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Cardiovascular and cancer mortality among Canadians of European, south Asian and Chinese origin from 1979 to 1993: an analysis of 1.2 million deaths.

BACKGROUND: Cardiovascular disease and cancer are important health problems worldwide, yet our knowledge of these conditions is derived principally from populations of European descent. To investigate ethnic variations in major causes of death in Canada, the authors examined total and cause-specific mortality among European, south Asian, and Chinese Canadians. METHODS: Canadians of European, south Asian and Chinese origin were identified in the Canadian Mortality Database by last name and country of birth and in the population census by self-reported ethnicity. Age-standardized death rates by cause, per 100,000 population, were calculated for ages 35 to 74 years from 1979 to 1993 and in 5-year intervals grouped around census years (1979/83, 1984/88 and 1989/93). RESULTS: Rates of death from ischemic heart disease were highest among Canadians of south Asian origin (men 320.2, women 144.5) and European origin (men 319.6, women 109.9) and were markedly lower among Canadians of Chinese origin (men 107.0, women 40.0); the rates declined significantly in all 3 groups over the study period. Rates of death from cerebrovascular disease were relatively low and showed less ethnic variation (Canadian men of European, south Asian and Chinese origin 49.5, 47.0 and 45.8 respectively; Canadian women of European, south Asian and Chinese origin 34.8, 39.0 and 42.2 respectively) and declined similarly in all groups over time. Rates of death from cancer were highest among Canadians of European origin (men 343.6, women 236.2), intermediate among those of Chinese origin (men 258.1, women 161.6) and lowest among those of south Asian origin (men 122.3, women 131.3). Over time, cancer mortality increased in Canadians of European origin but remained constant or declined in those of south Asian and Chinese origin. INTERPRETATION: Substantial differences exist in rates of death from ischemic heart disease and cancer among European, south Asian and Chinese Canadians.

Adult↗

[A study on the origins of 'Korean ginseng'].

Generally, the originating area of ginseng is known to be in Shangdang, China. The originating time, which has been estimated according to textual and archeological outcomes, is known to be the first century B.C., during the Han dynasty era. This can be referred to as the 'Chinese origin theory of ginseng'. According to such hypothesis, the Chinese only discovered ginseng 'suddenly' during this time when it should have been self-generating for thousands of years before. However, Shangdang has been one of the historic centers of China since the ancient period and specially took prominence in terms of the beginning and development of Chinese pharmaceutics, which makes this theory largely dismissable. Moreover, there were six characters that expressed at the early stage and were used together with each other up to the days of Ming and Qing dynasty. Also, this theory did not explain clearly about the formation of ginseng character. Hence, it is fairly obvious that the 'Chinese origin theory of ginseng' do not answer appropriately to the fundamental questions of the origin of ginseng. In order to approach such mystery , perspectives need to be newly shifted to the 'outer origins' of Chinese ginseng. In this case. 'outer' only points to Manchuria and Korea, since these areas are the only candidates regarding the natural circumstances of ginseng growth. So, it can be inferred that ginseng has first been identified with the locals of Manchuria and Korea, and then underwent influx to China to have been used as a medicinal stuff. Following such theory, the reason why ginseng suddenly appeared in Han China was that around this period, specially during the Han commandery epoch, it had just been introduced to China as a part of Korean culture. Also the reason there are many characters can be said that the sound of indigenous Korean 'sim' was considered in respect to selecting similarly-articulated words. Reaching such conclusion, the formating principle of can be no other than borrowing -sound character. To summarize our discussion, it is still unknown when was the actual origin of genseng but it was far earlier than two thousand years ago as was previously accepted as the origin of this medicine plant. . The originating place was not Shangdang of Shansi area of China as was commonly accepted, but Manchuria and Korea. Then, ginseng must have been known and utilized by the locals of these areas. This is 'Korean origin theory of ginseng' and simultaneously an indirect examination of the origin of 'Korean ginseng.'

China↗

Regulation of DNA-replication origins during cell-cycle progression.

We have shown previously that chromosome VI of Saccharomyces cerevisiae contains nine origins of DNA replication that differ in initiation frequency and replicate sequentially during the S phase of the cell cycle. Here we show that there are links between activation of these multiple origins and regulation of S-phase progression. We study the effects of a DNA-damaging agent, methyl methane sulphonate (MMS), and of mutations in checkpoint genes such as rad53 on the activity of origins, measured by two-dimensional gel analysis, and on cell-cycle progression, measured by fluorescence-activated cell sorting. We find that when MMS slows down S-phase progression it also selectively blocks initiation from late origins. A rad53 mutation enhances late and/or inefficient origins and releases the initiation block by MMS. Mutation of rad53 also results in a late origin becoming early replicating. We conclude that rad53 regulates the timing of initiation of replication from late origins during normal cell growth and blocks initiation from late origins in MMS-treated cells. rad53 is, therefore, involved in the cell's surveillance of S-phase progression. We also find that orc2, which encodes subunit 2 of the origin-recognition complex, is involved in suppression of late origins.

Cell Cycle↗

DnaA boxes in the P1 plasmid origin: the effect of their position on the directionality of replication and plasmid copy number.

The DnaA protein is essential for initiation of DNA replication in a wide variety of bacterial and plasmid replicons. The replication origin in these replicons invariably contains specific binding sites for the protein, called DnaA boxes. Plasmid P1 contains a set of DnaA boxes at each end of its origin but can function with either one of the sets. Here we report that the location of origin-opening, initiation site of replication forks and directionality of replication do not change whether the boxes are present at both or at one of the ends of the origin. Replication was bidirectional in all cases. These results imply that DnaA functions similarly from the two ends of the origin. However, origins with DnaA boxes proximal to the origin-opening location opened more efficiently and maintained plasmids at higher copy numbers. Origins with the distal set were inactive unless the adjacent P1 DNA sequences beyond the boxes were included. At either end, phasing of the boxes with respect to the remainder of the origin influenced the copy number. Thus, although the boxes can be at either end, their precise context is critical for efficient origin function.

Bacterial Proteins↗

Replication origins in Xenopus egg extract Are 5-15 kilobases apart and are activated in clusters that fire at different times.

When Xenopus eggs and egg extracts replicate DNA, replication origins are positioned randomly with respect to DNA sequence. However, a completely random distribution of origins would generate some unacceptably large interorigin distances. We have investigated the distribution of replication origins in Xenopus sperm nuclei replicating in Xenopus egg extract. Replicating DNA was labeled with [(3)H]thymidine or bromodeoxyuridine and the geometry of labeled sites on spread DNA was examined. Most origins were spaced 5-15 kb apart. This regular distribution provides an explanation for how complete chromosome replication can be ensured although origins are positioned randomly with respect to DNA sequence. Origins were grouped into small clusters (typically containing 5-10 replicons) that fired at approximately the same time, with different clusters being activated at different times in S phase. This suggests that a temporal program of origin firing similar to that seen in somatic cells also exists in the Xenopus embryo. When the quantity of origin recognition complexes (ORCs) on the chromatin was restricted, the average interorigin distance increased, and the number of origins in each cluster decreased. This suggests that the binding of ORCs to chromatin determines the regular spacing of origins in this system.

Animals↗

DNA replication origins fire stochastically in fission yeast.

DNA replication initiates at discrete origins along eukaryotic chromosomes. However, in most organisms, origin firing is not efficient; a specific origin will fire in some but not all cell cycles. This observation raises the question of how individual origins are selected to fire and whether origin firing is globally coordinated to ensure an even distribution of replication initiation across the genome. We have addressed these questions by determining the location of firing origins on individual fission yeast DNA molecules using DNA combing. We show that the firing of replication origins is stochastic, leading to a random distribution of replication initiation. Furthermore, origin firing is independent between cell cycles; there is no epigenetic mechanism causing an origin that fires in one cell cycle to preferentially fire in the next. Thus, the fission yeast strategy for the initiation of replication is different from models of eukaryotic replication that propose coordinated origin firing.

DNA Replication↗

DNA replication origin interference increases the spacing between initiation events in human cells.

Mammalian DNA replication origins localize to sites that range from base pairs to tens of kilobases. A regular distribution of initiations in individual cell cycles suggests that only a limited number of these numerous potential start sites are converted into activated origins. Origin interference can silence redundant origins; however, it is currently unknown whether interference participates in spacing functional human initiation events. By using a novel hybridization strategy, genomic Morse code, on single combed DNA molecules from primary keratinocytes, we report the initiation sites present on 1.5 Mb of human chromosome 14q11.2. We confirm that initiation zones are widespread in human cells, map to intergenic regions, and contain sequence motifs found at other mammalian initiation zones. Origins used per cell cycle are less abundant than the potential sites of initiation, and their limited use increases the spacing between initiation events. Between-zone interference decreases in proportion to the distance from the active origin, whereas within-zone interference is 100% efficient. These results identify a hierarchical organization of origin activity in human cells. Functional origins govern the probability that nearby origins will fire in the context of multiple potential start sites of DNA replication, and this is mediated by origin interference.

Base Pairing↗

Roles for internal and flanking sequences in regulating the activity of mating-type-silencer-associated replication origins in Saccharomyces cerevisiae.

ARS301 and ARS302 are inactive replication origins located at the left end of budding yeast (Saccharomyces cerevisiae) chromosome III, where they are associated with the HML-E and -I silencers of the HML mating type cassette. Although they function as replication origins in plasmids, they do not serve as origins in their normal chromosomal locations, because they are programmed to fire so late in S phase that they are passively replicated by the replication fork from neighboring early-firing ARS305 before they have a chance to fire on their own. We asked whether the nucleotide sequences required for plasmid origin function of these silencer-associated chromosomally inactive origins differ from the sequences needed for plasmid origin function by nonsilencer-associated chromosomally active origins. We could not detect consistent differences in sequence requirements for the two types of origins. Next, we asked whether sequences within or flanking these origins are responsible for their chromosomal inactivity. Our results demonstrate that both flanking and internal sequences contribute to chromosomal inactivity, presumably by programming these origins to fire late in S phase. In ARS301, the function of the internal sequences determining chromosomal inactivity is dependent on the checkpoint proteins Mec1p and Rad53p.

Cell Cycle Proteins↗

OriDB: a DNA replication origin database.

Replication of eukaryotic chromosomes initiates at multiple sites called replication origins. Replication origins are best understood in the budding yeast Saccharomyces cerevisiae, where several complementary studies have mapped their locations genome-wide. We have collated these datasets, taking account of the resolution of each study, to generate a single list of distinct origin sites. OriDB provides a web-based catalogue of these confirmed and predicted S.cerevisiae DNA replication origin sites. Each proposed or confirmed origin site appears as a record in OriDB, with each record comprising seven pages. These pages provide, in text and graphical formats, the following information: genomic location and chromosome context of the origin site; time of origin replication; DNA sequence of proposed or experimentally confirmed origin elements; free energy required to open the DNA duplex (stress-induced DNA duplex destabilization or SIDD); and phylogenetic conservation of sequence elements. In addition, OriDB encourages community submission of additional information for each origin site through a User Notes facility. Origin sites are linked to several external resources, including the Saccharomyces Genome Database (SGD) and relevant publications at PubMed. Finally, a Chromosome Viewer utility allows users to interactively generate graphical representations of DNA replication data genome-wide. OriDB is available at www.oridb.org.

Chromosomes, Fungal↗

The chromosome partitioning proteins Soj (ParA) and Spo0J (ParB) contribute to accurate chromosome partitioning, separation of replicated sister origins, and regulation of replication initiation in Bacillus subtilis.

Soj (ParA) and Spo0J (ParB) of Bacillus subtilis belong to a conserved family of proteins required for efficient plasmid and chromosome partitioning in many bacterial species. Unlike most Par systems, for which intact copies of both parA and parB are required for the Par system to function, inactivating soj does not cause a detectable chromosome partitioning phenotype whereas inactivating spo0J leads to a 100-fold increase in the production of anucleate cells. This suggested either that Soj does not function like other ParA homologues, or that a cellular factor might compensate for the absence of soj. We found that inactivating smc, the gene encoding the structural maintenance of chromosomes (SMC) protein, unmasked a role for Soj in chromosome partitioning. A soj null mutation dramatically enhanced production of anucleate cells in an smc null mutant. To look for effects of a soj null on other phenotypes perturbed in a spo0J null mutant, we analysed replication initiation and origin positioning in (soj-spo0J)+, Deltasoj, Deltaspo0J and Delta(soj-spo0J) cells. All of the mutations caused increased initiation of replication and, to varying extents, affected origin positioning. Using a new assay to measure separation of the chromosomal origins, we found that inactivating soj, spo0J or both led to a significant defect in separating replicated sister origins, such that the origins remain too close to be spatially resolved. Separation of a region outside the origin was not affected. These results indicate that there are probably factors helping to pair sister origin regions for part of the replication cycle, and that Soj and Spo0J may antagonize this pairing to contribute to timely separation of replicated origins. The effects of Deltasoj, Deltaspo0J and Delta(soj-spo0J) mutations on origin positioning, chromosome partitioning and replication initiation may be a secondary consequence of a defect in separating replicated origins.

Bacillus subtilis↗

DnaB helicase is unable to dissociate RNA-DNA hybrids. Its implication in the polar pausing of replication forks at ColE1 origins.

A series of plasmids were constructed containing two unidirectional ColE1 replication origins in either the same or opposite orientations and their replication mode was investigated using two-dimensional agarose gel electrophoresis. The results obtained showed that, in these plasmids, initiation of DNA replication occurred at only one of the two potential origins per replication round regardless of origins orientation. In those plasmids with inversely oriented origins, the silent origin act as a polar pausing site for the replication fork initiated at the other origin. The distance between origins (up to 5.8 kilobase pairs) affected neither the interference between them to initiate replication nor the pausing function of the silent origin. A deletion analysis indicated that the presence of a transcription promoter upstream of the origin was the only essential requirement for it to initiate replication as well as to account for its polar pausing function. Finally, in vitro helicase assays showed that Escherichia coli DnaB is able to melt DNA-DNA homoduplexes but is very inefficient to unwind RNA-DNA hybrids. Altogether, these observations strongly suggest that replication forks pause at silent ColE1 origins due to the inability of DnaB helicase, which leads the replication fork in vivo, to unwind RNA-DNA hybrids.

Autoradiography↗

Roles of a 106-bp origin enhancer and Escherichia coli DnaA protein in replication of plasmid R6K.

A dnaA 'null' strain could not support replication of intact plasmid R6K or derivatives containing combinations of its three replication origins (alpha, gamma, beta). DnaA binds in vitro to sites in two functionally distinct segments of the central gamma origin. The 277-bp core segment is common to all three origins and contains DnaA box 2, which cannot be deleted without preventing replication. Immediately to the left of the core lies the 106-bp origin enhancer, which contains DnaA box 1. When the origin enhancer is deleted, the core alone can still initiate replication if levels of wt pi protein are decreased or if copy-up pi mutant proteins are provided in trans. DnaA does not effect expression of R6K replication initiator protein pi, although several DnaA boxes were identified in the coding segment of the pir gene, which encodes pi. Together these data suggest that a single DnaA box, 2, is sufficient for initiation from the gamma origin and might be sufficient for initiation from the gamma origin and might be sufficient and required for the activity of the alpha and beta origins as well. Implications of the DnaA protein binding to two domains of the gamma origin and the role of the 106-bp origin enhancer in replication are discussed.

Bacterial Proteins↗

Dorsal nerve root origins of the cutaneous nerves of the feline pelvic limb.

The dorsal root origins of cutaneous nerves supplying the feline pelvic limb were determined electrophysiologically in 11 cats. Cutaneous nerves were surgically exposed and the presence or absence of an evoked potential in response to stimulation of individual dorsal roots was noted. The dorsal cutaneous branches of L3-L5 and S3, and the lateral cutaneous branch of L3 each arose solely from their parent spinal nerves. The L7, S1, and S2 dorsal cutaneous branches had multiple dorsal root origins. The lateral cutaneous femoral nerve originated from L3-L6 dorsal roots in 4 patterns of origin, and the saphenous nerve originated from L4-L6 dorsal roots in 2 patterns of origin. The lateral and caudal cutaneous sural nerves originated from L6-S1 roots in 2 and 3 patterns, respectively. The lateral and medial plantar nerves arose from L6-S2 roots in 4 and 2 patterns, respectively. The superficial and deep peroneal nerves originated from L6-S1 roots in 2 and 3 patterns, respectively. The caudal cutaneous femoral nerve or its branches arose from L7-S3 in 8 origin patterns. The dorsal nerve of the penis and the superficial perineal nerve arose from L7-S3 and S1-S3 roots, respectively, each in 4 patterns. A subtle correlation between plexus type and dorsal root origins of the cutaneous nerves was noted.

Animals↗

Intractable seizures of frontal lobe origin: clinical characteristics, localizing signs, and results of surgery.

PURPOSE: We analyzed the clinical characteristics of seizures of frontal lobe (FL) origin with particular emphasis on establishing different categories and determining if these categories had any localizing or lateralizing value. In addition, results of surgery are reported. METHODS: Seizure characteristics were established by historical review and electroencephalographic/videotape analysis of 449 seizures in 26 adult patients with refractory seizures of FL origin. RESULTS: No outstanding risk factor was identified for seizures of FL origin. Seizures were frequent (7.1 per week), brief (mean duration, 48.3 seconds), and had a nocturnal preponderance in 58% of the patients. Status epilepticus was reported in 54%, and generalized convulsions as a prominent seizure type were reported in 26% of patients. The most common reported aura was a nonspecific sensation, often localized to the head (35%). Early forced head and eye deviation was not a consistent lateralizing sign, whereas late head and eye deviation always occurred contralateral to the site of seizure origin. Early asymmetric tonic posturing occurred consistently contralateral to the side of seizure origin. Clinical seizure patterns did not consistently localize to specific regions of the frontal lobe, although there were some noticeable trends: focal clonic seizures were associated with seizure origin in the frontal convexity; tonic seizures were most often associated with origin in the supplementary motor area but also occurred with origin in other parts of the frontal lobe; seizures resembling typical temporal lobe seizures with oroalimentary automatisms were observed with seizure origin in the orbitofrontal region; and seizures with hyperactive, frenetic automatisms were not associated with any specific region within the frontal lobes. Eighty percent of patients had favorable seizure outcome after surgery (class I/II). CONCLUSION: Although certain clinical features are characteristic for seizures of frontal lobe origin and some have lateralizing value, they do not localize to specific areas within the FL. After careful presurgical evaluation, both lesional and nonlesional patients benefit from epilepsy surgery.

Age of Onset↗

Analysis of features contributing to activity of the single-stranded origin of Bacillus plasmid pBAA1.

The features which contribute to the activity of the single-stranded origin of the Bacillus plasmid pBAA1 were investigated. This origin is contained on a DNA fragment greater than 116 but less than 191 bases in size. There is the potential to form three stem-loop structures within this fragment. Comparison of the sequence of this origin from pBAA1 with the sequence of a homologous fragment from the Bacillus thuringiensis plasmid pGI2 indicates that both the structure and the relative positioning of the predicted stem-loops are important for origin activity. Deletion analysis suggests that it is the structure of stem-loop III which is important, because it can be replaced by a nonrelated dyad element without significant loss of origin activity. Three sequence motifs are conserved between the origins from pBAA1 and pGI2. Mutation of motif 1 leads to attenuation of single-stranded origin activity. A second motif (motif 3) shares significant homology with a group of single-strand initiation (ssi) sites found on plasmids isolated from Escherichia coli, suggesting that it also contributes to single-stranded origin activity. Our results also indicate that RNA polymerase is utilized to synthesize the RNA primer at the pBAA1 single-stranded origin and that this origin can function in both Bacillus subtilis and Staphylococcus aureus.

Bacillus subtilis↗

Analysis of origin of DNA replication of human papovavirus BK.

We have analyzed the cis-acting sequence elements and properties of the origin of DNA replication of human papovavirus BK (BKV). The precise boundaries of the origin varied, depending on the cell type and the viral T antigen used for assay. The BKV minimal origin of replication consisted of an inverted repeat, T-antigen-binding site II, and a 20-base-pair AT block when assayed in monkey kidney CV1 and HeLa cells by using the BKV T antigen. This 76-base-pair minimal origin did not replicate in COS cells in the presence of the simian virus 40 (SV40) T antigen. Unlike that from the SV40 minimal origin, replication from the BKV minimal origin was not enhanced by BKV ori-flanking sequences in CV1 or HeLa cells, using the BKV T antigen. BKV ori-flanking sequences did activate the SV40 minimal origin of replication in COS cells and relieved the orientation-dependent property of this origin. Finally, the BKV T antigen was found to autoregulate activity of the BKV early transcriptional regulatory region. The BKV origin of replication shows similarities to and differences from those of the related viruses SV40 and polyomavirus, suggesting that the proteins involved in the initiation of replication interact with origin sequences differently in these viruses.

Animals↗

Cloning, sequencing, and functional analysis of a Marek's disease virus origin of DNA replication.

Previously, we isolated a replicon from a defective Marek's disease virus (MDV), analogous to defective herpes simplex viruses (amplicons). Defective viruses contain cis-acting elements required for DNA synthesis and virus propagation such as an origin of DNA replication and a packaging-cleavage signal site. In this report, the MDV replicon was utilized to locate an origin of MDV DNA replication. A comparison of MDV replicon sequences with other herpesvirus replication origin sequences revealed a 90-bp sequence containing 72% identity to the lytic origin (oris) of herpes simplex virus type 1. This 90-bp sequence displayed no similarity to betaherpesvirus or gammaherpesvirus replication origins. The 90-bp sequence is arranged as an imperfect palindrome centered around an A+T-rich region. This sequence also contains a 9-bp motif (5'CGTTCGCAC3') highly conserved in alphaherpesvirus replication origins. To test functionality of the 90-bp putative MDV replication origin, we conducted DpnI replication assays with subclones generated from the 4-kbp MDV replicon. A 700-bp MDV replicon subfragment containing the 90-bp putative MDV replication origin sequence is capable of replicating in chicken embryo fibroblast cells cotransfected with helper virus DNA. In conclusion, we identified a functional origin of DNA replication in MDV. Similarity of MDV origin sequences to those of alphaherpesviruses supports the current contention that MDV is more closely related to alphaherpesviruses than to gammaherpesviruses.

Animals↗

Coronary arterial origins in transposition of the great arteries: factors that affect outcome. A morphological and clinical study.

OBJECTIVE: Transfer of the coronary arteries is crucial during the arterial switch operation for transposition, but little attention has been paid to the position of their orifices relative to the valvar sinuses. The objective of this study was to determine the factors which are important for effective transfer and to determine potential surgical significance. DESIGN: Morphological and clinical study. SETTING: Two national centres for neonatal cardiac surgery. PATIENTS: 277 patients with transposition of the great arteries. One group comprised 88 necropsy specimens (ages ranging from 17 weeks of fetal life to 17 years old), and the other comprised 189 children undergoing surgery. The coronary artery orifices were inspected relative to the depth of the aortic sinuses (vertical origin), relative to the commissures between the valvar leaflets (radial origin), and their angle of exit from the aortic wall (angle of origin). The data were compared with the surgical results. RESULTS: In the necropsy specimens, the vertical origin of the arteries was at, or above, the sinutubular junction in 20%, the radial origin was paracommissural in 3%, and the angle of origin was not orthogonal in 7%. Those with high take off and paracommissural origin were all intramural. In the clinical cases, those children with high take off, paracommissural origin or tangential origin had an increased risk at surgery. CONCLUSIONS: In 20% of hearts, high take off, paracommissural orifice, or tangential origin of coronary arteries is found. This may be recognised preoperatively by echocardiography and may cause technical difficulty in transfer during the arterial switch procedure.

Child↗