DNA replication is spatially and temporally regulated during S‐phase. DNA replication timing is established in early‐G1‐phase at a point referred to as timing decision point. However, how the ...genome‐wide replication timing domains are established is unknown. Here, we show that Rif1 (Rap1‐interacting‐factor‐1), originally identified as a telomere‐binding factor in yeast, is a critical determinant of the replication timing programme in human cells. Depletion of Rif1 results in specific loss of mid‐S replication foci profiles, stimulation of initiation events in early‐S‐phase and changes in long‐range replication timing domain structures. Analyses of replication timing show replication of sequences normally replicating early is delayed, whereas that normally replicating late is advanced, suggesting that replication timing regulation is abrogated in the absence of Rif1. Rif1 tightly binds to nuclear‐insoluble structures at late‐M‐to‐early‐G1 and regulates chromatin‐loop sizes. Furthermore, Rif1 colocalizes specifically with the mid‐S replication foci. Thus, Rif1 establishes the mid‐S replication domains that are restrained from being activated at early‐S‐phase. Our results indicate that Rif1 plays crucial roles in determining the replication timing domain structures in human cells through regulating higher‐order chromatin architecture.
The homologue of the yeast telomeric protein Rif1 regulates the complex temporal programme of human genome replication, possibly controlling chromatin domain establishment at the G1 ‘timing decision point’
DNA replication is central to cell proliferation. Studies in the past six decades since the proposal of a semiconservative mode of DNA replication have confirmed the high degree of conservation of ...the basic machinery of DNA replication from prokaryotes to eukaryotes. However, the need for replication of a substantially longer segment of DNA in coordination with various internal and external signals in eukaryotic cells has led to more complex and versatile regulatory strategies. The replication program in higher eukaryotes is under a dynamic and plastic regulation within a single cell, or within the cell population, or during development. We review here various regulatory mechanisms that control the replication program in eukaryotes and discuss future directions in this dynamic field.
Background
This study assessed the psychometric profile of 10 questionnaires (every 6 months, from 6 to 60 months) from the Japanese translation of the Ages and Stages Questionnaires, third edition ...(J‐ASQ‐3).
Methods
Data from 439 children in a birth cohort were used to identify the J‐ASQ‐3 score distribution, establish cut‐off scores, and calculate the instrument's internal consistency. Data were also collected from 491 outpatients to examine J‐ASQ‐3 test–retest reliability and concurrent validity, which was examined using the Kyoto Scale of Psychological Development (KSPD) and the Japanese version of the Denver Developmental Screening Test II (J‐Denver II). Both the original and the alternative screening criteria of the ASQ‐3 were used (failure in at least one and at least two domains, respectively).
Results
Cronbach's alpha for each J‐ASQ‐3 subscale on each questionnaire ranged from 0.45 to 0.89. Test–retest reliability was >0.75 for the subscales on almost all questionnaires. Concurrent validity was also adequate. In comparison with the screening results of the KSPD, the overall sensitivity and specificity were 96.0% and 48.8%, respectively, when the ASQ‐3 original criterion was used, and 92.1% and 74.9%, respectively, when the alternative criterion was used. In comparison with the screening results of the J‐Denver II, the overall sensitivity and specificity were 75.6% and 74.7%, respectively, when the ASQ‐3 original criterion was used, and 56.3% and 93.0%, respectively, when the alternative criterion was used.
Conclusions
This study quantified the psychometric profiles of the Japanese translations of 10 ASQ‐3 questionnaires. We demonstrated the validity of the J‐ASQ‐3 and determined new cut‐off scores. Further studies with larger samples from a greater range of locations are required to clarify the suitability of this tool for all Japanese children.
Antinuclear antibodies (ANAs) are detected in healthy individuals, they are more prevalent in women than in men. Pregnant women are immunologically unique, but epidemiological data on ANA positivity ...in them remain limited. The exposure received from the mother during the fetal period impacts the future health of the fetus and has thus received increased attention in recent years. Thus, we investigated the association between ANA positivity and chemical exposure among pregnant Japanese women, registered in the Japan Environment and Children's Study (JECS). ANA titers were assessed by indirect immunofluorescence with HEp-2 cells at a cutoff dilution of 1:40. Sociodemographic and other data were obtained in the JECS from a self-administered questionnaire. We analyzed 1,235 Japanese women in their first trimester of pregnancy. The ANA prevalence was 17.2%. Among ANA-positive women, a speckled pattern was the most common (95.3%), followed by a homogeneous pattern (72.3%). Exposure to chemicals more than once a week significantly increased the probability of ANA positivity (kerosene, petroleum, benzene, or gasoline: adjusted odds ratio AOR, 2.11; 95% confidence interval 95% CI, 1.03–4.34; chlorine bleach or germicide: AOR, 1.97; 95% CI, 1.10–3.54; organic solvents: AOR, 5.34; 95% CI, 1.40–20.36; and photocopying machines or laser printers: AOR, 1.73; 95% CI, 1.17–2.54). ANA positivity was associated with exposure to several chemicals in Japanese women. Our exploratory results suggested that ANAs as potential markers of chemical exposure warrant further research.
The objective of this study was to evaluate the interactions between various drugs and aojiru (green juice), a popular health food in Japan, using a simple centrifugation method. The mixture of drug ...solution and aojiru suspension was gently shaken and centrifuged. The drug concentration in the supernatant fluid was then determined by HPLC. The concentration of rhodamine 123 (Rho-123), a model compound, in the supernatant fluid significantly decreased after mixing with aojiru, indicating extensive binding of Rho-123 to the insoluble components of aojiru. When administered into rat small intestinal loops together with aojiru, the plasma Rho-123 concentrations became much smaller than those when administered alone. This result strongly suggested that a strong interaction observed in vitro was well reflected in modulated absorption. Among seven drugs tested, chlorpromazine and imipramine exerted binding properties to aojiru similar to or greater than Rho-123. As a small part of both Rho-123 and imipramine was released when the aojiru precipitate was resuspended, their binding to aojiru was considered to be tight. The binding of diltiazem, fexofenadine, glibenclamide, metformin, and norfloxacin to aojiru was much weaker or almost negligible compared with that of chlorpromazine and imipramine. The present results suggest that aojiru can decrease the intestinal absorption of some clinically relevant drugs through tight binding in the small intestine and that the present centrifugation method is useful for predicting in vivo interactions between drugs and aojiru.
Currently, various hyperphosphatemia drugs are administered orally to hemodialysis patients in order to lower serum phosphorus levels. However, it is known that medication adherence is poor, possibly ...due to greater pill burden taken each time and their complicated schedules. Therefore, large amounts of unused hyperphosphatemia drugs are likely to be leftover. The increase in leftover prescribed drugs leads to the unnecessary elevation of medical care costs. To date, however, the available information on leftover hyperphosphatemia drugs in hemodialysis outpatients is limited. In this study, we performed an interview survey of medication adherence to hyperphosphatemia drugs among 60 hemodialysis outpatients and evaluated the cost of the leftover drugs. Thirty-four patients showed good adherence. On the other hand, 19 patients self-adjusted to take hyperphosphatemia drugs according to their daily diet. When assessing the serum phosphorus levels for these patients over the past year, the values often exceeded the targeted range (3.5-6.0mg/mL). Furthermore, 35 patients kept hyperphosphatemia drugs at their home. When estimating the cost derived from leftover drugs using the bootstrap method, main distribution of drug cost was shown to be in the range of 2000 to 2500 yen. This drug cost seemed to in part reflect preparation for an emergency. A serious problem was that 14 patients had previous experience in discarding hyperphosphatemia drugs. This study suggested that more appropriate pharmaceutical care according to each patient's situation is essential in improving phosphorus control in hemodialysis outpatients and in reducing the waste of medical resources.
The relationship between allergic individuals and their responsiveness to routine vaccines has rarely been investigated. This study examined whether the seroprevalence of measles antibody differed ...between children with and without allergic diseases in the general pediatric population. The cross-sectional study was performed within a prospective general birth cohort (a pilot study of the Japan Environment & Children's Pilot Study JECS) of children aged 8 years. The clinical history of allergic diseases, measles, and the concentration of measles immunoglobulin G titers in serum enzyme immunoassay were examined. Fisher's exact tests were used to assess the relationships between the allergic characteristics of the children and their measles antibody positivity rates. This study included 162 children. Any allergic disease was reported in 75 (46.3%). The measles antibody positivity rate was 94.7% among children with any allergic diseases and 92.0% among children without allergic diseases. Our results revealed no differences in measles antibody seropositivity between children with allergies and controls. Children with allergies mount and maintain a comparable immune response to the measles vaccine.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Vitamin D is essential for calcium absorption and bone homeostasis. Although short-stature children were reported to have low vitamin D concentrations, there is no clear evidence of a link between ...vitamin D and height growth in young children not limited to those with short stature. We collected height and weight data at 2 and 4 years of age, serum vitamin D concentrations at 4 years, and questionnaire results on sun exposure from the Japan Environment and Children’s Study (JECS). We then analyzed the relationship between vitamin D deficiency and height growth. We also analyzed the correlation between serum vitamin D concentration and sun exposure. Overall, 3624 participants from JECS were analyzed. We identified cases of subclinical vitamin D deficiency and insufficiency. We further found that definitive vitamin D deficiency (<10 ng/mL) impaired height growth by 0.6 cm per year even in young children not limited to those with short stature. Furthermore, we clarified that children with vitamin D deficiency had reduced outdoor activity, especially during winter. In children with either short or normal stature, definitive vitamin D deficiency was associated with height growth decline, and reduction in outdoor activity, especially during winter, was a risk factor for vitamin D deficiency.
Several scoring methods for the Mediterranean diet, which is considered as a healthy diet, are available, but studies that have compared more than one of these scores are rare. In addition, the ...applicability of Mediterranean diet scoring has not been sufficiently examined outside of Mediterranean regions. We collected data on the Mediterranean diet during pregnancy and the incidence of type 1 allergies in offspring from the Japan Environment and Children's Study. Using multiple Mediterranean diet scoring methods, we analyzed the effect of adherence to the Mediterranean diet in pregnancy on the allergies of the offspring. Overall, 46,532 pairs of mothers and children were analyzed. In Japan, a high adherence to the Mediterranean diet during pregnancy was associated with a lower incidence of asthma in the offspring (odds ratio: 0.896, 95% confidence interval: 0.835, 0.962). Furthermore, we found that the selection of the Mediterranean diet scoring method and the setting of the reference value significantly altered the results. Our findings suggest that an appropriate selection of scoring methods and a reference value for food items are important to analyze the effects of adherence to the Mediterranean diet inside and outside of Mediterranean regions.
We have determined and compared the promoter, coding, and intronic sequences of the urate oxidase (Uox) gene of various primate species. Although we confirm the previous observation that the ...inactivation of the gene in the clade of the human and the great apes results from a single CGA to TGA nonsense mutation in exon 2, we find that the inactivation in the gibbon lineage results from an independent nonsense mutation at a different CGA codon in exon 2 or from either one-base deletion in exon 3 or one-base insertion in exon 5, contrary to the previous claim that the cause is a 13-bp deletion in exon 2. We also find that compared with other organisms, the primate functional Uox gene is exceptional in terms of usage of CGA codons which are prone to TGA nonsense mutations. Nevertheless, we demonstrate rather strong selective constraint against nonsynonymous sites of the functional Uox gene and argue that this observation is consistent with the fact that the Uox gene is unique in the genome and evolutionarily conserved not only among animals but also among eukaryotes. Another finding that there are a few substitutions in the cis-acting element or CAAT-box (or both) of primate functional Uox genes may explain the lowered transcriptional activity. We suggest that although the inactivation of the hominoid Uox gene was caused by independent nonsense or frameshift mutations, the gene has taken a two-step deterioration process, first in the promoter and second in the coding region during primate evolution. It is also argued that the high concentration of uric acid in the blood of humans and nonhuman primates has developed molecular coevolution with the xanthine oxidoreductase in purine metabolism. However, it remains to be answered whether loss of Uox activity in hominoids is related to protection from oxidative damage and the prolonged life span.
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