxyl third of tau is tightly bound to paired helical filaments.

To obtain definitive evidence that tau is a component of paired helical filaments (PHF) in Alzheimer's disease, we fractionated and sequenced PHF-derived peptides according to a previously described procedure. In the PHF digest, we found four independent tau peptides that were located in the carboxyl third of tau. Subsequent extensive analysis of the PHF digest did not provide any other tau peptides. The conventional PHF antiserum and a new antiserum directed toward formic acid-denatured PHF reacted with the distinct CNBr fragments of tau localized on the carboxy-terminal portion of tau by protein sequencing. From these observations, we conclude that the carboxyl third of tau is tightly bound to PHF.

A terahertz-driven non-equilibrium phase transition in a room temperature atomic vapour.

There are few demonstrated examples of phase transitions that may be driven directly by terahertz frequency electric fields, and those that are known require field strengths exceeding 1 MV cm-1. Here we report a non-equilibrium phase transition driven by a weak (≪1 V cm-1), continuous-wave terahertz electric field. The system consists of room temperature caesium vapour under continuous optical excitation to a high-lying Rydberg state, which is resonantly coupled to a nearby level by the terahertz electric field. We use a simple model to understand the underlying physical behaviour, and we demonstrate two protocols to exploit the phase transition as a narrowband terahertz detector: the first with a fast (20 µs) non-linear response to nano-Watts of incident radiation, and the second with a linearised response and effective noise equivalent power ≤1 pW Hz-1/2. The work opens the door to a class of terahertz devices controlled with low-field intensities and operating in a room temperature environment.

Effects of paraprobiotic Lactobacillus paracasei MCC1849 supplementation on symptoms of the common cold and mood states in healthy adults.

We investigated the effects of paraprobiotic Lactobacillus paracasei MCC1849 (LAC-Shield™) on symptoms of the common cold and mood states in healthy young adults. A total of 241 participants were randomised to receive 1×1010 heat-killed L. paracasei MCC1849 cell powder (10LP), 3×1010 heat-killed L. paracasei MCC1849 cell powder (30LP), or placebo powder without any L. paracasei cells once daily for 12 weeks based on the incidence of the common cold in the previous year, so that the risk of the incidence was equal among the groups. The incidence and severity of common cold symptoms were rated daily in a subject diary. Salivary secretory immunoglobulin A concentrations and saliva flow rates were analysed at 0 and 6 weeks. The Profile of Mood States (POMS) was assessed using POMS 2 0, 6, and 12 weeks after the intervention. No significant differences were observed in the incidence of the common cold among the groups. In a prespecified subgroup of subjects who had the common cold in the previous year, the incidence, total number of days of symptoms, and symptom scores of the common cold significantly improved in the 10LP-intake group, and were slightly lower in the 30LP-intake group than in the placebo group. The level of deterioration in the positive mood state caused by stress was less in the MCC1849-intake group than in the placebo group. These results indicate that L. paracasei MCC1849 has the potential to improve resistance to common cold infections in susceptible subjects and maintain a desirable mood state, even under mental stress conditions. Further randomised controlled trials are needed in order to investigate the possible beneficial effects of paraprobiotic L. paracasei MCC1849 on the common cold in susceptible populations.

Hibernation-associated gene regulation of plasma proteins with a collagen-like domain in mammalian hibernators.

In mammals, hibernation is expressed by only a limited number of species, and the molecular mechanisms underlying hibernation are not well understood. Recently, we have found plasma proteins which disappear from blood specifically during hibernation in a mammalian hibernator, the chipmunk. Here, we report the cDNA cloning of these chipmunk hibernation-related proteins, HP-20, -25, and -27, and analyses of their expression. All three proteins contain a collagen-like domain near the N terminus and are highly homologous to each other. Their mRNAs were detected only in liver in nonhibernating chipmunks, and in hibernating chipmunks, the amounts were reduced to less than 1/10 of those in nonhibernating chipmunks, indicating that HP-20, -25, and -27 mRNA expression is regulated similarly in association with hibernation. Southern blot analyses of the squirrel family with each of chipmunk HP-20, -25, and -27 cDNA revealed that a nonhibernating species (tree squirrel) as well as another hibernating species (ground squirrel) retained the corresponding genes. However, their transcripts were detected only with the hibernating species, and in hibernating ground squirrels, their levels were greatly reduced compared with those in nonhibernating animals, as were the cases with the chipmunk. These observations are the first line of evidence for occurrence of hibernation-associated gene regulation. The results would indicate the commitment of HP-20, -25, and -27 to hibernation and support the idea that genetic controls are involved in mammalian hibernation.

Molecular cloning and characterization of a novel type of regulatory protein (GDI) for smg p25A, a ras p21-like GTP-binding protein.

We recently purified to near homogeneity a novel type of regulatory protein for smg p25A, a ras p21-like GTP-binding protein, from bovine brain cytosol. This regulatory protein, named smg p25A GDP dissociation inhibitor (GDI), regulates the GDP-GTP exchange reaction of smg p25A by inhibiting dissociation of GDP from and subsequent binding of GTP to it. In the present studies, we isolated and sequenced the cDNA of smg p25A GDI from a bovine brain cDNA library by using an oligonucleotide probe designed from the partial amino acid sequence of purified smg p25A GDI. The cDNA has an open reading frame that encodes a protein of 447 amino acids with a calculated Mr of 50,565. This Mr is similar to those of the purified smg p25A GDI estimated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and sucrose density gradient ultracentrifugation, which are about 54,000 and 65,000, respectively. The isolated cDNA is expressed in Escherichia coli, and the encoded protein exhibits GDI activity. smg p25A GDI is hydrophilic overall, except for one hydrophobic region near the N terminus. smg p25A GDI shares low amino acid sequence homology with the Saccharomyces cerevisiae CDC25-encoded protein, which has been suggested to serve as a factor that regulates the GDP-GTP exchange reaction of the yeast RAS2-encoded protein, but not with the beta gamma subunits of GTP-binding proteins having an alpha beta gamma subunit structure, such as Gs and Gi. The smg p25A GDI mRNA was present in various tissues, including not only tissues in which smg p25A was detectable but also tissues in which it was not detectable. This fact has raised the possibility that smg p25A GDI interacts with another G protein in tissues in which smg p25A is absent.

Molecular cloning of cDNAs for mouse low-molecular-weight and high-molecular-weight prekininogens.

We isolated cDNAs encoding low-molecular-weight (L-) and high-molecular-weight (H-) prekininogens from a mouse liver cDNA library using rat T-kininogen cDNA and rat H-kininogen cDNA respectively, as probes. The signal peptide, the heavy chain, and the bradykinin moiety, which are common between the two prekininogens, consist of 20, 359, and 9 amino acids, respectively, while the light chains of the L- and H-prekininogens are composed of 44 and 273 amino acids, respectively. All 19 cysteine residues present in both mouse prekininogens are located at the same positions relative to those of human origin. The light chain of H-prekininogen contains a characteristic 15-repeated His-Gly sequence and a conserved sequence for binding prekallikrein or factor XI. Northern blotting or reverse transcription-polymerase chain reaction followed by Southern blotting using mouse L- and H-kininogen cDNAs demonstrated that both L- and H-kininogens are predominantly expressed in the liver and kidney. L-Kininogen mRNA was also expressed in other tissues, such as the adrenal gland, brain, spinal cord, testis, lung, heart, and skin, while levels of H-kininogen mRNA in these tissues were too low to detect, suggesting that L-kininogen is synthesized in various tissues of mouse, while H-kininogen is exclusively synthesized in the liver and kidney. A genomic Southern blot using H-prekininogen cDNA revealed that the L- and H-prekininogen mRNAs in mouse are probably encoded by a single gene, as is the case in both human and bovine.

1,2-diacylglycerol content and its fatty acid composition in thoracic aorta of diabetic rats.

These experiments were conducted to determine 1,2-diacylglycerol (DAG) in the thoracic aorta obtained from streptozocin-induced diabetic rats because 1,2-DAG is assumed to be a second messenger associated with phosphoinositide metabolism. After preincubation for a 25-min stabilization, 1,2-DAG content in isolated thoracic aortas 4 and 8 wk after streptozocin injection was significantly decreased by 42 and 31%, respectively, compared with age-matched control rats on 10-min norepinephrine stimulation (10(-5) M). However, 4 wk of daily insulin injection after 4 wk of untreated diabetes significantly shifted 1,2-DAG toward normal levels. Analysis of its fatty acid composition showed a significant difference between control and diabetic rat aortas at both 4 and 8 wk. In particular, the percentage of arachidonate, a precursor of eicosanoids, decreased. Such alteration in the fatty acid profile in diabetic rat aortas was inhibited by insulin treatment. 1,2-DAG content in the 8-wk diabetic group was also significantly decreased by 33% compared with control in the absence of norepinephrine, whereas 1,2-DAG content was lower than in the presence of norepinephrine in both the control and diabetic groups. Cholesterol, triglyceride, and phosphatidylcholine content in diabetic rat aortas was lower than control. Lower levels of 1,2-DAG in the thoracic aorta from diabetic rats were observed in the presence and absence of norepinephrine, suggesting that a defect in 1,2-DAG production may be associated with abnormalities of vascular smooth muscle responsiveness by agonists, as described previously.

Angiographic no-reflow phenomenon as a predictor of adverse long-term outcome in patients treated with percutaneous transluminal coronary angioplasty for first acute myocardial infarction.

OBJECTIVES: We sought to elucidate the long-term prognostic importance of angiographic no-reflow phenomenon after percutaneous transluminal coronary angioplasty (PTCA) for acute myocardial infarction (AMI). BACKGROUND: Angiographic no-reflow phenomenon, a reduced coronary antegrade flow (Thrombolysis in Myocardial Infarction [TIMI] flow grade < or =2) without mechanical obstruction after recanalization, predicts poor left ventricular (LV) functional recovery and survival in the early phase of AMI. We hypothesized that angiographic no-reflow phenomenon also predicts long-term clinical outcome. METHODS: We studied 120 consecutive patients with their first AMI treated by PTCA without flow-restricting lesions. The patients were classified as either no-reflow (n = 30) or reflow (TIMI-3) (n = 90) based on post-PTCA cineangiograms to follow up (5.8 +/- 1.2 years) for cardiac death and nonfatal events. RESULTS: Patients with no-reflow had congestive heart failure (p < 0.0001), malignant arrhythmia (p = 0.038), and cardiac death (p = 0.002) more often than did those with reflow. Kaplan-Meier curves showed lower cardiac survival and cardiac event-free survival (p < 0.0001) in patients with no-reflow than in those with reflow. Multivariate analyses disclosed that no-reflow phenomenon was an independent predictor of long-term cardiac death (relative risk [RR] 5.25, 95% confidence interval [CI] 1.85 to 14.9, p = 0.002) and cardiac events (RR 3.71, 95% CI 1.79 to 7.69, p = 0.0004). At follow-up, survivors with no-reflow had higher end-diastolic and end-systolic LV volume indices and plasma brain natriuretic peptide levels, and lower LV ejection fractions (p = 0.0002, p < 0.0001, p = 0.002, p < 0.0001, respectively) than did those with reflow, indicating that no-reflow may be involved in LV remodeling. CONCLUSIONS: Angiographic no-reflow phenomenon strongly predicts long-term cardiac complications after AMI; these complications are possibly associated with LV remodeling.

Changes in ventricular 1,2-diacylglycerol content in rats following monocrotaline treatment.

OBJECTIVE: 1,2-Diacylglycerol may initiate cardiac hypertrophy, probably by activating protein kinase C. To test this hypothesis we determined the 1,2-diacylglycerol content of hypertrophied tissue. METHODS: Rats were treated with monocrotaline and developed severe right ventricular hypertrophy followed by congestive heart failure. 1,2-Diacylglycerol content and fatty acid composition, DNA concentrations, and RNA concentrations in the right ventricle from monocrotaline treated rats were compared with values obtained from the left side or from control rats. RESULTS: During the first week, the right ventricle showed no significant change in 1,2-diacylglycerol content and a small increase in RNA concentration. However, the 1,2-diacylglycerol content was significantly increased by 55% at two weeks after monocrotaline injection, when DNA and RNA synthesis was also enhanced to its highest level when compared with control rats (37% and 18%, respectively). At four weeks after monocrotaline injection, conversely, the 1,2-diacylglycerol content was decreased by 25% in the right ventricle from monocrotaline treated rats, most of which had pleural and peritoneal effusions indicating congestive heart failure, although RNA synthesis was sustained at a high level. The fatty acid composition of 1,2-diacylglycerol did not differ significantly between the right and left ventricles or control rat ventricles. CONCLUSIONS: These results suggest that 1,2-diacylglycerol accumulation is associated with development of hypertrophy in monocrotaline treated rats. In contrast, at a stage of congestive heart failure 1,2-diacylglycerol production decreased, suggesting that intracellular transduction mechanisms may be attenuated.

Reperfusion hastens appearance and extent of distribution of type I collagen in infarct zone: immunohistochemical study in rat experimental infarction.

BACKGROUND: The effects of reperfusion on time-dependent alteration of type I collagen have not been examined. OBJECTIVES: We compared the sequential changes in the appearance and distribution of type I collagen in reperfused infarct rat hearts to those in non-reperfused hearts. METHODS: Using an experimental rat model of infarction, we performed immunohistochemical staining with a polyclonal antibody to type I collagen by the avidin-biotin-peroxidase method. Reperfusion was established after 2-h coronary ligation that produced complete necrosis of myocytes. RESULTS: In reperfused hearts, type I collagen appeared in the peripheral zone of the infarct at day 2, which was 1 day earlier than in non-reperfused hearts. The extent of distribution of type I collagen in reperfused hearts was comparable to that observed approximately 1 day later in non-reperfused hearts. CONCLUSION: Reperfusion can accelerate collagen matrix formation compared with that in non-reperfused hearts after acute myocardial infarction.

1,2-diacylglycerol content in thoracic aorta of spontaneously hypertensive rats.

Phosphoinositide metabolism participates in the control of cell calcium homeostasis. Because a notable neutral lipid (1,2-diacylglycerol) is generated from phosphoinositide hydrolysis and is assumed to be a secondary messenger, we determined 1,2-diacylglycerol content and its fatty acid profiles in the thoracic aorta of spontaneously hypertensive rats (SHR) and compared it with those of normotensive Wistar-Kyoto (WKY) rats. After the aorta was exposed to 10(-5) M norepinephrine as a stimulant, 1,2-diacylglycerol content in SHR was significantly higher by 33% than in WKY rats at 4 weeks of age, whereas there was no difference in 1,2-diacylglycerol content between the two strains at 20 weeks of age. Before norepinephrine stimulation, there was no significant difference in 1,2-diacylglycerol level between the two strains at 4 weeks of age. Analysis on a gas chromatograph showed that 1,2-diacylglycerol was composed of similar molecular species of fatty acids in aortas obtained from SHR and WKY rats. On the other hand, the cholesterol content of aortas was higher in SHR than in WKY rats at 20 weeks of age, whereas the difference at 4 weeks was not significant. Phosphatidylcholine, phosphatidylethanolamine, and triglyceride showed no significant difference between the two strains. It is concluded that norepinephrine-induced 1,2-diacylglycerol production increases in the thoracic aorta of SHR before the development of hypertension.

Expression of multiple alpha1-antitrypsin-like genes in hibernating species of the squirrel family.

In the chipmunk, a mammalian hibernator, a 140 kDa protein complex found in the blood, drastically decreases in concentration during hibernation. This complex contains four species of proteins, HP-20, -25, -27 and -55. In the present study, cDNA clones coding for the chipmunk HP-55 were isolated from a liver cDNA library. Sequence analysis revealed that HP-55 is produced as a precursor protein of 413 amino acids (aa), that it has a signal peptide of 24 aa, and that it contains four potential N-glycosylation sites. The deduced aa sequence shows 63% identity with that of rat alpha1-antitrypsin (alpha1-AT); however, the sequence corresponding to the reactive center P1-P1' residues was found to be Met-Leu, whereas it is Met-Ser in the rat alpha1-AT. During screening of the chipmunk liver cDNA library, four other related classes of cDNA clones were obtained, each also coding for an alpha1-AT-like protein. In spite of more than 86% overall aa sequence identity among the five chipmunk alpha1-AT-like proteins, they are highly divergent in the putative reactive center region; the putative P1-P1' sequences are Met-Leu (HP-55 or CM55-ML), Met-Met (CM55-MM), Met-Ser (CM55-MS), Ser-Ile (CM55-SI) and Ser-Thr (CM55-ST). Each of the alpha1-AT-like protein mRNAs was expressed in chipmunk liver, and the HP-55 mRNA level was greatly reduced during hibernation. Genomic Southern blot analysis and screening of a liver cDNA library from another hibernating squirrel species, the ground squirrel, also revealed expression of multiple members of the alpha1-AT gene family, whereas analysis of a cDNA library from a non-hibernating species, the tree squirrel, found only a single alpha1-AT gene.

Inhibition of DNA synthesis and tube morphogenesis of cultured vascular endothelial cells by chondromodulin-I.

Cartilage is an avascular tissue, and exhibits anti-angiogenic properties. Cartilage extracts have been shown to contain an inhibitor for DNA synthesis in vascular endothelial cells in vitro. Here we purified the inhibitory activity in the 10-50 kDa fraction of guanidine extracts from fetal bovine epiphyseal cartilage, and found that the inhibitor was identical with chondromodulin-I (ChM-I). Purified ChM-I inhibited tube morphogenesis of cultured vascular endothelial cells, as well as DNA synthesis. These results indicate that cartilage-specific glycoprotein ChM-I may participate in the maintenance of avascularity and anti-angiogenic properties of cartilage.