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PubMed2002

Automating the drug scheduling of cancer chemotherapy via evolutionary computation.

This paper presents the optimal control of drug scheduling in cancer chemotherapy using a distributed evolutionary computing software. Unlike conventional methods that often require gradient information or hybridization of different approaches in drug scheduling, the proposed evolutionary optimization methodology is simple and capable of automatically finding the near-optimal solutions for complex cancer chemotherapy problems. It is shown that different number of variable pairs in evolutionary representation for drug scheduling can be easily implemented via the software, since the computational workload is shared and distributed among multiple computers over the Internet. Simulation results show that the proposed evolutionary approach produces excellent control of drug scheduling in cancer chemotherapy, which are competitive or equivalent to the best solutions published in literature.

Antineoplastic Agents↗

PubMed1990

Quantitative genetic analysis of longitudinal trends in height: preliminary results from the Louisville Twin Study.

A preliminary series of quantitative genetic models was applied to a subset of longitudinal height data, spanning birth to maturity, gathered from twin families in the Louisville Twin Study. Descriptive Cholesky factor parameterization was found to give more satisfactory results than did a system of constraints based on a model of developmental transmission of a time-constant and time-specific factors. The results from application of two autosomal sex-limitation models are contrasted with those from a model specifying both autosomal and sex-chromosomal patterns of inheritance. The latter model was more conducive to parameter reduction. Although these models do not constitute conclusive tests of autosomal sex-limitation versus sex-linkage, the more parsimonious model is consistent with previous research suggesting a stature locus on the long arm of the Y chromosome. Heritability of height is estimated at about 90% or greater from 6 years of age on. Substantial and fairly constant longitudinal genetic correlations are found from 3 years of age on. Shared environmental effects unrelated to parental height were seen for birth length, corrected for gestational age, to height at 3 years of age, but these are not satisfactorily differentiated from possible twin effects in the present sample. The genetic consequences of assortative mating are emphasized since failure to take assortment into account can lead to overestimation of shared environmental effects and under-estimation of genetic effects. The results indicate that about 20% of within-gender variability for mature height can be attributed to the genetic consequences of assortment, even though the phenotypic marital correlation of 0.22 is quite modest. The importance of testing the assumption of multivariate normality underlying the application of the method of maximum-likelihood is also highlighted.

Body Height↗

PubMed1994

Psychosocial risk factors for future adolescent suicide attempts.

An array of psychosocial risk factors for making a suicide attempt were examined in a representative sample of 1,508 older (14- to 18-year-old) high school students, 26 of whom made a suicide attempt during the year following entry into the study. Strongest predictors of future suicide attempt were history of past attempt, current suicidal ideation and depression, recent attempt by a friend, low self-esteem, and having been born to a teenage mother. The results suggest that adolescents who are depressed and those who attempt suicide share many psychosocial risk factors. The efficacy of two screeners (one consisting of 4 items and the other of 6 variables) is reported. Potential usefulness for research and communitywide prevention is discussed.

Adolescent↗

PubMed2005

Somatic events modify hypertrophic cardiomyopathy pathology and link hypertrophy to arrhythmia.

Sarcomere protein gene mutations cause hypertrophic cardiomyopathy (HCM), a disease with distinctive histopathology and increased susceptibility to cardiac arrhythmias and risk for sudden death. Myocyte disarray (disorganized cell-cell contact) and cardiac fibrosis, the prototypic but protean features of HCM histopathology, are presumed triggers for ventricular arrhythmias that precipitate sudden death events. To assess relationships between arrhythmias and HCM pathology without confounding human variables, such as genetic heterogeneity of disease-causing mutations, background genotypes, and lifestyles, we studied cardiac electrophysiology, hypertrophy, and histopathology in mice engineered to carry an HCM mutation. Both genetically outbred and inbred HCM mice had variable susceptibility to arrhythmias, differences in ventricular hypertrophy, and variable amounts and distribution of histopathology. Among inbred HCM mice, neither the extent nor location of myocyte disarray or cardiac fibrosis correlated with ex vivo signal conduction properties or in vivo electrophysiologically stimulated arrhythmias. In contrast, the amount of ventricular hypertrophy was significantly associated with increased arrhythmia susceptibility. These data demonstrate that distinct somatic events contribute to variable HCM pathology and that cardiac hypertrophy, more than fibrosis or disarray, correlates with arrhythmic risk. We suggest that a shared pathway triggered by sarcomere gene mutations links cardiac hypertrophy and arrhythmias in HCM.

Animals↗

PubMed2002

RanBPM, a nuclear protein that interacts with and regulates transcriptional activity of androgen receptor and glucocorticoid receptor.

The androgen receptor (AR) is a ligand-dependent transcription factor that has an essential role in the normal growth, development, and maintenance of the prostate gland. The AR is part of a large family of steroid receptors that also includes the glucocorticoid, progesterone, and mineralocorticoid receptors. Steroid receptor family members share significant homology at their DNA and ligand-binding domains. However, these receptors exhibit a high degree of sequence variability at their NH(2)-terminal domain, which suggests the possibility of receptor-specific interactions with co-regulator proteins. Transcriptional co-regulators that interact with the AR may have a role in defining AR activity and may be involved in directing AR-specific responses. Here we have identified Ran-binding protein in the microtubule-organizing center (RanBPM) to be a novel AR-interacting protein by yeast two-hybrid assay and have confirmed this interaction by glutathione S-transferase- and His-tagged pull-down assays. In addition, transient overexpression of RanBPM in prostate cancer cell lines resulted in enhanced AR activity in a ligand-dependent fashion. Glucocorticoid receptor activity was also enhanced when RanBPM was overexpressed, whereas estrogen receptor activity remained unchanged. These data demonstrate that RanBPM interacts with steroid receptors to selectively modify their activity.

Adaptor Proteins, Signal Transducing↗

PubMed2006

NMR structure of the full-length linear dimer of stem-loop-1 RNA in the HIV-1 dimer initiation site.

The packaging signal of HIV-1 RNA contains a stem-loop structure, SL1, which serves as the dimerization initiation site for two identical copies of the genome and is important for packaging of the RNA genome into the budding virion and for overall infectivity. SL1 spontaneously dimerizes via a palindromic hexanucleotide sequence in its apical loop, forming a metastable kissing dimer form. Incubation with nucleocapsid protein causes this form to refold to a thermodynamically stable mature linear dimer. Here, we present an NMR structure of the latter form of the full-length SL1 sequence of the Lai HIV-1 isolate. The structure was refined using nuclear Overhauser effect and residual dipolar coupling data. The structure presents a symmetric homodimer of two RNA strands of 35 nucleotides each; it includes five stems separated by four internal loops. The central palindromic stem is surrounded by two symmetric adenine-rich 1-2 internal loops, A-bulges. All three adenines in each A-bulge are stacked inside the helix, consistent with the solution structures of shorter SL1 constructs determined previously. The outer 4-base pair stems and, proximal to them, purine-rich 1-3 internal loops, or G-bulges, are the least stable parts of the molecule. The G-bulges display high conformational variability in the refined ensemble of structures, despite the availability of many structural restraints for this region. Nevertheless, most conformations share a similar structural motif: a guanine and an adenine from opposite strands form a GA mismatch stacked on the top of the neighboring stem. The two remaining guanines are exposed, one in the minor groove and another in the major groove side of the helix, consistent with secondary structure probing data for SL1. These guanines may be recognized by the nucleocapsid protein, which binds tightly to the G-bulge in vitro.

Base Sequence↗

PubMed2004

Genetic and environmental sources on familial transmission in Biscayan families. III. The dynamometric strength.

The present research analyses a cross-sectional sample of 284 individuals (86 fathers, 86 mothers, 54 sons and 58 daughters) in 86 nuclear families living in the province of Biscay (Basque Country, Spain), with the aim of estimating both transmissible and non-transmissible components acting on familial resemblance for the maximum dynamometric strength of both hands, by means of a path analysis. Standardised data of each generation and sex were adjusted to a BETA model of path analysis independent of sex effects, allowing nevertheless the possibility to differentiate between transmissible (genetic and cultural) and non-transmissible (environmental) components acting on the observed phenotypic variance in Biscayan offspring. The results supported the full model of familial transmission for the two variables, in addition to other reduced models that gave rise to transmission effects regardless of any influence from the siblings' shared environment on the environmental transmitted component from their parents (b = 0), and without social homogamy between mates (u = 0). The most parsimonious model created, based on the previous ones, was accepted for both traits. The total transmissible variance (t2) explained between 21% (right hand) and 44% (left hand) of the observed phenotypic variation. These values are close to those from the literature (t2 = 37%). However, we should take into account that these kinds of estimations are specific for each group or population.

Adult↗

PubMedDate not supplied

Genetic and environmental sources on familial transmission in Basque families. II. Stature, weight and body mass index.

PRIMARY OBJECTIVE: The present research analyses a cross-sectional sample of 359 individuals (107 fathers, 107 mothers, 71 sons and 74 daughters) in 107 nuclear families from the Basque Country (Spain). The aim was the estimation of both transmissible and non-transmissible components acting on familial resemblance for stature, weight and body mass index (BMI). METHODS: Standardized data of each generation and sex were adjusted to a BETA model of path analysis independent of sex effects, allowing the possibility of differentiating between transmissible (genetic and cultural) and non-transmissible (environmental) components acting on the observed phenotypic variance in Biscayan offspring. RESULTS: The results supported the full model of familial transmission for the three variables, in addition to other reduced models that gave rise to transmission effects regardless of any influence from the siblings' shared environment on the environmental transmitted component from their parents (b = 0), and without genetic effects on the phenotype (h = z = 0). The most parsimonious model was accepted for weight and rejected for stature and BMI. The correlations existing between children and their mothers were higher than those with their fathers. CONCLUSION: The results confirmed the hypothesis of maternal effects influencing the inheritance of stature.

Adolescent↗

PubMed2006

Evolutionary history of a mosquito endosymbiont revealed through mitochondrial hitchhiking.

Due to cytoplasmic inheritance, spread of maternally inherited Wolbachia symbionts can result in reduction of mitochondrial variation in populations. We examined sequence diversity of the mitochondrial NADH dehydrogenase subunit 4 (ND4) gene in Wolbachia-infected (South Africa (SA), California and Thailand) and uninfected (SA) Culex pipiens complex populations. In total, we identified 12 haplotypes (A-L). In infected populations, 99% of individuals had haplotype K. In the uninfected SA population, 11 haplotypes were present, including K. Nuclear allozyme diversity was similar between infected and uninfected SA populations. Analysis of nuclear DNA sequences suggested that haplotype K presence in uninfected SA Cx. pipiens was probably due to a shared ancestral polymorphism rather than hybrid introgression. These data indicate that Wolbachia spread has resulted in drastic reduction of mitochondrial variability in widely separated Cx. pipiens complex populations. In contrast, the uninfected SA population is probably a cryptic species where Wolbachia introgression has been prevented by reproductive isolation, maintaining ancestral levels of mitochondrial diversity. Molecular clock analyses suggest that the Wolbachia sweep occurred within the last 47000 years. The effect of Wolbachia on mitochondrial dynamics can provide insight on the potential for Wolbachia to spread transgenes into mosquito populations to control vector-borne diseases.

Animals↗

PubMed2005

Widespread clone of Burkholderia cenocepacia in cystic fibrosis patients in the Czech Republic.

The morbidity and mortality rates in patients with cystic fibrosis (CF) are significantly affected by infections with Burkholderia cepacia complex. In a Czech CF Centre, the prevalence of the infection reached up to 30 %, with the majority of patients found to be infected with Burkholderia cenocepacia (formerly genomovar III of the Burkholderia cepacia complex). Since B. cenocepacia is associated with patient-to-patient transmission and epidemic outbreaks among CF patients, this study sought to examine the epidemiological relatedness between the Czech isolates belonging to the genomovar-homogeneous group. Eighty-three clinical isolates recovered from 67 CF patients were analysed using a random amplified polymorphic DNA (RAPD) assay and macrorestriction typing (SpeI and XbaI) followed by PFGE. A single predominant banding pattern shared by multiple isolates was detected, although SpeI-generated PFGE results yielded a higher rate of inter-pattern variability in comparison to the more uniform RAPD and XbaI-generated PFGE results for this clone. Both typing systems also showed that only three out of 67 patients harboured strains distinct from the major strain type. The dominant clone was characterized by PCR positivity for the B. cepacia epidemic strain marker, PCR negativity for the cable pilin subunit gene and close genetic relatedness to the epidemic strain of RAPD 01 type previously identified in Canada.

Adolescent↗

PubMed2006

Full-length genome sequences of two SARS-like coronaviruses in horseshoe bats and genetic variation analysis.

Bats were recently identified as natural reservoirs of SARS-like coronavirus (SL-CoV) or SARS coronavirus-like virus. These viruses, together with SARS coronaviruses (SARS-CoV) isolated from human and palm civet, form a distinctive cluster within the group 2 coronaviruses of the genus Coronavirus, tentatively named group 2b (G2b). In this study, complete genome sequences of two additional group 2b coronaviruses (G2b-CoVs) were determined from horseshoe bat Rhinolophus ferrumequinum (G2b-CoV Rf1) and Rhinolophus macrotis (G2b-CoV Rm1). The bat G2b-CoV isolates have an identical genome organization and share an overall genome sequence identity of 88-92 % among themselves and between them and the human/civet isolates. The most variable regions are located in the genes encoding nsp3, ORF3a, spike protein and ORF8 when bat and human/civet G2b-CoV isolates are compared. Genetic analysis demonstrated that a diverse G2b-CoV population exists in the bat habitat and has evolved from a common ancestor of SARS-CoV.

Animals↗

PubMed2004

The small chromosomes of Trypanosoma brucei involved in antigenic variation are constructed around repetitive palindromes.

Most eukaryotic genomes contain large regions of satellite DNA. These arrays are often associated with essential chromosomal functions, but remain largely absent from genome projects because of difficulties in cloning and sequence assembly. The numerous small chromosomes of the parasite Trypanosoma brucei fall into this category, yet are critical to understanding the genome because of their role in antigenic variation. Their relatively small size, however, makes them particularly amenable to physical mapping. We have produced fine-resolution maps of 17 complete minichromosomes and partial maps of two larger intermediate-sized chromosomes. This revealed a canonical structure shared by both chromosomal classes based around a large central core of 177-bp repeats. Around the core are variable-length genic regions, the lengths of which define chromosomal class. We show the core region to be a repetitive palindrome with a single inversion point common to all the chromosomes of both classes, suggesting a mechanism of genesis for these chromosomes. Moreover, palindromy appears to be a feature of (peri)centromeres in other species that can be easily overlooked. We propose that sequence inversion is one of the higher-order sequence motifs that confer chromosomal stability.

Animals↗

PubMed2006

Buying time II: an economic evaluation of a joint NHS/Social Services residential rehabilitation unit for older people on discharge from hospital.

The study's aim was to investigate the cost-effectiveness of an NHS/Social Services short-term residential rehabilitation unit (a form of intermediate care) for older people on discharge from community hospital compared with 'usual' community services. An economic evaluation was conducted alongside a prospective controlled trial, which explored the effectiveness of a rehabilitation unit in a practice setting. The aim of the unit was to help individuals regain independence. A matched control group went home from hospital with the health/social care services they would ordinarily receive. The research was conducted in two matched geographical areas in Devon: one with a rehabilitation unit, one without. Participants were recruited from January 1999 to October 2000 in 10 community hospitals and their eligibility determined using the unit's strict inclusion/exclusion criteria, including 55 years or older and likely to benefit from a short-term rehabilitation programme: potential to improve, realistic, achievable goals, motivation to participate. Ninety-four people were recruited to the intervention and 112 to the control group. Details were collated of the NHS and Social Services resources participants used over a 12-month follow-up. The cost of the resource use was compared between those who went to the unit and those who went straight home. Overall, costs were very similar between the two groups. Aggregated mean NHS/Social Services costs for the 12 months of follow-up were pound 8542.28 for the intervention group and pound 8510.68 for the control. However, there was a clear 'seesaw' effect between the NHS and Social Services: the cost of the unit option fell more heavily on Social Services (pound 5011.56, whereas pound 3530.72 to the NHS), the community option more so on the NHS (pound 5146.74, whereas pound 3363.94 to Social Services). This suggests that residential rehabilitation for older people is no more cost-effective over a year after discharge from community hospital than usual community services. The variability in cost burden between the NHS and Social Services has implications for 'who pays' and being sure that agencies share both pain and gain.

Aged↗

PubMed1993

Corpora amylacea could be an indicator of neurodegeneration.

We describe an investigation of corpora amylacea (CA) in the brain tissue of Alzheimer's disease (AD) cases and normal ageing controls, using both light (LM) and electron (EM) microscopic techniques. CA populations were shown by routine histological staining of LR White resin sections with methenamine silver and PAS, and were compared with those shown by immunocytochemistry using antibodies to tau, GFAP, tubulin, ubiquitin, beta-amyloid and serum amyloid P component in serial sections. All CA were immunoreactive with anti-tau and all were unreactive with anti-beta-amyloid. Most were immunoreactive with anti-serum amyloid P component, although this was often weak in AD. CA from normal ageing brain were immunoreactive for proteins that are associated with the neuronal cytoskeleton and cell injury. CA from AD brain shared some of these but differed from those in normal ageing brain by being in much larger number and more variable in their immunoreactivity. In all CA, X-ray microanalysis illustrated the presence of the metallic elements Ca, Fe and Cu. Aluminium, often associated with AD, was not present, even in CA from AD brain. Phosphorus and sulphur, probably from phosphorylated proteins associated with degenerating cytoskeleton elements, were usually detected. In AD brain, the greater numbers of CA and their variable biochemical and elemental composition, when compared with CA in the normal ageing brain, suggests that they may derive from a number of sources both neuronal and glial as a result of the neurodegenerative disease.

Alzheimer Disease↗

PubMed1998

Nerve dependency of developing and mature sensory receptor cells.

Old and recent data concerning development of sensory cells and trophic interdependency of sensory neurons and sensory cells is reviewed for the ear, the lateral line system, the electroreceptive system, and the taste system. All sensory neurons originate from placodes. However, only most ear, lateral line and electrosensory cells derive from placodes, while the taste sensory cell originate locally. All sensory cells apparently are nerve independent for their formation, and at least sensory cells in the ear and the taste system share the neurotrophic support for their specific sensory neurons. Later, most of these sensory cells appear to depend, to a variable degree, on some innervation for maintenance. While the molecular nature of the signal cascade from sensory cells to sensory neurons is known in at least two systems, nothing is known about the molecular nature of the signal cascade from the sensory neurons back to the sensory cells.

Animals↗

PubMed2005

The B7 family of immune-regulatory ligands.

The B7 family consists of structurally related, cell-surface protein ligands, which bind to receptors on lymphocytes that regulate immune responses. Activation of T and B lymphocytes is initiated by engagement of cell-surface, antigen-specific T-cell receptors or B-cell receptors, but additional signals delivered simultaneously by B7 ligands determine the ultimate immune response. These 'costimulatory' or 'coinhibitory' signals are delivered by B7 ligands through the CD28 family of receptors on lymphocytes. Interaction of B7-family members with costimulatory receptors augments immune responses, and interaction with coinhibitory receptors attenuates immune responses. There are currently seven known members of the family: B7.1 (CD80), B7.2 (CD86), inducible costimulator ligand (ICOS-L), programmed death-1 ligand (PD-L1), programmed death-2 ligand (PD-L2), B7-H3, and B7-H4. Members of the family have been characterized predominantly in humans and mice, but some members are also found in birds. They share 20-40% amino-acid identity and are structurally related, with the extracellular domain containing tandem domains related to variable and constant immunoglobulin domains. B7 ligands are expressed in lymphoid and non-lymphoid tissues. The importance of the family in regulating immune responses is shown by the development of immunodeficiency and autoimmune diseases in mice with mutations in B7-family genes. Manipulation of the signals delivered by B7 ligands has shown potential in the treatment of autoimmunity, inflammatory diseases and cancer.

Animals↗

PubMed2000

Hypercapnic ventilatory response in patients with and without obstructive sleep apnea: do age, gender, obesity, and daytime PaCO(2) matter?

STUDY OBJECTIVE: To evaluate the relationship between obstructive sleep apnea (OSA) and ventilatory responsiveness to carbon dioxide in both men and women. DESIGN: An analysis of 219 patients referred to an university-based sleep center between 1989 to 1994 was conducted (104 with OSA and 115 without OSA; 43 women and 176 men). These patients had spirometry and a daytime hypercapnic ventilatory response (HCVR) test that was corrected to the patient's ability to attain maximal ventilation. Comparisons between OSA and no-OSA groups, as well as between men and women, were made using multivariate modeling techniques. RESULTS: There was no significant difference in the slope of correlated HCVR (cHCVR) between those with and without OSA (1.57 +/- 0.57 vs 1.63 +/- 0.66; p = 0.48). In men, an inverse correlation between daytime PCO(2) and cHCVR was observed in both crude and multivariate analyses (crude beta-coefficient = - 0.04 +/- 0.02, p = 0.02; adjusted beta-coefficient = 0.07 +/- 0.02, p < 0.01). Although age and cHCVR did not share a significant relationship in the crude analysis (crude beta-coefficient = - 0.01 +/- 0.01, p = 0.10), with adjustments for confounding variables, a significant inverse relationship between age and cHCVR was observed (beta-coefficient = - 0.02 +/- 0.01, p = 0.04). On the other hand, in women, only body mass index (BMI) was positively correlated with cHCVR (crude beta-coefficient = 0.03 +/- 0.01, p = 0.01; adjusted beta-coefficient = 0.04 +/- 0.01, p < 0.01). CONCLUSION: OSA disorder is not associated with a blunted ventilatory chemoresponsiveness to carbon dioxide. Elevated PaCO(2) and older age are significant correlates for a low cHCVR in men. For women only, BMI was associated with cHCVR. These findings suggest that men and women may have different ventilatory control mechanisms.

Adult↗

PubMed2003

An unusual intraerythrocytic parasite of Parablennius cornutus from South Africa.

An intertidal horned blenny, Parablennius cornutus, captured at De Hoop Nature Reserve, South Africa, was found to harbor an unusual blood parasite and the haemogregarine Haemogregarina bigemina. In Giemsa-stained blood films, the enigmatic parasite occurred primarily as intraerythrocytic ringlike stages, with unstained centers and peripheral bands of beaded chromatin, not unlike Haemohormidium spp. Larger forms of the same organism stained pink with Giemsa, with nuclei occurring as 4-8 minute structures around the parasite body or distributed within it. These larger parasites apparently segmented into up to 8 individuals that were rounded or oval with deep-stained, comma-shaped or polar regions surrounding blue cytoplasm. Extracellular, binucleate, sporelike structures in clusters of as many as 16 individuals were also seen in blood films. Praniza larvae of the isopod Gnathia africana were seen in histological sections of gill tissue. Examination of spleen tissue by transmission electron microscopy showed intraerythrocytic organisms with ultrastructural characteristics like those of Haematractidium scombri, namely, a single boundary membrane, sometimes closely apposed nuclei with nucleoli, and profiles of dense material of variable structure. It is concluded that the parasite is probably related to Haemohormidium spp. and H. scombri, but it also shares features with some Microsporida.

Animals↗