Measurement of personal radio frequency exposure in Japan: The Hokkaido Study on the Environment and Children's health.

The opportunities for exposure to radiofrequency electromagnetic fields (RF-EMF) among children are increasing. Children's exposure to RF-EMF in Japan was recorded using a personal exposure meter (ExpoM-RF), and factors associated with the exposure examined. A total of 101 children, aged 10-15 years old, participated in the prospective birth cohort "Hokkaido study". RF-EMF data were recorded in the 700 MHz-5.8 GHz frequency range for 3 days. The recorded data were summarized into six groups of frequency bands: downlink from mobile phone base stations (DL), uplink from mobile phones to a base station (UL), Wireless Local Area Network (LAN), terrestrial digital TV broadcasting (digital TV), 2.5 GHz and 3.5 GHz Time Division Duplex (TDD), 1.9 GHz TDD, and total (the summation of power density in all measured frequency bands). A questionnaire was used to document the internet environment (at home) and mobile phone usage. Personal RF-EMF exposure in Japanese children was lower than that reported in studies in Europe. The DL signals from mobile phone base stations were the most significant contributors to total exposure, while Wireless LAN and digital TV were only higher at home. The urban residence was consistently associated with increases in the four groups of frequency bands (DL, UL, digital TV, and TDD). TDD level has several associations with mobile phone usage (calls using mobile phones, video viewing, text message service, and online game). The association between inattention/hyperactivity subscale of the Strengths and Difficulties Questionnaire (SDQ) and higher Wireless LAN exposure at nighttime was also noted. Further studies with additional data will shed light on factors involved in RF-EMF exposure among Japanese children.

Cross-sectional associations between early mobile device usage and problematic behaviors among school-aged children in the Hokkaido Study on Environment and Children's Health.

BACKGROUND: Concerns have been raised about the adverse health impacts of mobile device usage. The objective of this cross-sectional study was to examine the association between a child's age at the first use of a mobile device and the duration of use as well as associated behavioral problems among school-aged children. METHODS: This study focused on children aged 7-17 years participating in the Hokkaido Study on Environment and Children's Health. Between October 2020 and October 2021, the participants (n = 3,021) completed a mobile device use-related questionnaire and the strengths and difficulties questionnaire (SDQ). According to the SDQ score (normal or borderline/high), the outcome variable was behavioral problems. The independent variable was child's age at first use of a mobile device and the duration of use. Covariates included the child's age at the time of survey, sex, sleep problems, internet addiction, health-related quality of life, and history of developmental concerns assessed at health checkups. Logistic regression analysis was performed for all children; the analysis was stratified based on the elementary, junior high, and senior high school levels. RESULTS: According to the SDQ, children who were younger at their first use of a mobile device and used a mobile device for a longer duration represented more problematic behaviors. This association was more pronounced among elementary school children. Moreover, subscale SDQ analysis showed that hyperactivity, and peer and emotional problems among elementary school children, emotional problems among junior high school children, and conduct problems among senior high school children were related to early and long usage of mobile devices. CONCLUSIONS: Elementary school children are more sensitive to mobile device usage than older children, and early use of mobile devices may exacerbate emotional instability and oppositional behaviors in teenagers. Longitudinal follow-up studies are needed to clarify whether these problems disappear with age.

D3M: detection of differential distributions of methylation levels.

MOTIVATION: DNA methylation is an important epigenetic modification related to a variety of diseases including cancers. We focus on the methylation data from Illumina's Infinium HumanMethylation450 BeadChip. One of the key issues of methylation analysis is to detect the differential methylation sites between case and control groups. Previous approaches describe data with simple summary statistics or kernel function, and then use statistical tests to determine the difference. However, a summary statistics-based approach cannot capture complicated underlying structure, and a kernel function-based approach lacks interpretability of results. RESULTS: We propose a novel method D(3)M, for detection of differential distribution of methylation, based on distribution-valued data. Our method can detect the differences in high-order moments, such as shapes of underlying distributions in methylation profiles, based on the Wasserstein metric. We test the significance of the difference between case and control groups and provide an interpretable summary of the results. The simulation results show that the proposed method achieves promising accuracy and shows favorable results compared with previous methods. Glioblastoma multiforme and lower grade glioma data from The Cancer Genome Atlas show that our method supports recent biological advances and suggests new insights. AVAILABILITY AND IMPLEMENTATION: R implemented code is freely available from https://github.com/ymatts/D3M/ CONTACT: ymatsui@med.nagoya-u.ac.jp or shimamura@med.nagoya-u.ac.jp SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Graphical representation of the effects on tumor and OAR for determining the appropriate fractionation regimen in radiation therapy planning.

PURPOSE: The authors propose a graphical representation of the relation between the effect on the tumor and the damage effect on an organ at risk (OAR) against the irradiation dose, as an aid for choosing an appropriate fractionation regimen. METHODS: The graphical relation is depicted by the radiation effect on the tumor E(1) versus that on an OAR E(0). By observing the features of the E(1) vs E(0) relation curve, i.e., convex or concave shape, one can judge whether multifractionation is better or not. This method is applied to the linear-quadratic model (with α and ß parameters) as an example. Further, the method is extended to the general case for nonuniform dose distribution to the OAR, which is frequently seen in clinical situations. RESULTS: The criterion for selecting multi- or hypofractionation is based on the relation between the dose for the OAR and the α∕ß ratio of the OAR to the tumor. It is also shown that the graphical relation enables us to estimate the final effect after multifractionated treatment by plotting a tangent line on the curve. CONCLUSIONS: The graphical representation method is of use for improving planning in radiotherapy by determining the effective fractionation scheme.

DNA duplexes and triplex-forming oligodeoxynucleotides incorporating modified nucleosides forming stable and selective triplexes.

We have previously reported DNA triplexes containing the unnatural base triad G-PPI·C3, in which PPI is an indole-fused cytosine derivative incorporated into DNA duplexes and C3 is an abasic site in triplex-forming oligonucleotides (TFOs) introduced by a propylene linker. In this study, we developed a new unnatural base triad A-ψ·C(R1) where ψ and C(R1) are base moieties 2'-deoxypseudouridine and 5-substituted deoxycytidine, respectively. We examined several electron-withdrawing substituents for R1 and found that 5-bromocytosine (C(Br)) could selectively recognize ψ. In addition, we developed a new PPI derivative, PPI(Me), having a methyl group on the indole ring in order to achieve selective triplex formation between DNA duplexes incorporating various Watson-Crick base pairs, such as T-A, C-G, A-ψ, and G-PPI(Me), and TFOs containing T, C, C(Br), and C3. We studied the selective triplex formation between these duplexes and TFOs using UV-melting and gel mobility shift assays.

Comparison of dimension reduction methods on fatty acids food source study.

Serum fatty acids (FAs) exist in the four lipid fractions of triglycerides (TGs), phospholipids (PLs), cholesteryl esters (CEs) and free fatty acids (FFAs). Total fatty acids (TFAs) indicate the sum of FAs in them. In this study, four statistical analysis methods, which are independent component analysis (ICA), factor analysis, common principal component analysis (CPCA) and principal component analysis (PCA), were conducted to uncover food sources of FAs among the four lipid fractions (CE, FFA, and TG + PL). Among the methods, ICA provided the most suggestive results. To distinguish the animal fat intake from endogenous fatty acids, FFA variables in ICA and factor analysis were studied. ICA provided more distinct suggestions of FA food sources (endogenous, plant oil intake, animal fat intake, and fish oil intake) than factor analysis. Moreover, ICA was discovered as a new approach to distinguish animal FAs from endogenous FAs, which will have an impact on epidemiological studies. In addition, the correlation coefficients between a published dataset of food FA compositions and the loading values obtained in the present ICA study suggested specific foods as serum FA sources. In conclusion, we found that ICA is a useful tool to uncover food sources of serum FAs.

Exposure to Radiofrequency Electromagnetic Field in the High-Frequency Band and Cognitive Function in Children and Adolescents: A Literature Review.

With increasing use of mobile phones, exposure to radiofrequency electromagnetic field (RF-EMF) in the high-frequency band associated with mobile phones has become a public concern, with potentially adverse effects on cognitive function in children and adolescents. However, findings regarding the relation of RF-EMF and cognitive function in children and adolescents have been inconsistent due to a number of study design-related factors, such as types of exposure and outcome measures, age of participants, and the era of study conduction. The present literature review focused on these possible factors that could explain this inconsistency. This review identified 12 eligible studies (participants ages 4 to 17 years) and extracted a total 477 relations. In total, 86% of the extracted relations were not statistically significant; in the remaining 14%, a negative relation between RF-EMF and cognitive performance was detected under limited conditions: when (1) RF-EMF was assessed using objective measurement not subjective measurement (i.e., questionnaire), (2) participants were relatively older (12 years and above) and had greater opportunity of exposure to RF-EMF, and (3) the collection of cognitive function data was conducted after 2012. Given that 86% of the extracted relations in this analysis were not statistically significant, the interpretation should be approached with caution due to the possibility of the 14% of significant relationships, extracted in this review, representing chance findings.

Multivariate Analysis for Molecular Species of Cholesteryl Ester in the Human Serum.

Cholesteryl ester (CE) is an ester of cholesterol and fatty acid (FA). Plasma CE reflects complicated metabolisms of cholesterol, phospholipids, lipoproteins, and dietary FAs. An informatics approach could be useful for analysis of the CE species. In this study, two basic dimension reduction methods, principal component analysis (PCA) and factor analysis, were applied to serum CE species determined by LC-MS/MS in a Japanese population (n = 545). PCA and factor analysis both reflected the size (concentration), food source, fat solubility, and biological aspect of the CE species. In a comparison between PCA (PC4) and factor analysis (factor 4), the latter was found to be more suggestive from a biological aspect of n-6 FAs. Cholesteryl docosahexaenoate (DHA) was found to be unique by a factor analysis, possibly relevant to the unique accumulation of DHA in the brain. An informatics approach, especially factor analysis, might be useful for the analysis of complicated metabolism of CE species in the serum.

Fluorescence properties of pyrimidopyrimidoindole nucleoside dC(PPI) incorporated into oligodeoxynucleotides.

A series of oligodeoxynucleotides labeled by a pyrimidopyrimidoindole deoxynucleoside (1a: dC(PPI)) and its derivatives 2a and 3a substituted with electron-donating and -withdrawing groups, respectively, were synthesized according to the phosphoramidite approach. The photophysical properties and quenching efficiencies of oligonucleotides incorporating dC(PPI) derivatives were studied in detail. The thermal denaturation experiments and molecular dynamics simulation of DNA duplexes incorporating dC(PPI) suggested that a modified base of dC(PPI) could form base pairs with guanine and adenine in canonical Watson-Crick and reverse-wobble geometries, respectively. The fluorescence of oligonucleotides incorporating dC(PPI) derivatives increased upon binding to the counter strands, except when dC(PPI) and guanine formed a base pair. It was revealed that dGMP quenched the fluorescence of the cyano derivative 3a most effectively, whereas it affected that of the methoxy derivative 2a least effectively. The involvement of the electron transfer from guanine to the dC(PPI) derivatives in the fluorescence quenching was supported by energy considerations.

New nucleotide pairs for stable DNA triplexes stabilized by stacking interaction.

New nucleotide pairs applicable to formation of DNA triplexes were developed. We designed oligonucleotides incorporating 5-aryl deoxycytidine derivatives (dC5Ars) and cyclic deoxycytidine derivatives, dCPPP and dCPPI, having an expanded aromatic area, as the second strand. As pairing partners, two types of abasic residues (C3: propylene linker, phi: abasic base) were chosen. It was concluded that, when the 5-aryl-modified cytosine bases paired with the abasic sites in TFOs in a space-fitting manner, the stability of the resulting triplexes significantly increased. The recognition of C3 toward dC5Ars was selective because of the stacking interactions between their aromatic part and the nucleobases flanking the abasic site. These results indicate the potential utility of new nucleotide triplets for DNA triplex formation, which might expand the variety of structures and sequences and might be useful for biorelated fields such as DNA nanotechnologies.

Comparison of the average surviving fraction model with the integral biologically effective dose model for an optimal irradiation scheme.

In this paper, we compare two radiation effect models: the average surviving fraction (ASF) model and the integral biologically effective dose (IBED) model for deriving the optimal irradiation scheme and show the superiority of ASF. Minimizing the effect on an organ at risk (OAR) is important in radiotherapy. The biologically effective dose (BED) model is widely used to estimate the effect on the tumor or on the OAR, for a fixed value of dose. However, this is not always appropriate because the dose is not a single value but is distributed. The IBED and ASF models are proposed under the assumption that the irradiation is distributed. Although the IBED and ASF models are essentially equivalent for deriving the optimal irradiation scheme in the case of uniform distribution, they are not equivalent in the case of non-uniform distribution. We evaluate the differences between them for two types of cancers: high α/ß ratio cancer (e.g. lung) and low α/ß ratio cancer (e.g. prostate), and for various distributions i.e. various dose-volume histograms. When we adopt the IBED model, the optimal number of fractions for low α/ß ratio cancers is reasonable, but for high α/ß ratio cancers or for some DVHs it is extremely large. However, for the ASF model, the results keep within the range used in clinical practice for both low and high α/ß ratio cancers and for most DVHs. These results indicate that the ASF model is more robust for constructing the optimal irradiation regimen than the IBED model.

Determination of Serum 25-Hydroxyvitamin D3 by LC/MS/MS and Its Monthly Variation in Sapporo Indoor Workers.

25-Hydroxyvitamin D3 (25(OH)D3) as the metabolite of vitamin D, is connected with various of diseases, and important to people with limited sunshine. Thus, the investigation of serum 25-hydroxyvitamin D and its variation in these people is necessary. In this study, a simple, precise, and accurate method for serum 25(OH)D3 determination by LC/MS/MS was developed. Serum samples were obtained monthly for one year from 11 male and 11 female indoor workers in Sapporo, Japan, and the overall 25(OH)D3 concentration was 12.9 ± 4.7 ng/mL. The 25(OH)D3 in females was significantly lower than that in males (14.0 ± 5.0 vs. 11.9 ± 4.3 ng/mL). The serum 25(OH)D3 concentration in males and females were both strongly correlated to UV-B radiation (r2 = 0.8477 and 0.7384, respectively), with a two-month's lag. Also the monthly change in 25(OH)D3 in males was more significant than that in females.

A pyrimidopyrimidoindole nucleoside (dC PPI): photophysical properties and thermal stability of the modified DNA duplexes.

A new fluorescent deoxycytidine analog, 10-(2-deoxy-beta -D-ribofuranosyl)-pyrimido[4',5' :4,5]-pyrimido[1,6-a]indole-6,9(7H)-dione (dC(PPI)) was synthesized. Its fluorescent properties were studied in detail. It was found that this fluorescent nucleoside dC(PPI) could be used as a fluorescent label for DNA probes with minimal disturbance of their overall structure.

Change in Plasma Total, Esterified and Non-esterified Capric Acid Concentrations during a Short-term Oral Administration of Synthetic Tricaprin in Dogs.

We studied change in the plasma total, esterified and non-esterified capric acid (FA10:0) and its effect on longer fatty acid concentrations during the short-term oral administration of synthetic tricaprin in dogs. We administered 150 and 1500 mg tricaprin/kg body weight per day orally to dogs for 7 consecutive days. Blood samples were collected at 0, 0.5, 1, 2, 4, 8, and 24 h on the 1st and 7th days for measuring the total-, esterified- and non-esterified-FA10:0. The total-FA10:0 concentration increased in a dose-dependent manner, reaching a peak at 1 h on the 1st day and at 2 to 4 h on the 7th day; it then mostly disappeared within 24 h. The mean esterified FA10:0 concentration was found be 75.5 and 60.3% of total-FA10:0 in dogs fed 150 and 1500 mg of tricaprin/kg body weight, respectively. The plasma level of FA10:0 depends on the duration and dose of tricaprin administration, but are rapidly cleared from circulation within several hours.

Optimization of the fractionated irradiation scheme considering physical doses to tumor and organ at risk based on dose-volume histograms.

PURPOSE: Radiotherapy of solid tumors has been performed with various fractionation regimens such as multi- and hypofractionations. However, the ability to optimize the fractionation regimen considering the physical dose distribution remains insufficient. This study aims to optimize the fractionation regimen, in which the authors propose a graphical method for selecting the optimal number of fractions (n) and dose per fraction (d) based on dose-volume histograms for tumor and normal tissues of organs around the tumor. METHODS: Modified linear-quadratic models were employed to estimate the radiation effects on the tumor and an organ at risk (OAR), where the repopulation of the tumor cells and the linearity of the dose-response curve in the high dose range of the surviving fraction were considered. The minimization problem for the damage effect on the OAR was solved under the constraint that the radiation effect on the tumor is fixed by a graphical method. Here, the damage effect on the OAR was estimated based on the dose-volume histogram. RESULTS: It was found that the optimization of fractionation scheme incorporating the dose-volume histogram is possible by employing appropriate cell surviving models. The graphical method considering the repopulation of tumor cells and a rectilinear response in the high dose range enables them to derive the optimal number of fractions and dose per fraction. For example, in the treatment of prostate cancer, the optimal fractionation was suggested to lie in the range of 8-32 fractions with a daily dose of 2.2-6.3 Gy. CONCLUSIONS: It is possible to optimize the number of fractions and dose per fraction based on the physical dose distribution (i.e., dose-volume histogram) by the graphical method considering the effects on tumor and OARs around the tumor. This method may stipulate a new guideline to optimize the fractionation regimen for physics-guided fractionation.

A mathematical study to select fractionation regimen based on physical dose distribution and the linear-quadratic model.

PURPOSE: Hypofractionated irradiation is often used in precise radiotherapy instead of conventional multifractionated irradiation. We propose a novel mathematical method for selecting a hypofractionated or multifractionated irradiation regimen based on physical dose distribution adding to biologic consideration. METHODS AND MATERIALS: The linear-quadratic model was used for the radiation effects on tumor and normal tissues, especially organs at risk (OARs). On the basis of the assumption that the OAR receives a fraction of the dose intended for the tumor, the minimization problem for the damage effect on the OAR was treated under the constraint that the radiation effect on the tumor is fixed. RESULTS: For an N-time fractionated irradiation regimen, the constraint of tumor lethality was described by an N-dimensional hypersphere. The total dose of the fractionated irradiations was considered for minimizing the damage effect on the OAR under the hypersphere condition. It was found that the advantage of hypofractionated or multifractionated irradiation therapies depends on the magnitude of the ratio of α/ß parameters for the OAR and tumor in the linear-quadratic model and the ratio of the dose for the OAR and tumor. CONCLUSIONS: Our mathematical method shows that multifractionated irradiation with a constant dose is better if the ratio of α/ß for the OAR and tumor is less than the ratio of the dose for the OAR and tumor, whereas hypofractionated irradiation is better otherwise.

Recognition of target chain-length by use of oligonucleotides having bulky substituents at the terminal bases.

We synthesized 2'-O-methyl RNAs having bulky substituents at the 5' and 3'-terminal bases and examined their hybridization properties. The hybridization of the modified RNAs to the targets RNA was studied varying the chain length of the targets. As the result, it was proved that the duplex of the modified 2'-O-methyl RNAs and the long targets were destabilized in comparison with that of the modified 2'-O-methyl RNAs and the short targets. We hope that these oligonucleotides which could recognize the target chain-length would be the simple and convenient tool for the detection of small RNAs such as the microRNAs.

Fluorescent pyrimidopyrimidoindole nucleosides: control of photophysical characterizations by substituent effects.

10-(2-Deoxy-beta-D-ribofuranosyl)pyrimido[4',5':4,5]pyrimido[1,6-a]indole-6,9(7H)-dione (dCPPI) and its derivatives were synthesized via the Suzuki-Miyaura coupling reaction of 5-iododeoxycytidine with 5-substituted N-Boc-indole-2-borates and characterized by UV-vis and fluorescence spectroscopy. The new fluorescent nucleosides showed rather large Stokes shifts (116-139 nm) in an aqueous buffer. The fluorescent intensities were dependent on the nature of the substituents on the indole rings. The electron-withdrawing groups increased the fluorescent intensity while the electron-donating groups having lone pairs decreased it. Among the substituted dCPPI derivatives tested, the trimethylammonium derivative of dCPPI was found to emit the brightest fluorescent light. The solvatochromism of dCPPI and its derivatives was also studied. Some of the dCPPI derivatives showed interesting solvent-dependent fluorescence enhancement and could be useful as new fluorescent structural probes for nucleic acids. The Lippert-Mataga analyses of the Stokes shift were also carried out to obtain estimated values of the dipole moment of the excited states of some of the derivatives.

Recognition of triplex forming oligodeoxynucleotides incorporating abasic sites by 5-arylcytosine residues in duplex DNAs.

In this paper, we reported our attempt to use a 5arylcytosine (dC(ar)) and the abasic site () as an artificial base pair for DNA triplex. The idea was confirmed by the molecular modeling studied in which the aromatic group of (ph) which protrudes in the major groove was buried into the cleft formed by the residue in the TFO. We synthesized three kinds of dC(ar) and the oligonucleotides incorporating them. Our UV-melting experiments revealed that the DNA triplex containing the dC(ph).phi was more stable than that containing dC.phi pair. Moreover, the dC.phi pair was more stable than any other dC.Y pairs such as dC(ph).G, dC(ph).C, dC(ph).T and dC(ph).A. These results indicated the possibility that the appropriate pair of dC(Ar) and could be the new sequence code of DNA triplex. We also carried out the Tm analyses of other TFOs incorporating dC(Ar) and , and clarified the stability of these triplexes.

Synthesis and fluorescent properties of bi- and tricyclic 4-N-carbamoyldeoxycytidine derivatives.

New bi- and tricyclic deoxycytidine derivatives (dChpd, dCmpp, dCtpp, dCppp) were synthesized as analogues of a fluorescent nucleoside, dChpp, previously reported. The carbamoyl group of dChpd and the 5-position of the cytosine ring are bridged via an ethylene linker so that the modified group forms a nonplanar structure with the cytosine ring. The fluorescent study of dChpd indicated that the coplanar structure between the carbamoyl group and the cytosine ring is of importance. N-Methylation of the carbamoyl group (dCmpp) weakened the intensity of the fluorescence of dChpp, and the derivative (dCtpp), which had a thiocarbamoyl group, lost its fluorescent property. Moreover, addition of a pyrrolo-ring (dCppp) to dChpp enhanced the intensity of fluorescence, and an emission light was observed with a marked Stokes shift of 120 nm.