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PubMed1999

On the origin of metabolic pathways.

The heterotrophic theory of the origin of life is the only proposal available with experimental support. This comes from the ease of prebiotic synthesis under strongly reducing conditions. The prebiotic synthesis of organic compounds by reduction of CO(2) to monomers used by the first organisms would also be considered an heterotrophic origin. Autotrophy means that the first organisms biosynthesized their cell constituents as well as assembling them. Prebiotic synthetic pathways are all different from the biosynthetic pathways of the last common ancestor (LCA). The steps leading to the origin of the metabolic pathways are closer to prebiotic chemistry than to those in the LCA. There may have been different biosynthetic routes between the prebiotic and the LCAs that played an early role in metabolism but have disappeared from extant organisms. The semienzymatic theory of the origin of metabolism proposed here is similar to the Horowitz hypothesis but includes the use of compounds leaking from preexisting pathways as well as prebiotic compounds from the environment.

Amino Acids↗
PubMed2000

Mcm10 and the MCM2-7 complex interact to initiate DNA synthesis and to release replication factors from origins.

MCM2-7, a complex of six subunits, is an essential component of the prereplication chromatin that is assembled at Saccharomyces cerevisiae replication origins during G(1) phase. It is also believed to be the processive helicase at growing forks. To elucidate the action of MCM2-7 during the transition from initiation to elongation replication, we have focused our studies on Mcm10, a replication initiation protein that physically interacts with members of the MCM2-7 complex. We show that Mcm10 is a chromatin-associated protein that mediates the association of the MCM2-7 complex with replication origins. Furthermore, diminished interaction between Mcm10 and Mcm7, a subunit of the MCM2-7 complex, by a mutation in either Mcm10 or Mcm7 inhibits replication initiation. Surprisingly, a double mutant containing both the mcm10-1 and mcm7-1 (cdc47-1) alleles restores interaction between Mcm10 and Mcm7 and corrects all of the defects exhibited by each of the single mutants, including the stalling of replication forks at replication origins typically seen in mcm10-1 cells. This mutual compensation of defects between two independently isolated mutations is allele specific. These results suggest that Mcm10, like Mcm7, is a critical component of the prereplication chromatin and that interaction between Mcm10 and Mcm7 is required for proper replication initiation and prompt release of origin-bound factors.

Alleles↗
PubMed2000

Cdc6p modulates the structure and DNA binding activity of the origin recognition complex in vitro.

An interaction between the origin recognition complex (ORC) and Cdc6p is the first and a key step in the initiation of chromosomal DNA replication. We describe the assembly of an origin-dependent complex containing ORC and Cdc6p from Saccharomyces cerevisiae. Cdc6p increases the DNA binding specificity of ORC by inhibiting non-specific DNA binding of ORC. Cdc6p induces a concomitant change in the conformation of ORC and mutations in the Cdc6p Walker A and Walker B motifs, or ATP-gamma-S inhibited these activities of Cdc6p. These data suggest that Cdc6p modifies ORC function at DNA replication origins. On the basis of these results in yeast, we propose that Cdc6p may be an essential determinant of origin specificity in metazoan species.

Cell Cycle Proteins↗
PubMedDate not supplied

[Attachment of DNA loops to an artificial matrix does not affect the origin of replication initiation in early development of African clawed frog].

Replication initiation proceeds in a random fashion in early development of Xenopus laevis. The replication origins become fixed only at later stages of development after the mid-blastula transition. Specification of replication origins occurs at the same time with the specification of the DNA attachment to the nuclear matrix. Replication origins of many species coincide or are located in the vicinity of sites of DNA attachment to the nuclear matrix. The present work was dedicated to development of an experimental system where DNA loops were specifically attached to an artificial matrix and a study of an effect of this attachment on specificity of DNA replication initiation in extracts of Xenopus laevis oocytes. We have found that DNA attachment to the artificial matrix increases the efficacy of DNA replication as compared to the control, but does not affect the replication specificity. It is likely that the transition from non-specific to specific replication is determined by a combination of several factors, and specificity of DNA attachment to a matrix alone is not sufficient for specification of a replication origin.

Animals↗
PubMedDate not supplied

Self-regulating model for control of replication origin firing in budding yeast.

A major research area concentrates on understanding the regulation of replication origin firing. It is now appreciated that checkpoint signaling participates in this controlled process and that defects in such signaling systems affect genome integrity. Inhibition of replication origin firing is most obviously apparent under conditions of replication stress, but origin firing must also be regulated on a minute-by-minute basis as cells progress normally through an unabated S-phase. Here we summarize a straightforward model to account for how origin firing could be controlled by a self-regulating system.

Cell Cycle Proteins↗
PubMed1990

[Fever of unknown origin: re-evaluation of 67Ga scintigraphy in detecting causes of fever].

Radioactive gallium citrate has been known to accumulate not only in neoplasms but also in inflammatory foci, and thus widely used to find out pyrogenic lesions in cases of unexplainable prolonged fever. However, with developments and improvements of other imaging modalities, its diagnostic significance may have changed. To probe that issue, recent 65 scans for the patients with fever of unknown origin were reviewed retrospectively. Of these, 56 had sufficient clinical assessment and laboratory examinations to evaluate causative illnesses. Gallium images of 33 patients were interpreted as positive. Local inflammatory lesions were detected in 23 cases, with lung tuberculosis, urinary tract infection, and inflammatory joint diseases as prevalent final diagnoses. Pyogenic abscesses, though popular in the literatures on fever of unknown origin, were found in only 2 cases in our present series. This seemed to be due to earlier detection of affected sites by other imaging technics. Osteomyelitis, other major cause of fever in the past, was not found this time, probably owing to wide use of antibiotics. Besides localized diseases, seven cases of generalized disorders were found. There were 3 patients with hematological malignancies, 3 with systemic autoimmune diseases, and 1 with severe infectious mononucleosis. There were three false positive cases; intestinal gallium radioactivity in 2 cases and physiological pulmonary hilar accumulation in 1 were erroneously read as abnormal. Of 23 cases with negative gallium scan, no definite cause of fever were found in 19; twelve patients had spontaneous reduction of fever, 2 did so with antibiotics, and 5 with corticosteroids. False negative cases were; two with urinary tract infection on antibiotics, one with bacterial meningitis, and one with polyarteritis nodosa. Our results reconfirmed the excellent sensitivity and accuracy of gallium scan in the diagnosis of fever of unknown origin. In addition to the detection of focal inflammations, it may sometimes contribute to an early diagnosis of unexpected systemic diseases. From the results obtained, it is advisable that, in patients with fever of unknown origin, this test should be done early in diagnostic schedule and before administration of drugs that may mask potential sites of abnormal accumulation.

Adolescent↗
PubMedDate not supplied

[Usefulness of the histologic and microbiologic study of liver biopsy in the diagnosis of fever of unknown origin].

Since the usefulness of liver biopsy in the diagnosis of fever of unknown origin is still controversial, we analyzed the charts of 54 patients with fever of unknown origin in whom histological and microbiological studies of a liver biopsy were performed. The cause of fever was established in 43 (80%) patients and it was most frequently of an infectious origin (52%). Histological analysis of liver biopsy was useful in determining the final diagnosis in 26 patients (48%) and was the main/only diagnostic method in a third of them. It was useful even in patients with no evidence of hepatic disfunction. Microbiological analysis of liver biopsy was positive in 7 cases (25% of infectious causes). We consider that liver biopsy should be performed early in the work-up of patients with fever of unknown origin.

Adolescent↗
PubMed1996

RNA-DNA hybrid formation at the human mitochondrial heavy-strand origin ceases at replication start sites: an implication for RNA-DNA hybrids serving as primers.

Critical elements of a mammalian mitochondrial DNA heavy-strand replication origin include a promoter and three downstream conserved sequence blocks (CSBIII, CSBII and CSBI). We found recently that a stable and persistent RNA-DNA hybrid forms during in vitro transcription at Saccharomyces cerevisiae mitochondrial origins; hybrid formation was dependent on the conserved CSBII element. We report here that during in vitro transcription with human mitochondrial RNA polymerase, stable and persistent RNA-DNA hybrid formation is also evident at the human mitochondrial heavy-strand origin. As predicted, hybrid formation was dependent on the GC-rich CSBII element. The human RNA-DNA hybrids terminate within or downstream of CSBI at locations implicated in initiation of mitochondrial DNA replication. Interestingly, efficient hybrid formation in the human system is influenced by sequence 5' to the RNA-DNA hybrid, including the CSBIII element. These results suggest that the RNA-DNA hybrids formed during transcription across the mitochondrial DNA heavy-strand origin provide RNA primers for initiation of mitochondrial DNA replication.

Base Sequence↗
PubMed1996

[Fever of unknown origin].

Febrile episodes of unknown origin are a great challenge for physicians practitioners, but often a great problem too, as they remain unsolved in a certain percentage of patients. Increased temperature is the most common characteristic of infections, so that is why febrile episodes of unknown origin are mostly part of the practice of epidemiologists. This study shows that febrile episodes of unknown origin can be caused by a great number of other diseases and gives the sequence of diagnostic procedures in regard to the age and subjective difficulties as well as therapeutic approach to solving the cause of the febrile episode of unknown origin.

Fever of Unknown Origin↗
PubMed1996

Unilateral focal preponderance of interictal epileptiform discharges as a predictor of seizure origin.

OBJECTIVE: To test the hypothesis that seizure origin may be predicted from scalp-recorded electroencephalographic interictal epileptiform patterns that occur exclusively or preponderantly over a single focal region. PATIENTS AND METHODS: Fifty-nine of 98 patients (>=16 years old) with intractable epilepsy who underwent sphenoidal/scalp electroencephalographic video monitoring were identified as having interictal epileptiform discharges preponderantly (>=75% of all discharges) or exclusively over a single unilateral region (basal-temporal, midposterior temporal, frontopolar, superior frontal, central). Ictal recordings in 48 patients could be interpreted as demonstrating focal origins, and the ictal findings were compared with the interictal findings. Eleven patients had uninterpretable ictal recordings or no seizures during monitoring and were not further considered. RESULTS: All seizures arose from the expected region in 39 of the 48 patients (Fisher's exact test, P<.001). Interictal discharges occurred exclusively over a single region in 23 of the 48 patients, and all seizures arose from the expected region in 22 of the 23 patients (P<.001). Seventeen patients among this group of 23 had exclusively unilateral basal-temporal discharges, and all seizures arose from the expected side, with the exception of one seizure that arose from the opposite side in one patient, with her other seizure arising from the expected side (P<.001). All seizures arose from the expected region in three patients who exhibited all interictal discharges arising from a single superior frontal region, in two patients with discharges only over a single midposterior temporal region, and in one patient with exclusively unilateral frontopolar discharges. CONCLUSIONS: Interictal discharges that demonstrate a consistent unilateral focal preponderance over a single region, regardless of location, generally predict seizure origin. If the discharges are exclusive to a single region, there is a greater than 95% probability that all recorded seizures will originate from the expected region.

Adolescent↗
PubMed1999

Origin of thalamic inputs to the primary, premotor, and supplementary motor cortical areas and to area 46 in macaque monkeys: a multiple retrograde tracing study.

The origin of thalamic inputs to distinct motor cortical areas was established in five monkeys to determine whether the motor areas receive inputs from a common thalamic nucleus and the extent to which the territories of origin overlap. To not rely on the rough definition of cytoarchitectonic boundaries in the thalamus, monkeys were subjected to multiple injections of tracers (four to seven) in the primary (M1), premotor (PM), and supplementary (SMA) motor cortical areas and in area 46. The cortical areas were distributed into five groups, each receiving inputs from a specific set of thalamic nuclei: 1) M1; 2) SMA-proper and the caudal part of the dorsal PM (PMdc); 3) the rostral and caudal parts of the ventral PM (PMvr and PMvc); 4) the rostral part of the dorsal PM (PMdr); and 5) the superior and inferior parts of area 46 (area 46sup and area 46inf). A major degree of overlap was obtained for the origins of the thalamocortical projections directed to areas 46inf and 46sup and for those terminating in SMA-proper and PMdc. PMvc and PMvr received inputs from adjacent and/or common thalamic regions. In contrast, the degree of overlap between M1 and SMA was smaller. The projection to M1 shared relatively limited zones of origin with the projections directed to PM. Thalamic inputs to the motor cortical areas (M1, SMA, PMd, and PMv), in general, were segregated from those directed to area 46, except in the mediodorsal nucleus, in which there was clear overlap of the territories sending projections to area 46, SMA-proper, and PMdc.

Afferent Pathways↗
PubMed1998

The National Cancer Data Base report on the relationship of race and national origin to the histology of nasopharyngeal carcinoma.

BACKGROUND: The development of nasopharyngeal carcinoma reflects interactions of genetics, diet, and viral agents. It is more common in Asians than non-Asians, with different characteristic histologic types. This study examined nasopharyngeal carcinoma in the U.S. as a function of patient origin and histology. METHODS: The data were from the National Cancer Data Base (NCDB). The 5069 nasopharyngeal carcinoma cases were grouped by histologic type: keratinizing squamous cell, nonkeratinizing, and undifferentiated carcinoma. Patient origin was derived from race, Hispanic ethnicity, and place of birth. RESULTS: World Health Organization (WHO) type 1 keratinizing squamous cell carcinomas comprised 75% of the U.S. nasopharyngeal carcinoma cases and were found most often in U.S.-born, non-Hispanic whites. WHO-2 nonkeratinizing and WHO-3 undifferentiated carcinomas of the nasopharnyx comprised the remaining 25% of nasopharyngeal carcinomas and were more common in Asians. Histologic composition varied for each of the 12 patient origin groups in the study and correlated with survival after treatment with ionizing radiation. Asians had the highest proportion of radioresponsive WHO-2 nonkeratinizing and WHO-3 undifferentiated carcinomas of the nasopharynx and better survival than African-Americans and Hispanic and non-Hispanic whites, who had the greatest number of the less radioresponsive keratinizing squamous cell carcinomas of the nasopharynx. The 5-year relative survival was 65% for the nonkeratinizing and undifferentiated carcinomas of the nasopharynx and 37% for the keratinizing variety. CONCLUSIONS: The survival rate of the patient origin groups correlated with the histologic composition of their nasopharyngeal carcinomas. Those with the highest proportion of radioresponsive nonkeratinizing and undifferentiated carcinomas had the best survival.

Adolescent↗
PubMed1998

Identification, distribution, and tissular origin of the alpha5(IV) and alpha6(IV) collagen chains in the developing human intestine.

The basement membrane type IV collagen is a family composed of six genetically distinct but structurally similar polypeptide chains, alpha1-alpha6. The alpha1(IV) and alpha2(IV) chains are ubiquitous components of all BMs whereas the other four have a restricted tissue distribution. In the present study, we have analyzed the expression, distribution, and cellular origin of the alpha5(IV) and alpha6(IV) chains in the developing and adult human small intestine and in well-characterized in vitro models by indirect immunofluorescence, Western blot, and RT-PCR. We have found that in the fetal small intestine, alpha(IV) and alpha6(IV) are present in the epithelial BM and, in contrast to alpha1(IV) and alpha2(IV), are produced by both epithelial and mesenchymal cells. A distinct tissular origin for the alpha1/alpha2(IV) and alpha5/alpha6(IV) chains suggests that alpha5(IV) and alpha6(IV) associate as a heterotrimer in this organ. We have also found that a particular situation of alpha5(IV)/alpha6(IV) chain expression occurs in the adult intestine. Indeed, as compared with the fetal intestine, alpha6(IV) chain production is maintained while the expression of the alpha5(IV) chain is substantially reduced. Altered expression of the alpha5(IV) chain was also observed in the differentiating enterocytic-like Caco-2/15 cells, suggesting that in the intestinal model, the alpha5(IV) chain is subject to a regulated expression. Taken together, these observations indicate that the human intestinal epithelial BM contains up to four type IV collagen chains: the classical alpha1(IV)/alpha2(IV) chains, which originate from mesenchymal cells, and the alpha5(IV)/alpha6(IV) chains, which are of both epithelial and mesenchymal origin and have their expression regulated throughout development.

Caco-2 Cells↗
PubMed1997

The origin of hyaluronectin in human tumors.

The origin of tumor stroma hyaluronectin (HN), a glycoprotein that binds to hyaluronan (HA), has long remained unknown. Histological observations of human tumors suggest that tumor HN could originate from stroma fibroblasts, and in some cases from inflammatory cells. The fibroblast origin was confirmed by the discovery of HN-like antigen along with hyaluronan in culture medium of tumor-derived fibroblasts. An HA-binding protein was characterized in the culture medium of peripheral blood mononuclear cells (PBMC) in both normal subjects and tumor-bearing patients and was found to be human HN. Cultivated monocytes did not produce HA. HN was not related to the HA-binding site CD44. Sequencing of brain HN-derived peptides demonstrated that each determined peptide sequence was similar to a sequence of the proteoglycan PG-M/versican, suggesting that HN is the HA-binding moiety of the proteoglycan. One probe was synthesized from human PBMC by polymerase chain reaction with primers derived from HN sequences also found in versican. Northern blots were positive only with HN-producing cells. The main RNAs were in the 6-8 kb range, and there was a limited proportion of smaller RNA, which was compatible with the size expected from the HN molecular mass. Southern blotting of monocytes and tumor cells demonstrated that the gene was limited to a unique band. We conclude that HN, an extracellular component of brain, connective embryonic, inflammatory and tumoral tissues, is a PG-M/versican-derived molecule. Our results suggest that tumor HN, which originates from fibroblasts and monocytes of tumor stroma, is a molecular component of the host-tumor relationship and could play a role in the regulation of HA activity in oncogenesis.

Adenocarcinoma↗
PubMed1999

Variables influencing the origins of diverse abnormal behaviors in a large sample of captive chimpanzees (Pan troglodytes).

The developmental origin of abnormal behaviors is generally associated with early rearing environments that lack sufficient physical and sensory stimulation. However, other factors should also be considered. A large sample of captive chimpanzees (128 males and 140 females) was surveyed for the presence or absence of 18 abnormal behaviors. Origin variables included the subject's source (zoo, pet, performer, or laboratory), rearing (mother- or hand-reared), and sex. Animals were assessed while held at the Primate Foundation of Arizona, University of Texas M. D. Anderson Cancer Center, or White Sands Research Center. There was a confound among origin variables; more hand-reared animals than expected were from laboratories. Logistic regression tested the relationship of rearing and source, with sex as a secondary predictor variable, to each of the abnormal behaviors. There was no clear association between any abnormal behavior and source. However, for coprophagy, relative to animals from the laboratory, zoo animals tended to show a higher prevalence, while performers tended to show a lower prevalence (when rearing and sex were controlled). Rocking and self-sucking were significantly more likely in hand-reared animals. Coprophagy and depilation of self were significantly more likely in mother-reared animals. When rearing and source were statistically controlled, the only significant sex difference was a higher prevalence of coprophagy in females and a higher prevalence of rocking in males. In a second, smaller sample of 25 males and 33 females from Southwest Foundation for Biomedical Research, no significant sex association was found for coprophagy, urophagy, rocking, or self-depilation. In this second sample, coprophagy was also significantly more likely in mother-reared than hand-reared subjects. The association of some abnormal behaviors with mother-rearing suggests that some form of social learning may be involved in the origin of some of these behavior patterns. This indicates that some abnormal behaviors may not be always be indicative of reduced psychological well-being in captive chimpanzees.

Animals↗
PubMed1998

Results of termino-lateral neurorrhaphy to original and adjacent nerves.

In this comprehensive investigation, we studied three different neurorrhaphy models in an attempt to elucidate the potential of termino-lateral nerve repair to original and adjacent nerves. In experimental group 1, the peroneal nerve was sectioned and then attached to the posterior tibial nerve in a termino-lateral fashion. In experiment group 2, the motor nerves to the gastrocnemius muscle were sectioned and then attached to the posterior tibial nerve in a termino-lateral fashion. In experimental group 3, the obturator nerve (L2-4) was sectioned and attached to the sciatic nerve (L4-6) in a termino-lateral fashion. For the control in each group, the same type of nerve used in each respective group was transected without repair. Experimental groups 1 and 2 showed viable axons in the peroneal nerve distal to the neurorrhaphy site. Experimental group 3 showed no viable axons at these sites. No regeneration was observed in the transected nerve without repair in all three control groups. This study suggests that termino-lateral neurorrhaphy is a viable means of repairing damaged nerves if the distal segment of the sectioned nerve is reattached to its original trunk distal to its original branch point. However, the results from experimental group 3 demonstrate that termino-lateral neurorrhaphy cannot be used to repair nerves when the donor and recipient nerves originate from different spinal cord levels.

Anastomosis, Surgical↗
PubMed2000

Female with autistic disorder and monosomy X (Turner syndrome): parent-of-origin effect of the X chromosome.

We have ascertained and examined a patient with autistic disorder (AD) and monosomy X (Turner syndrome). The patient met Diagnostic and Statistical Manual of Mental Disorders (DSM-IV)/International Classification of Diseases (ICD-10) criteria for AD verified by the Autism Diagnostic Interview-Revised. The patient exhibited both social and verbal deficits and manifested the classical physical features associated with monosomy X. Skuse et al. [1997: Nature 387:705-708] reported three such cases of AD and monosomy X in their study of Turner syndrome and social cognition. They observed that monosomy X females with a maternally inherited X chromosome had reduced social cognition when compared with monosomy X females with a paternally inherited X chromosome. All three cases of AD and monosomy X were maternally inherited. Based on their data, they suggested that there was a gene for social cognition on the X chromosome that is imprinted and not expressed when the X chromosome is of maternal origin. Thus, we conducted parent-of-origin studies in our AD/monosomy X patient by genotyping X chromosome markers in the patient and her family. We found that the patient's X chromosome was of maternal origin. These findings represent the fourth documented case of maternal inheritance of AD and monosomy X and provide further support for the hypothesis that parent-of-origin of the X chromosome influences social cognition.

Adult↗
PubMed2000

mtDNA lineage analyses: origins and migrations of Micronesians and Polynesians.

The islands of Micronesia and Polynesia collectively comprise the last major region of the globe to be settled by humans. Both of these groups of islands were colonized within the last 4,000 years by Austronesian-speaking agriculturists. Based on biogeographic and linguistic patterns, central-eastern Micronesia and Polynesia are included by many in a single category called Remote Oceania. Similarities of biologic, linguistic, and cultural traits within Remote Oceania highlight a question central to Oceanic studies: Are similarities among islands due to a common origin of isolated communities, to ongoing interactions among islands, or both? Analyses of mitochondrial DNA (mtDNA) sequences reveal that most remote Oceanic populations are polyphyletic. These polyphyletic populations violate the assumptions of many genetic distance and population demography models and so are problematic to interpret. The majority of mtDNA sequences from Micronesian and Polynesian populations are derived from Asia, whereas others are inferred to have originated in New Guinea. These data support an Island Southeast Asian origin and a colonization route along the north coast of New Guinea. The Marianas and Yap proper (main island) appear to have been independently settled directly from Island Southeast Asia, and both have received migrants from Central-Eastern Micronesia since then. Palau clearly demonstrates a complex prehistory including a significant influx of lineages from New Guinea. Thus genetic similarities among Micronesian and Polynesian populations result, in some cases, from a common origin, and in others, from extensive gene flow.

DNA, Mitochondrial↗