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PubMed1994

The specific roles of finger and kringle 2 domains of tissue-type plasminogen activator during in vitro fibrinolysis.

The specific roles of the finger (F) and kringle 2 (K2) domains of tissue-type plasminogen activator (t-PA) were quantified with regard to fibrin binding and kinetic parameters for plasminogen activation by employing domain-deletion variants. On an intact fibrin clot, active site-blocked 125I-t-PA has a dissociation constant (Kd) of 0.36 +/- 0.08 microM and a single binding site per fibrin monomer (n = 1.1 +/- 0.1). Deletion of the K2 domain results in a 3-fold increase of the Kd (1.1 +/- 0.2 microM) and a 2-fold increase of the binding sites per fibrin monomer (n = 2.0 +/- 0.3). Deletion of the F domain results in nonsaturable binding with high Kd (3.2 +/- 0.6 microM). These results indicate that the high affinity binding of t-PA to intact fibrin is the resultant of the cooperation of two low affinity binding sites assembled on intact t-PA. Furthermore, fibrin clot lysis experiments were performed, using polymerized fibrin and plasminogen. Enzymatic activity of t-PA (variants) was assessed by following the decrease in turbidity of the polymerized fibrin. Intact recombinant t-PA exhibited a Michaelis constant for plasminogen activation (Km) of 37 +/- 2 nM. Deletion of either the K2 or F domain results in an increase of the Km for plasminogen of 4- and 16-fold, respectively. We interpret these kinetic parameters in terms of the ternary complex model: binding of t-PA to fibrin, mediated simultaneously by both the F and K2 domain, is essential for a correct orientation of the enzyme on the fibrin polymer to yield the optimal "Km-driven" stimulation of fibrin on the activation of plasminogen. The different potencies of various deletion mutants in a plasma clot are explained by decreased affinity of the enzymes both for fibrin and for the substrate plasminogen.

Binding Sites↗
PubMed2025

Machine learning detection of heteroresistance in Escherichia coli.

BACKGROUND: Heteroresistance (HR) is a significant type of antibiotic resistance observed for several bacterial species and antibiotic classes where a susceptible main population contains small subpopulations of resistant cells. Mathematical models, animal experiments and clinical studies associate HR with treatment failure. Currently used susceptibility tests do not detect heteroresistance reliably, which can result in misclassification of heteroresistant isolates as susceptible which might lead to treatment failure. Here we examined if whole genome sequence (WGS) data and machine learning (ML) can be used to detect bacterial HR. METHODS: We classified 467 Escherichia coli clinical isolates as HR or non-HR to the often used β-lactam/inhibitor combination piperacillin-tazobactam using pre-screening and Population Analysis Profiling tests. We sequenced the isolates, assembled the whole genomes and created a set of predictors based on current knowledge of HR mechanisms. Then we trained several machine learning models on 80% of this data set aiming to detect HR isolates. We compared performance of the best ML models on the remaining 20% of the data set with a baseline model based solely on the presence of β-lactamase genes. Furthermore, we sequenced the resistant sub-populations in order to analyse the genetic mechanisms underlying HR. FINDINGS: The best ML model achieved 100% sensitivity and 84.6% specificity, outperforming the baseline model. The strongest predictors of HR were the total number of β-lactamase genes, β-lactamase gene variants and presence of IS elements flanking them. Genetic analysis of HR strains confirmed that HR is caused by an increased copy number of resistance genes via gene amplification or plasmid copy number increase. This aligns with the ML model's findings, reinforcing the hypothesis that this mechanism underlies HR in Gram-negative bacteria. INTERPRETATION: We demonstrate that a combination of WGS and ML can identify HR in bacteria with perfect sensitivity and high specificity. This improved detection would allow for better-informed treatment decisions and potentially reduce the occurrence of treatment failures associated with HR. FUNDING: Funding provided to DIA from the Swedish Research Council (2021-02091) and NIH (1U19AI158080-01).

Machine Learning↗
PubMed2003

Generation and use of a tailored gene array to investigate vascular biology.

Vasculogenesis, angiogenesis and vascular remodelling are complex processes where the fate of several cell types is determined by different signalling networks. Many of these networks ultimately function by changing the abundance of RNA transcripts within the cells which constitute blood vessel walls. Researchers can now map these transcript abundance changes using gene array technology. In this review, we describe the design, production and use of a gene array specifically tailored to investigate vascular biology. We describe the advantages of tailored gene arrays, and give detailed protocols based on our experience to allow the reader to use such gene arrays to generate meaningful data. We list the issues to consider when choosing and verifying the genes and splice variants included in an array, and describe our use of Arabidopsis sp. RNA spikes for quality control. We present data that illustrates the absolute necessity for both technical and biological replicates to be incorporated in the design of gene array experiments using primary cells such as HUVECS. Finally, we describe methods for the normalisation and interpretation of the data that gene arrays produce. The approach to gene array technology described here is easily within reach of the budget and expertise of most academic research groups.

Cardiovascular Physiological Phenomena↗
PubMed1999

Homocysteine.

Homocysteine is a sulfur-containing amino acid generated through the demethylation of methionine. It is largely catabolized by trans-sulfuration to cysteine, but it may also be remethylated to methionine. Regulation of homocysteine is dependent on nutrient intake, especially folate, vitamins B6 and B12. It is also controlled by individual genetic differences in how vitamins are utilized as cofactors in the reactions controlling homocysteine metabolism. In excess quantities, homocysteine is thought to be thrombophilic and to damage the vascular endothelium. Total plasma homocysteine (tHcy) is now established as a clinical risk factor for coronary artery disease, as well as other arterial and venous occlusive disease in adult populations. These effects are probably related to its role as a teratogen in the pathogenesis of neural tube defects--genetic variants causing hyperhomocysteinemia are associated with both neural tube defects in susceptible pregnancies and with risks for vaso-occlusive disease in later years. Considerable care must be taken in assaying tHcy. Plasma should be separated shortly after collection to avoid artifactual increases due to synthesis by blood cells in vitro. tHcy concentrations must be interpreted in light of the fact that serum albumin, urate, creatinine, and vitamin concentrations may be important analytical covariates. Moreover, concentrations are age- and sex-dependent and are altered by renal function, hormonal status, drug intake, and a variety of other common clinical factors. Why then is homocysteine now of such great clinical and scientific interest? If the homocysteine moiety itself is important in the pathogenesis of vaso-occlusive disease, then simple treatment of hyperhomocysteinemia with vitamins should lead to a significant reduction in disease risk. Such a possibility lies behind the growing momentum to recommend increased supplements of folate and B vitamins to at-risk populations and patient groups today.

Amino Acid Metabolism, Inborn Errors↗
PubMed1972

Selection in finite populations with multiple alleles. 3. Genetic divergence with centripetal selection and mutation.

Natural selection for an intermediate level of gene or enzyme activity has been shown to lead to a high frequency of heterotic polymorphisms in populations subject to mutation and random genetic drift. The model assumes a symmetrical spectrum of mutational variation, with the majority of variants having only minor effects on the probability of survival. Each mutational event produces a variant which is novel to the population. Allelic effects are assumed to be additive on the scale of enzyme activity, heterosis arising whenever a heterozygote has a mean level of activity closer to optimal than that of other genotypes in the population.-A new measure of genetic divergence between populations is proposed, which is readily interpreted genetically, and increases approximately linearly with time under centripetal selection, drift and mutation. The parameter is closely related to the rate of accumulation of mutational changes in a cistron over an evolutionary time span.-A survey of published data concerning polymorphic loci in man and Drosophila suggests than an alternative model, based on the superiority of hybrid molecules, is not of general importance. Thirteen loci giving rise to hybrid zones on electrophoresis have a mean heterozygote frequency of 0.22 +/-.06, compared with a value of 0.23 +/-.04 for 16 loci classified as producing no hybrid enzyme.

Alleles↗
PubMed2002

Hepatitis C virus infection in a hematology ward: evidence for nosocomial transmission and impact on hematologic disease outcome.

BACKGROUND AND OBJECTIVES: Hepatitis C virus (HCV) infection is frequent among patients with hematologic malignancies and unapparent routes of infection may be important in this setting. Moreover, the impact of this infection on the outcome of the hematologic disease needs to be better defined. DESIGN AND METHODS: To define sources and clinical courses of HCV infection, an epidemiologic study was performed on 13 patients newly admitted over one year who showed transaminase elevation and anti-HCV seroconversion. The investigation, started in August 1998, included laboratory tests and molecular analysis of virus isolates, and was extended to staff and blood donors. Clinical, hematologic and serologic surveillance of all infected patients were part of the subsequent follow-up study which started in September 1998 and was completed in December 2001. RESULTS: Anti-HCV seroconversion was observed in 13 of 294 patients (4.4%), admitted to the unit from August 1997 and August 1998; 11 of the seroconverted cases had central catheters, 12 received transfusions. Transmission via blood derivatives and staff was ruled out. All patients were infected by genotype 1b and 11 harbored the same viral variant. HCV infection did not influence the course of the underlying disease or the use of specific therapies. Forty months after the outbreak, five patients are alive (one after autologous and one after allogeneic stem cell transplantation), while eight have died, seven of hematologic disease, and one of cardiac failure. None died of liver disease. INTERPRETATION AND CONCLUSIONS: The molecular data suggest a patient-to-patient nosocomial HCV transmission. After having analyzed all the possible routes of transmission, a series of preventive measures were adopted: search for HCV RNA in newly admitted patients, protection of mucosae and isolation of patients during neutropenic phases, and avoidance of multidose vials. As regards the impact of HCV infection on the outcome of the hematologic diseases, changes in the scheduled therapy, including stem cell transplantation, were not required.

Adolescent↗
PubMed2006

Identification of candidates for tumor-specific alternative splicing in the thyroid.

Alternative splicing is the differential processing of exon junctions to produce a new transcript variant from one gene. Some aberrant splicing, however, has been shown to be cancer specific. Identification of these specific splice variations will provide important insight into the molecular mechanism of normal cellular physiology as well as the disease processes. To gain knowledge about whether alternative splicing is linked to thyroid tumorigenesis, we used our prediction database to select targets for analysis. Fifteen putatively new alternative splicing isoforms were selected on the basis of their expression in thyroid libraries and/or their origin in genes previously associated with carcinogenesis. Using a set of 66 normal, benign, and malignant thyroid tissue samples, new splicing events were confirmed by RT-PCR for 13 of 15 genes (a validation rate of 87%). In addition, new alternative splicing isoforms not predicted by the system and not previously described in public databases were identified. Five genes (PTPN18, ABI3BP, PFDN5, SULF2, and ST5) presented new and/or additional unpredicted isoforms differentially expressed between malignant and benign or normal thyroid tissues, confirmed by sequencing. PTPN18, ABI3BP, and PFDN5 revealed a statistically significant differential splicing profile. In addition, real-time PCR analysis revealed that expression of an alternative PFDN5 variant was higher in malignant lesions than in benign lesions or normal tissues.

Alternative Splicing↗
PubMed2001

Airway eosinophilia is associated with wheeze but is uncommon in children with persistent cough and frequent chest colds.

The role of eosinophilic airway inflammation in the variant asthma syndromes of cough and chest colds is not well defined. We tested the hypothesis that children with persistent cough and chest colds have increased sputum eosinophils, similar to those with wheeze. The parents of 390 primary school children completed a symptoms questionnaire. Children with wheeze (n = 28), cough (n = 12), recurrent chest colds (n = 17), and no symptoms (control subjects, n = 26), underwent allergy skin prick tests, spirometry, hypertonic saline inhalation challenge, and sputum induction, and then completed a peak expiratory flow (PEF) and symptoms diary over a 2-mo period. Children with wheeze had significantly reduced PEF (p = 0.001) and higher sputum eosinophils when compared with the cough, chest cold, and control groups (3.1% versus 0.5%, 0%, 0%; p = 0.03). The prevalence of eosinophilic bronchitis (sputum eosinophils > 2.5%) was 45% in the wheeze group, which was significantly higher than the control group (9.35%, p = 0.04). Eosinophilic bronchitis was present in two children with cough (20%) and two with chest colds (15%, p > 0.05 versus control). In these groups, eosinophilic bronchitis was not associated with airway hyperresponsiveness (AHR) to hypertonic saline (p > 0.05). Children with cough and chest colds reported greater exposure to environmental tobacco smoke. In conclusion, this community-based survey of children with chronic respiratory symptoms has shown that wheeze is a good discriminator for the presence of eosinophilic bronchitis, and that persistent cough and recurrent chest colds without wheeze should not be considered a variant of asthma. Eosinophilic bronchitis did occur in a significant minority of these "variant asthma" syndromes.

Age Factors↗
PubMed2006

Fine-needle aspirates of hepatocellular carcinoma that are misclassified as adenocarcinoma: correlating cytologic features and performance in the College of American Pathologists Nongynecologic Cytology Program.

CONTEXT: The cytologic features of hepatocellular carcinoma in fine-needle aspirates are well described. While some cases are easily distinguished from adenocarcinoma, poorly differentiated tumors can be difficult to differentiate. We reviewed the cytologic findings for 9 aspirates from cases of hepatocellular carcinoma that were frequently misclassified as adenocarcinoma and compared them with another 10 cases of hepatocellular carcinoma that were rarely misclassified. OBJECTIVE: To compare the cytologic features of cases of hepatocellular carcinoma in fine-needle aspirates that were both rarely and frequently misclassified as adenocarcinoma. DESIGN: We reviewed a total of 762 interpretations from 19 different cases of hepatocellular carcinoma in liver fine-needle aspiration specimens in the College of American Pathologists Nongynecologic Cytology Program and correlated the cytologic features with performance in the program. RESULTS: Overall, cases that were frequently misclassified as adenocarcinoma were misclassified 39% of the time (range, 18%-70%), while cases that were rarely misclassified were classified as adenocarcinoma 2% of the time (range, 0%-8%). The difference was statistically significant (P < .001). On review, 4 cytologic patterns were found. The most common pattern for cases that were rarely misclassified was prominent trabeculae of cells and endothelial cells wrapping the trabeculae (6/10 cases vs 2/9 cases that were frequently misclassified). The most common pattern among cases that were frequently misclassified was clusters of cells with granular cytoplasm and associated stripped nuclei (5/9 cases vs 2/10 cases that were rarely misclassified). However, the distribution of neither pattern was significantly different (P = .16 for both). One case with large atypical granular cells, as seen in the fibrolamellar variant, was rarely misclassified. The remaining 3 cases (2 frequently misclassified, 1 rarely misclassified) had a nonspecific a pattern of cells with granular cytoplasm without obvious trabeculae or stripped nuclei. CONCLUSION: Correctly classifying hepatocellular carcinoma by cytology alone remains a significant challenge. While some patterns are more common in cases that performed well and other patterns are more common in cases that performed poorly, there was no significant difference in the distribution of these patterns. These results suggest that people should support their interpretations of aspirations with either immunologic evidence, biopsy evidence, or review by an experienced cytopathologist. Continued educational efforts in this area may be of value.

Adenocarcinoma↗
PubMed1993

Influenza--United States, 1988-89.

PROBLEM/CONDITION: CDC monitors the emergence and spread of new influenza virus variants and the impact of influenza on morbidity and mortality annually from October through May. REPORTING PERIOD COVERED: This report covers United States influenza surveillance conducted from October 1988 through May 1989. DESCRIPTION OF SYSTEM: Weekly reports from the vital statistics offices of 121 cities provided an index of influenza's impact on mortality; 58 WHO collaborating laboratories reported weekly identification of influenza viruses; weekly morbidity reports were received both from the state and territorial epidemiologists and from 153 sentinel family practice physicians. Nonsystematic reports of outbreaks and unusual illnesses were received throughout the year. RESULTS: During the 1988-89 influenza season, influenza A (H1N1) and B viruses were identified in the United States with essentially equal frequency overall, although both regional and temporal patterns of predominance shifted over the course of the season. Throughout the season increases in the indices of influenza morbidity in regions where influenza B predominated. Only 7% of identified viruses were influenza A (H3N2), but not isolations of this subtype increased as the season waned and it subsequently predominated during the 1989-90 season. During the 1988-89 season outbreaks in nursing homes were reported in association with influenza B and A (H3N2), but not influenza A (H1N1). INTERPRETATION: The alternating temporal and geographic predominance of influenza strains A (H1N1) and B during the 1988-89 season emphasizes the importance of continual attention to regional viral strain surveillance, since amantadine is effective only for treatment and prophylaxis of influenza A. ACTIONS TAKEN: Weekly interim analyses of surveillance data produced throughout the season allow physicians and public health officials to make informed choices regarding appropriate use of amantadine. CDC's annual surveillance allows the observed viral variants to be assessed as candidates for inclusion as components in vaccines used in subsequent influenza seasons.

Disease Outbreaks↗
PubMed2000

A relational interpretation of the Rorschach color determinants.

This article presents a contemporary relational interpretation of the Rorschach that is consistent with the empirical features of the Comprehensive System. The specific focus is on color determinants and the FC:CF+C ratio. The approach follows that of Schachtel ( 1959), who argued that how one perceives others reveals the quality of relatedness between oneself and others. Schachtel identified a developmental sequence of relatedness (perceptual-relatedness modes) and linked these levels of perceiving and relating to the Rorschach color determinants. I suggest that this developmental sequence, elaborated in a contemporary context, defines the expected or normative course of relatedness, whether across a lifetime, a particular relationship, or an interpersonal encounter. I further propose that relationships emerge and develop through organized trial-and-error activity, in the sense of Piaget's (1952) trying out (assimilating) and simultaneously modifying (accommodating) one's understanding within a relationship. Relatedness levels and the developmental transitions between them are described in terms of the underlying assimilation and accommodation processes. Within this general approach, the FC:CF+C ratio is defined as reflecting styles of relating to one's interpersonal environment, with each relational style based on normative or on variant relational development. Four fundamental relational styles-healthy, egocentric, veneered egocentric, and defensive-are described and coordinated with the Comprehensive System FC:CF+C potential findings.

Adaptation, Psychological↗
PubMed1998

DRD2 allele frequencies and linkage disequilibria, including the -141CIns/Del promoter polymorphism, in European-American, African-American, and Japanese subjects.

Although many studies have addressed the possible association of D2 dopamine receptor (DRD2) alleles-particularly in the TaqI "A" system (with the DRD2*A1 allele)-with positive results for a range of behavioral phenotypes in populations of European origin, the interpretation of those results remains controversial; they could reflect physiological relationships between gene and phenotype, population stratification, or random variation. Since mutational analysis studies of the DRD2 gene have thus far failed to reveal a mutation that could provide a physiological basis for these results, functional meaning for them depends on linkage disequilibrium with a functional variant. A recently described functional variant in the DRD2 promoter (-141CIns/Del), which is about 250 kb 5' to the variants studied in psychiatric illness, could conceivably provide an explanation for the positive findings, if it were in linkage disequilibrium with DRD2*A1 in populations similar to those for which an association has been reported. We studied linkage disequilibrium (LD) and frequencies of haplotypes containing the DRD2*A, DRD2*D, and -141CIns/Del systems in European-Americans, African-Americans, and Japanese subjects. Although we found evidence for LD across the 250-kb first intron in both American populations, we did not find significant LD between the DRD2*A system and the -141CIns/Del system in the European-Americans. This newly described functional variant therefore does not provide a straightforward physiological explanation for previously reported genetic associations with DRD2*A1 in European-American subjects.

Alleles↗
PubMed1993

Cognitive load as a determinant of the dimensionality of the electroencephalogram: a replication study.

A sequel study to that reported by Gregson, Britton, Campbell and Gates (1990), partially replicating and extending findings which relate estimates of the dimensionality of the EEG to the complexity of task load in a visual scanning task, is described. The correlation dimensionality D2 of the attractor was computed using a variant of the Grassberger-Procaccia algorithm, and was shown to change in the expected direction, increasing as the task became more complicated. The effects are slight but consistent, and may be attenuated by nonstationarity over time, and by idiosyncratic factors. The results are numerically and qualitatively compatible with other recent reported studies, and support an interpretation linking brain dynamics to implied cognitive processes.

Adult↗
PubMed2002

Identification of two highly sialylated human tear-fluid DMBT1 isoforms: the major high-molecular-mass glycoproteins in human tears.

Human open eye tear fluid was separated by low-percentage SDS/PAGE to detect high-molecular-mass protein components. Two bands were found with apparent molecular masses of 330 and 270 kDa respectively. By peptide-mass fingerprinting after tryptic digestion, the proteins were found to be isoforms of the DMBT1 gene product, with over 30% of the predicted protein covered by the tryptic peptides. By using gradient SDS/agarose/polyacrylamide composite gel electrophoresis and staining for glycosylation, it was shown that the two isoforms were the major high-molecular-mass glycoproteins of >200 kDa in human tear fluid. Western blotting showed that the proteins expressed sialyl-Le(a). After the release of oligosaccharides by reductive beta-elimination from protein blotted on to PVDF membrane, it was revealed by liquid chromatography-MS that the O-linked oligosaccharides were comprised mainly of highly sialylated oligosaccharides with up to 16 monosaccharide units. A majority of the oligosaccharides could be described by the formula dHex(0-->2)NeuAc(1-->)(x)Hex(x)HexNAc(x)(-ol), x=1-6, where Hex stands for hexose, dHex for deoxyhexose, HexNAc for N-acetylhexosamine and NeuAc for N-acetylneuraminate. The number of sialic acids in the formula is less than 5. Interpretation of collision-induced fragmentation tandem MS confirmed the presence of sialic acid and suggested the presence of previously undescribed structures carrying the sialyl-Le(a) epitopes. Small amounts of neutral and sulphated species were also present. This is the first time that O-linked oligosaccharides have been detected and described from protein variant of the DMBT1 gene.

Agglutinins↗
PubMed2002

Theoretical analysis of alternative splice forms using computational methods.

Nowadays understanding alternative splicing is one of the greatest challenges in biology, because it is a genetic process much more important than thought at the time of its discovery. In this paper, we explain the approach of using the different available databases and software tools to start a large scale investigation of alternative splice forms. To collect information about alternative splicing we investigated known data in the databases using different computational methods. The investigations proceeded from the genomic sequence data to structural protein data. Then, we interpreted those data to find the relationship between alternative splice forms and protein function and structure. We found some interesting features of alternative splicing which are presented here. We discuss the results of one chosen example. They concern the coverage quality of the protein sequence of a known structure, an EST analysis, the validation of splice variants, the determination of the alternative splice type, and finally the link between alternative splicing and disease.

Algorithms↗
PubMed2006

Does caloric restriction extend life in wild mice?

To investigate whether mice genetically unaltered by many generations of laboratory selection exhibit similar hormonal and demographic responses to caloric restriction (CR) as laboratory rodents, we performed CR on cohorts of genetically heterogeneous male mice which were grandoffspring of wild-caught ancestors. Although hormonal changes, specifically an increase in corticosterone and decrease in testosterone, mimicked those seen in laboratory-adapted rodents, we found no difference in mean longevity between ad libitum (AL) and CR dietary groups, although a maximum likelihood fitted Gompertz mortality model indicated a significantly shallower slope and higher intercept for the CR group. This result was due to higher mortality in CR animals early in life, but lower mortality late in life. A subset of animals may have exhibited the standard demographic response to CR in that the longest-lived 8.1% of our animals were all from the CR group. Despite the lack of a robust mean longevity difference between groups, we did note a strong anticancer effect of CR as seen in laboratory rodents. Three plausible interpretations of our results are the following: (1) animals not selected under laboratory conditions do not show the typical CR effect; (2) because wild-derived animals eat less when fed AL, our restriction regime was too severe to see the CR effect; or (3) there is genetic variation for the CR effect in wild populations; variants that respond to CR with extended life are inadvertently selected for under conditions of laboratory domestication.

Aging↗
PubMed1980

Recombination and linkage between structural and regulatory genes of herpes simplex virus type 1: study of the functional organization of the genome.

Phenotypic and genetic properties of 12 markers in structural and regulatory functions of herpes simplex virus type 1 were characterized, and their recombination and segregation behavior was investigated and interpreted with reference to available information on their physical locations. The markers were: (i) ts markers in a structural glycoprotein (tsB5) and in alpha (immediate early; tsLB2, tsc75) or beta (early, delayed early; tsB1) functions with regulatory effects; together with (ii) plaque morphology (syn), phosphonoacetate resistance (Pr), and thymidine kinase (TK) phenotypes; and (iii) electrophoretically distinct variants of glycosylated (glycoprotein C, gpC; ICP10) and non-glycosylated [VP(13-14), VP23] structural and nonstructural [ICP(47-48)] polypeptides. Mean two-factor recombination frequencies ranged from 2% (for noncomplementing mutants tsLB2 and tsc75) to 35 to 40% (for unlinked markers) and were influenced by the relative contributions of parental viruses to the mixed infection. Even with control of this variable, standard deviations of mean measures of recombination frequency ranged from a minimum of 14% (with n greater than or equal to 10) to 65% (with n = 3) of mean values; no recombination frequencies higher than 55% were observed. Differences in mean two-factor recombination frequencies between a small number of loosely linked markers were, therefore, not reliable measures of real differences in linkage. Measurements of the segregation of unselected markers among recombinant progeny were, therefore, used as measures of linkage. These experiments (i) established a linkage group for markers in the long unique region of the genome additional to, but consistent with, existing physical data, i.e., TK-syn-tsB5-(tsB1.Pr)-[gpC.VP(13-14)]; (II) identified markers, e.g., ICP(47-48), linked to regulatory mutations (tsLB2, tsc75) in redundant DNA sequences; and (iii) used the segregation of these regulatory mutations and linked markers among unselected progeny to demonstrate the linkage groups: Pr-syn-TK-tsc75-ICP(47-48), [VP(13-14).gpC]-Pr-syn-TK, and TK-tsc75-[VP(13-14).gpC]. These results were most simply explained if bi- or intermolecular recombination occurred between circular molecules or molecules catenated "head-to-tail" and were incompatible with intermolecular recombination as the mechanism of isomerization of herpes simplex virus DNA.

Genes↗
PubMed2004

Kin-cohort estimates for familial breast cancer risk in relation to variants in DNA base excision repair, BRCA1 interacting and growth factor genes.

BACKGROUND: Subtle functional deficiencies in highly conserved DNA repair or growth regulatory processes resulting from polymorphic variation may increase genetic susceptibility to breast cancer. Polymorphisms in DNA repair genes can impact protein function leading to genomic instability facilitated by growth stimulation and increased cancer risk. Thus, 19 single nucleotide polymorphisms (SNPs) in eight genes involved in base excision repair (XRCC1, APEX, POLD1), BRCA1 protein interaction (BRIP1, ZNF350, BRCA2), and growth regulation (TGFss1, IGFBP3) were evaluated. METHODS: Genomic DNA samples were used in Taqman 5'-nuclease assays for most SNPs. Breast cancer risk to ages 50 and 70 were estimated using the kin-cohort method in which genotypes of relatives are inferred based on the known genotype of the index subject and Mendelian inheritance patterns. Family cancer history data was collected from a series of genotyped breast cancer cases (N = 748) identified within a cohort of female US radiologic technologists. Among 2,430 female first-degree relatives of cases, 190 breast cancers were reported. RESULTS: Genotypes associated with increased risk were: XRCC1 R194W (WW and RW vs. RR, cumulative risk up to age 70, risk ratio (RR) = 2.3; 95% CI 1.3-3.8); XRCC1 R399Q (QQ vs. RR, cumulative risk up to age 70, RR = 1.9; 1.1-3.9); and BRIP1 (or BACH1) P919S (SS vs. PP, cumulative risk up to age 50, RR = 6.9; 1.6-29.3). The risk for those heterozygous for BRCA2 N372H and APEX D148E were significantly lower than risks for homozygotes of either allele, and these were the only two results that remained significant after adjusting for multiple comparisons. No associations with breast cancer were observed for: APEX Q51H; XRCC1 R280H; IGFPB3 -202A>C; TGFss1 L10P, P25R, and T263I; BRCA2 N289H and T1915M; BRIP1 -64A>C; and ZNF350 (or ZBRK1) 1845C>T, L66P, R501S, and S472P. CONCLUSION: Some variants in genes within the base-excision repair pathway (XRCC1) and BRCA1 interacting proteins (BRIP1) may play a role as low penetrance breast cancer risk alleles. Previous association studies of breast cancer and BRCA2 N372H and functional observations for APEX D148E ran counter to our findings of decreased risks. Due to the many comparisons, cautious interpretation and replication of these relationships are warranted.

Aged↗