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PubMed2001

DNA replication forks pause at silent origins near the HML locus in budding yeast.

Chromosomal replicators in budding yeast contain an autonomously replicating sequence (ARS) that functions in a plasmid, but certain ARSs are silent as replication origins in their natural chromosomal context. In chromosome III, the HML ARS cluster (ARS302-ARS303-ARS320) and ARS301 flank the transcriptionally silent mating-type locus HML, and all of these ARSs are silent as replication origins. ARS301 and ARS302 function in transcriptional silencing mediated by the origin recognition complex (ORC) and a heterochromatin structure, while the functions of ARS303 and ARS320 are not known. In this work, we discovered replication fork pause sites at the HML ARS cluster and ARS301 by analyzing DNA replication intermediates from the chromosome via two-dimensional gel electrophoresis. The replication fork pause at the HML ARS cluster was independent of cis- and trans-acting mutations that abrogate transcriptional silencing at HML. Deletion of the HML ARS cluster led to loss of the pause site. Insertion of a single, heterologous ARS (ARS305) in place of the HML ARS cluster reconstituted the pause site, as did multiple copies of DNA elements (A and B1) that bind ORC. The orc2-1 mutation, known to alter replication timing at origins, did not detectably affect the pause but activated the silent origin at the HML ARS cluster in a minority of cells. Delaying the time of fork arrival at HML led to the elimination of the pause sites at the HML ARS cluster and at the copy of ARS305 inserted in place of the cluster. Loss of the pause sites was accompanied by activation of the silent origins in the majority of cells. Thus, replication fork movement near HML pauses at a silent origin which is competent for replication initiation but kept silent through Orc2p, a component of the replication initiator. Possible functions for replication fork pause sites in checkpoints, S-phase regulation, mating-type switching, and transcriptionally silent heterochromatin are discussed.

DNA Replication↗
PubMed2005

Structure of protonated water clusters: low-energy structures and finite temperature behavior.

The structure of protonated water clusters H+(H2O)n (n=5-22) are examined by two Monte Carlo methods in conjunction with the OSS2 potential [L. Ojamae, I. Shavitt, and S. J. Singer J. Chem. Phys. 109, 5547 (1998)]. The basin-hopping method is employed to explore the OSS2 potential energy surface and to locate low-energy structures. The topology of the "global minimum," the most stable low-energy structure, changes from single ring to multiple ring to polyhedral cage as the cluster size grows. The temperature dependence of the cluster geometry is examined by carrying out parallel tempering Monte Carlo simulations. Over the temperature range we studied (25-330 K), all water clusters undergo significant structural changes. The trends are treelike structures dominating at high temperature and single-ring structures appearing in slightly lower temperatures. For n> or =7, an additional transition from single ring to multiple rings appears as the temperature decreases. Only for n> or =16 do polyhedral structures dominate the lowest temperature range. Our results indicate very dynamic structural changes at temperature range relevant to atmospheric chemistry and current experiments. The structures and properties of medium-sized protonated clusters in this temperature range are far from their global minimum cousins. The relevance of these findings to recent experiments and theoretical simulations is also discussed.

Journal Article↗
PubMed2003

Chi-square test for R x C contingency tables with clustered data.

In ophthalmologic or dental studies, observations are frequently taken from multiple sites (called units), such as eyes or teeth, of each subject. In this case, observations within each subject (called clusters) may be dependent, although those from different subjects are independent. When a categorical observation is made from each site, application of the usual Pearson chi-square tests is invalid since sites within the same subject tend to be dependent. We propose a modified chi2 statistic for testing no treatment effect in these cases. The proposed methods do not require correct specification of the dependence structure within cluster. Simulation studies are conducted to show the finite-sample performance of the new methods. The proposed methods are applied to real-life data.

Animals↗
PubMed2002

Alcohol mortality: a comparison of spatial clustering methods.

The identification of spatial clusters of alcohol mortality can be a key tool in identifying locations that are suffering from alcohol-related problems or are at risk of experiencing those types of problems. This study compares two methods for identifying statistically significant spatial clusters of county-level alcohol mortality rates in New York. One method utilizes a local indicator of spatial association to determine which groups of neighboring counties have rates that are significantly related to each other. The other method is a spatial scan technique that calculates a maximum likelihood ratio of cases relative to the underlying population to identify the group of counties that rejects the null hypothesis of "no clustering". The results show that because each technique bases its cluster detection on its own criteria, different counties are selected by each method. However, the overlap of the selections indicates that the two analytic methods illustrate different elements of the same clusters. Consequently, these spatial analytic techniques are seen as complimentary and are best used in tandem rather than individually. These findings suggest that multiple methods are a preferred approach to identifying clusters of alcohol-related mortality at the county level.

Age Distribution↗
PubMed2006

Symptom clusters in cancer patients.

GOALS OF WORK: Cancer patients often experience multiple symptoms, many of which have been reported to correlate with each other. The goals of this study were to understand which cancer-related symptoms cluster together and to test the conceptual meanings of the revealed symptom clusters. PATIENTS AND METHODS: Patients with various cancer diagnoses (N=151) were recruited from a medical center in northern Taiwan. The 13-item M.D. Anderson symptom inventory was used to assess patients' symptom severity. Selected symptoms were factored using principal-axis factoring with oblique rotation. The known-group technique was used to validate the conceptual meanings of revealed factors. MAIN RESULTS: Patients' symptom severity ratings fit a three-factor solution that explained 55% of the variance. These three factors (symptom clusters) were named sickness symptom cluster, gastrointestinal symptom cluster, and emotional symptom cluster. Patients with pain and with advanced diseases had significantly higher mean scores in the sickness symptom cluster than patients without pain and with earlier-stage diseases. The patients' functional status was negatively correlated with mean scores in the sickness symptom cluster. Patients under chemotherapy demonstrated significantly higher mean scores in the gastrointestinal symptom cluster than patients under other treatments. Patients with anxiety or depression also had significantly higher mean scores in the emotional symptom cluster than patients without anxiety or depression. CONCLUSIONS: This study identified three underlying symptom clusters and verified their conceptual meaning in cancer patients. Knowing these symptom clusters may help healthcare professionals understand plausible mechanisms for the aggregation of symptoms.

Activities of Daily Living↗
PubMed1992

Functional asymmetry of the regions juxtaposed to the membrane-binding sequence of polyomavirus middle T antigen.

The functional importance of the two clusters of positively charged amino acids which flank the hydrophobic membrane-anchoring sequence of polyomavirus middle T (mT) protein has been investigated by using site-directed mutagenesis. A clear asymmetry was apparent. No effect on transformation was seen following multiple alterations or complete removal of the cluster at the carboxyl end of the protein. In contrast, a single substitution replacing the first arginine amino terminal to the hydrophobic stretch with glutamic acid, but not with lysine, histidine, or methionine, produced a partially transformation-defective mutant with a novel phenotype. This mutant failed to confer anchorage-independent growth on F111 established rat embryo fibroblasts but induced foci with altered morphology compared with wild-type mT. Biochemical studies on this mutant revealed that F111 clones expressing levels of mutant mT equivalent to those of wild-type controls showed a 65% reduction in pp60c-src activation and an 87% reduction in mT-associated phosphatidylinositol 3-kinase activity. However, F111 clones expressing seven times more mutant mT than did wild-type controls showed equal or greater levels of kinase activities yet remained incompletely transformed. Possible mechanisms involving this transformation-sensitive region of mT are discussed.

Animals↗
PubMed2000

Structure of the MLT gene and molecular characterization of the genomic breakpoint junctions in the t(11;18)(q21;q21) of marginal zone B-cell lymphomas of MALT type.

The t(11;18)(q21;q21) between the inhibitor of apoptosis API2 and the MLT gene is a distinct feature of marginal zone B-cell lymphomas of MALT-type. Hitherto the chimeric API2-MLT transcripts are all "in-frame" and predominantly fuse exon 7 of API2 to different MLT exons. Recurrent chromosomal translocations are common in lymphoid neoplasms and might represent by-products of the rearrangement processes generating antigen receptor diversity. The genomic structure of the MLT gene was determined to facilitate amplification of the genomic breakpoint junctions from 5 MALT-type lymphomas with t(11;18). Their sequence analysis showed scattering of the chromosome 11 breakpoints in intron 7 of API2 whereas rearrangements in MLT occurred in intron 2, 4, 7, or 8, respectively. Sequences around the junctions did not display recognition signal sequences mediating lymphocytic V(D)J recombination or other sequence motifs associated with recombination. The breakpoints occurred in a copy of an AluSx repeat in three cases, but interchromosomal Alu-mediated homologous recombination could be ruled out as the repeat resided only on one of the participating chromosomes. The t(11;18) was associated with a deletion in 4 out of 5 cases, ranging in size from 53 bp up to more than 200 kb. These deletions were observed on one or sometimes both derivative chromosomes that might indicate the susceptibility of these regions for breakage. Our data suggest that the API2-MLT fusion might result from a non-homologous end joining event after multiple double-strand breaks. The clustering of breaks in intron 7 of API2 and the consistent "in frame" API2-MLT fusions could therefore reflect certain functional constraints crucial for clonal outgrowth.

Apoptosis↗
PubMed2005

Two major spondylarthropathy phenotypes are distinguished by pattern analysis in multiplex families.

OBJECTIVE: To examine whether spondylarthropathy (SpA) disease manifestations would combine in any ordered pattern among patients from SpA multiplex families. METHODS: SpA patients (n = 540) belonging to 190 multiplex families were thoroughly investigated. Clinical data was collected, systematic pelvic radiographs were taken, and HLA-B27 status was determined. The patterns of SpA manifestations were examined by several methods, including multiple correspondence analysis, nonhierarchical and hierarchical clustering, and discriminant analysis. RESULTS: The nonhierarchical cluster analysis allowed us to classify patients, independent of disease duration, into 2 major groups of comparable size. Group A contained a majority of the women, whereas group B predominantly consisted of men. The 2 groups were very similar regarding axial symptoms, radiographic sacroiliitis, and uveitis. Group B was characterized by a younger age at onset and a higher frequency of clinical enthesitis, peripheral arthritis, dactylitis, psoriasis, and inflammatory bowel disease than group A. Patients belonging to those groups exhibited some degree of familial aggregation, thereby supporting their intrinsic validity. CONCLUSION: Pattern analysis of SpA manifestations among familial SpA allowed us to recognize 2 main clusters independent of disease duration. Furthermore, there was a trend toward aggregation by cluster among families, suggesting that they are determined by specific genetic factors. These clusters may indeed correspond to different severity patterns.

Adolescent↗
PubMed2004

Distribution of trigeminothalamic and spinothalamic lamina I terminations in the macaque monkey.

Thalamic terminations from trigeminal, cervical, and lumbosacral lamina I neurons were investigated with Phaseolus vulgaris leucoagglutinin (PHA-L) and labeled dextrans. Iontophoretic injections guided by physiological recordings were restricted to lamina I or laminae I-II. PHA-L-labeled trigemino- and spinothalamic (TSTT) terminations were identified immunohistochemically. TRITC- and FITC-labeled dextrans were injected at different levels to confirm topography. Terminations consistently occurred in two main locations: a distinguishable portion of posterolateral thalamus identified cytoarchitectonically as the posterior part of the ventral medial nucleus (VMpo) and a portion of posteromedial thalamus designated as the ventral caudal part of the medial dorsal nucleus (MDvc). In addition, isolated fibers bearing boutons of passage were observed in the ventral posterior medial and lateral (VPM and VPL) nuclei, and spinal terminations occurred in the ventral posterior inferior nucleus (VPI). Isolated terminations occasionally occurred in other sites (e.g., suprageniculate, zona incerta, hypothalamic paraventricular n.). Terminations in MDvc occurred in concise foci that were weakly organized topographically (posteroanterior = rostrocaudal). Terminations in VMpo consisted of dense clusters of ramified terminal arbors bearing multiple large boutons that were well organized topographically (anteroposterior = rostrocaudal). Terminations in VMpo colocalized with a field of calbindin-immunoreactive terminal fibers; double-labeled terminals were documented at high magnification. This propitious marker was especially useful at anterior levels, where VMpo can easily be misidentified as VPM. These findings demonstrate phylogenetically novel primate lamina I TSTT projections important for sensory and motivational aspects of pain, temperature, itch, muscle ache, sensual touch, and other interoceptive feelings from the body.

Animals↗
PubMed1991

Structural analysis of recombinant proteins prepared by semi-dry electroblotting after sodium dodecyl sulfate-polyacrylamide gel electrophoresis.

Proteins that were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis were electroblotted onto polyvinylidene difluoride membranes in procedures to prepare homogeneous recombinant proteins for direct N-terminal sequence analysis. A semi-dry blotting procedure was employed to immobilize protein bands on the membranes for subsequent sequence analysis. This method has been used routinely to evaluate the quality of recombinant proteins, which are present in crude cell extracts produced by different expression systems or under different expression conditions. N-Terminal processing, amino acid misincorporation, as well as the inefficient secretion of recombinant proteins can be detected by direct N-terminal sequence analysis of the purified electroblotted samples. Consequently, time-consuming chromatographic procedures can be eliminated. These procedures are also especially valuable for determining degradation sites of a purified recombinant protein, as well as evaluating multiple gene products expressed by isolated cluster genes.

Amino Acid Sequence↗
PubMed1987

High-resolution ultrasonography of wrist ganglia.

High-resolution ultrasonography was performed on 14 patients with soft tissue swelling of the wrist and hand. The examination was done using a real-time 10-MHz sector probe placed directly on the lesion. The sonographic image could always demonstrate the liquid nature of cystic lesions. In recent ganglia, the fluid content was anechoic, and the cystic walls were rather thin; in some older lesions, irregular internal echoes and thicker walls were found. Rather often, multiple ganglia were observed, grouped in clusters. The presence of a liquid-filled duct directed to the articular space was demonstrated in 8/11 cases (73%). This finding is considered a diagnostic characteristic of ganglia, and it is very useful for correct surgical planning. In extensor cystic tenosynovitis, the echographic picture was quite different: the anechoic cavity was longitudinal in shape, following the tendon sheath, and the communicating duct was absent. Finally, the sonographic pattern of one case of de Quervain's disease was analyzed and discussed.

Adult↗
PubMed1994

Cox regression analysis of multivariate failure time data: the marginal approach.

Multivariate failure time data are commonly encountered in scientific investigations because each study subject may experience multiple events or because there exists clustering of subjects such that failure times within the same cluster are correlated. In this paper, I present a general methodology for analysing such data, which is analogous to that of Liang and Zeger for longitudinal data analysis. This approach formulates the marginal distributions of multivariate failure times with the familiar Cox proportional hazards models while leaving the nature of dependence among related failure times completely unspecified. The baseline hazard functions for the marginal models may be identical or different. Simple estimating equations for the regression parameters are developed which yield consistent and asymptotically normal estimators, and robust variance-covariance estimators are constructed to account for the intra-class correlation. Simulation results demonstrate that the large-sample approximations are adequate for practical use and that ignoring the intra-class correlation could yield rather misleading variance estimators. The proposed methodology has been fully implemented in a simple computer program which also incorporates several alternative approaches. Detailed illustrations with data from four clinical or epidemiologic studies are provided.

Adolescent↗
PubMed1997

Analysis of the 5' sequence, genomic structure, and alternative splicing of the presenilin-1 gene (PSEN1) associated with early onset Alzheimer disease.

Mutations in the human presenilin genes (PSEN1 and PSEN2) are associated with early onset familial Alzheimer disease. The presenilin genes encode integral membrane proteins with similar structures, which suggests that they may have closely related, but as yet unknown functions. Analysis of the 5' upstream sequence and the structure of the PSEN1 gene reveals that the 5' sequence contains multiple putative transcription regulatory elements including clusters of STAT elements involved in transcriptional activation in response to signal transduction. The first four exons contain untranslated sequences, with Exons 1 and 2 representing alternate initial transcription sites. The function of these alternate initial exons is unclear. Exon 4 bears the first ATG sequence. The last 12 bp of Exon 4 is used as an alternative splice donor site. Exon 9 is alternately spliced in leukocytes, but not in most other tissues. Splicing of Exon 9 is predicted to cause significant structural changes to the protein. The majority of transcripts expressed in most tissues are polyadenylated 1127 bp from the TAG stop codon in Exon 13. A small proportion of transcripts contain the same 5'UTR and ORF but are polyadenylated 4435 bp from the stop codon. The longer polyadenylated transcripts contain three additional palindromes and at least one additional stem-loop structure with stabilities greater than -16 kcal/mol.

Alternative Splicing↗
PubMed1997

The tax gene sequences form two divergent monophyletic lineages corresponding to types I and II of simian and human T-cell leukemia/lymphotropic viruses.

Evolutionary associations of human and simian T-cell leukemia/lymphotropic viruses I and II (HTLV-I/II and STLV-I/II) are inferred from phylogenetic analysis of tax gene sequences. Samples studied consisted of a geographically diverse assemblage of viral strains obtained from 10 human subjects and 20 individuals representing 12 species of nonhuman primates. Sequence analyses identified distinct substitutions, which distinguished between viral types I and II, irrespective of host species. Phylogenetic reconstruction of nucleotide sequences strongly supported two major evolutionary groups corresponding to viral types I and II. With the type I lineage, clusters were composed of strains from multiple host species. A genetically diverse, monophyletic lineage consisting of eight new viral strains from several species of Asian macaques was identified. The second lineage consisted of a monophyletic assemblage of HTLV-II/STLV-II strains from Africa and the New World, including an isolate from a pygmy chimp (Pan paniscus) as an early divergence within the lineage. High levels of genetic variation among strains from Asian STLV-I macaque suggest the virus arose in Asia. Evidence of the origin of the type II virus is less clear, but diversity among HTLV-II variants from a single isolated population of Mbati villagers is suggestive but not proof of an African origin.

Amino Acid Sequence↗
PubMed2005

Control by cytokinins of the cellular behavior in the plate meristem of zucchini cotyledons.

The temporal and spatial effects of exogenous cytokinins on both cell expansion and division activity in the plate meristem of cultured zucchini cotyledons were studied. N6-benzylaminopurine (1-100 microM) and N-(2-chloro-4pyridyl)-N'-phenylurea (4PU-30) (0.1-100 microM) greatly stimulated the cell growth and division. They provoked multiple cell cycles, formation of larger clusters of daughter cells and an increase of the final number of cells. Both cytokinins led to earlier achievement of final cotyledon size and shortened the cell doubling time. By contrast to the purine cytokinin, phenylurea cytokinin 4PU-30 enlarged the cotyledon predominantly in length. Zeatin and kinetin were less effective, particularly in stimulating cell expansion. In low concentrations, all cytokinins were more effective in stimulating division activity rather than expansion. The cells in the cotyledon margins displayed a higher division activity, especially when treated with exogenous cytokinins. The final cotyledon and cluster areas were not of the strict proportional dependence upon the number of their cells. These results provide a novel example where stimulated cell division fails to evoke a respective increase in the final organ size.

Benzyl Compounds↗
PubMed1986

Structural organizations of replicon domains during DNA synthetic phase in the mammalian nucleus.

In mammalian cells, it has been shown that adjacent multiple DNA replicons, termed a replicon cluster or a replicon domain, are replicated coordinately in a defined temporal order during the DNA synthetic (S) phase. However, no intranuclear structure of this replicon domain has been revealed in the nucleus labelled with [3H]thymidine at the limited resolution level of autoradiography. By immunofluorescent staining with antibody against 5-bromodeoxyuridine (BrdU), we succeeded in detecting novel, intranuclear ring-like structures of replicating replicon domains that were organized temporarily during the S phase of mammalian cells with incorporated BrdU.

Animals↗
PubMed1985

Genomic organization and nucleotide sequence of two distinct histone gene clusters from Xenopus laevis. Identification of novel conserved upstream sequence elements.

We have performed a detailed analysis of the genomic organization and the nucleotide sequence of two distinct Xenopus laevis histone gene clusters totaling approximately 23.5 X 10(3) base-pairs. Each cluster contains at least one copy of each of the five histone genes. However, these genes are present in different arrangements within each cluster and different H1A, H2A and H2B proteins (variants) are encoded by the respective genes of each cluster. Southern blot analysis of genomic X. laevis DNA indicates that each cluster is a member of a distinct family of tandemly repeated histone gene clusters. A comparative analysis of the nucleotide sequences flanking the histone genes within these two clusters has revealed the presence of multiple conserved sequence elements that are specific for each histone gene class and located at preferred upstream positions. Several of these elements correspond to sequences that are known to be required for maximal transcription of the corresponding genes. Most of these sequence elements have not been identified previously, although we find that many of them are present at corresponding locations upstream of histone genes from other organisms. We suggest that the conserved upstream sequence elements may play an important role in the expression of histone genes in vivo.

Amino Acid Sequence↗