Integrating functional genomics data using maximum likelihood based simultaneous component analysis

Background  

In contemporary biology, complex biological processes are increasingly studied by collecting and analyzing measurements of the same entities that are collected with different analytical platforms. Such data comprise a number of data blocks that are coupled via a common mode. The goal of collecting this type of data is to discover biological mechanisms that underlie the behavior of the variables in the different data blocks. The simultaneous component analysis (SCA) family of data analysis methods is suited for this task. However, a SCA may be hampered by the data blocks being subjected to different amounts of measurement error, or noise. To unveil the true mechanisms underlying the data, it could be fruitful to take noise heterogeneity into consideration in the data analysis. Maximum likelihood based SCA (MxLSCA-P) was developed for this purpose. In a previous simulation study it outperformed normal SCA-P. This previous study, however, did not mimic in many respects typical functional genomics data sets, such as, data blocks coupled via the experimental mode, more variables than experimental units, and medium to high correlations between variables. Here, we present a new simulation study in which the usefulness of MxLSCA-P compared to ordinary SCA-P is evaluated within a typical functional genomics setting. Subsequently, the performance of the two methods is evaluated by analysis of a real life Escherichia coli metabolomics data set.     

INCITE: A randomised trial comparing constraint induced movement therapy and bimanual training in children with congenital hemiplegia

Background  

Congenital hemiplegia is the most common form of cerebral palsy (CP) accounting for 1 in 1300 live births. These children have limitations in capacity to use the impaired upper limb and bimanual coordination deficits which impact on daily activities and participation in home, school and community life. There are currently two diverse intensive therapy approaches. Traditional therapy has adopted a bimanual approach (BIM training) and recently, constraint induced movement therapy (CIMT) has emerged as a promising unimanual approach. Uncertainty remains about the efficacy of these interventions and characteristics of best responders. This study aims to compare the efficacy of CIMT to BIM training to improve outcomes across the ICF for school children with congenital hemiplegia.     

Functional relevance of the cannabinoid receptor 2 — heme oxygenase pathway: A novel target for the attenuation of portal hypertension

Aims

In liver cirrhosis, inflammation triggers portal hypertension. Kupffer cells (KC) produce vasoconstrictors upon activation by bacterial constituents. Here, we hypothesize that the anti-inflammatory action of the cannabinoid receptor 2 (CB₂) agonists JWH-133 and GP 1a attenuate portal hypertension.

Main methods

In vivo measurements of portal pressures and non-recirculating liver perfusions were performed in rats 4 weeks after bile duct ligation (BDL). Zymosan (150 μg/ml, isolated liver perfusion) or LPS (4 mg/kg b.w., in vivo) was infused to activate the KC in the absence or presence of JWH-133 (10 mg/kg b.w.), GP 1a (2.5 mg/kg b.w.) or ZnPP IX (1 μM). Isolated KC were treated with Zymosan (0.5 mg/ml) in addition to JWH-133 (5 μM). The thromboxane (TX) B₂ levels in the perfusate and KC media were determined by ELISA. Heme oxygenase-1 (HO-1) and CB₂ were analyzed by Western blot or confocal microscopy.

Key findings

JWH-133 or GP 1a pre-treatment attenuated portal pressures following KC activation in all experimental settings. In parallel, HO-1 expression increased with JWH-133 pre-treatment. However, the inhibition of HO-1 enhanced portal hypertension, indicating the functional role of this novel pathway. In isolated KC, the expression of CB₂ and HO-1 increased with Zymosan, LPS and JWH-133 treatment while TXB₂ production following KC activation was attenuated by JWH-133 pre-treatment.

Significance

JWH-133 or GP 1a treatment attenuates portal hypertension. HO-1 induction by JWH-133 plays a functional role. Therefore, the administration of JWH-133 or GP 1a represents a promising new treatment option for portal hypertension triggered by microbiological products.     

Linkage disequilibrium on chromosome 6 in Australian Holstein-Friesian cattle

We analysed linkage disequilibrium (LD) in Australian Holstein-Friesian cattle by genotyping a sample of 45 bulls for 15 closely-spaced microsatellites on two regions of BTA6 reported to carry important QTL for dairy traits. The order and distance of markers were based on the USDA-MARC linkage map. Frequencies of haplotypes were estimated using the E-M approach and a more computationally-intensive Bayesian approach as implemented in PHASE. LD was then estimated using the Hedrick multiallelic extension of Lewontin normalised coefficient D''. Estimates of D'' from the two approaches were in close agreement (r = 0.91). The mean estimates of D'' for marker pairs with an inter-marker distance of less than 5 cM (n = 13) are 0.57 and 0.51, and for distances more than 20 cM (n = 44) are 0.29 and 0.17, estimated from the E-M and Bayesian approaches, respectively. The Malecot model was fitted for the exponential decline of LD with map distance between markers. The swept radii (the distance at which LD has declined to 1/e (~37%) of its initial value) are 11.6 and 13.7 cM for the above two methods, respectively. The Malecot model was also fitted using map distance in Mb from the bovine integrated map (bovine location database, bLDB) in addition to cM from the MARC map. Overall, the results indicate a high level of LD on chromosome 6 in Australian dairy cattle.     

Contrasting evolutionary rates in the duplicate chaperonin genes of Mycobacterium tuberculosis and M. leprae

A phylogenetic analysis of chaperonin (heat shock protein 60) sequences from prokaryotes and eukaryotes indicated that a single gene duplication event in the common ancestor of Mycobacterium tuberculosis, M. leprae, and Streptomyces albus gave rise to the duplicate chaperonin genes found in these species (designated HSP65 and GroEL in the mycobacterial species). Comparison of rates of synonymous and nonsynonymous nucleotide substitution in different gene regions suggested that the 5' end of the HSP65 gene was homogenized by an ancient recombination event between M. tuberculosis and M. leprae. In S. albus, the two duplicated chaperonin genes have evolved at essentially the same rate. In both M. tuberculosis and M. leprae, however, the GroEL gene has evolved considerably more rapidly at nonsynonymous nucleotide sites than has the HSP65 gene. Because this difference is not seen at synonymous sites, it must be due to a difference in selective constraint on the proteins encoded by the two genes, rather than to a difference in mutation rate. The difference between GroEL and HSP65 is striking in regions containing epitopes recognized by T cells of the vertebrate host; in certain cross-reactive epitopes conserved across all organisms, nonsynonymous sites in GroEL have evolved twice as fast as those in HSP65. It is suggested that these differences are correlated with differences in the way in which the duplicate chaperonins of M. tuberculosis and M. leprae interact with the host immune system.      

Further evidence of the African antiquity of hyaenodontid (‘Creodonta’, Mammalia) evolution

We report here the new ‘creodont’ Lahimia selloumi gen. et sp. nov. from the late Palaeocene of the Ouled Abdoun Basin (Morocco) as the oldest known Hyaenodontidae with Tinerhodon from the Ouarzazate Basin (Morocco). By contrast to Tinerhodon, Lahimia is unexpectedly derived. Most of its specializations, such as the shortening of the anterior dentition (e.g. loss of P₁) and the talonid reduction and simplification, are strikingly shared with Boualitomus from the Ypresian of the Ouled Abdoun Basin, and are distinctive from other hyaenodontids, including ‘proviverrines’. They are interpreted as synapomorphies evidencing a precociously specialized early African hyaenodontid lineage. Although Lahimia and Boualitomus remain known only by the lower dentition, their relationships with Koholia are suggested by comparison of their molar occlusal pattern. Lahimia and Boualitomus are referred to the Koholiinae, which is representative of an old African endemic lineage, as initially recognized. This remarkable lineage is characterized by synapomorphies of Lahimia and Boualitomus, and also by a shared original prevallum/postvallid shearing. The discovery of Lahimia provides direct evidence for the antiquity of the African evolution of the Hyaenodontidae. This is in agreement with an African origin of the Hyaenodontidae, and with the probable diphyletism of the ‘Creodonta’. Lahimia and the Koholiinae, as well as the diversity of the first Laurasian hyaenodontid lineages, emphasize our poor knowledge of the striking early African hyaenodontid radiation.     

Development and prospective validation of a model for predicting weaning in chronic ventilator dependent patients

Background

HTLV-I infection has been linked to lung pathology and HTLV-II has been associated with an increased incidence of pneumonia and acute bronchitis. However it is unknown whether HTLV-I or -II infection alters pulmonary function.

Methods

We performed pulmonary function testing on HTLV-I, HTLV-II and HTLV seronegative subjects from the HTLV outcomes study (HOST), including vital capacity (VC), forced expiratory volume in one second (FEV₁), and diffusing lung capacity for carbon monoxide (DLCO) corrected for hemoglobin and lung volume. Multivariable analysis adjusted for differences in age, gender, race/ethnicity, height and smoking history.

Results

Mean (standard deviation) pulmonary function values among the 257 subjects were as follows: FVC = 3.74 (0.89) L, FEV₁ = 2.93 (0.67) L, DLCO_corr = 23.82 (5.89) ml/min/mmHg, alveolar ventilation (VA) = 5.25 (1.20) L and DLCO_corr/VA = 4.54 (0.87) ml/min/mmHg/L. There were no differences in FVC, FEV1 and DLCO_corr/VA by HTLV status. For DLCO_corr, HTLV-I and HTLV-II subjects had slightly lower values than seronegatives, but neither difference was statistically significant after adjustment for confounding.

Conclusions

There was no difference in measured pulmonary function and diffusing capacity in generally healthy HTLV-I and HTLV-II subjects compared to seronegatives. These results suggest that previously described HTLV-associated abnormalities in bronchoalveolar cells and fluid may not affect pulmonary function.     

Spatial distribution of vectors of Ross River virus and Barmah Forest virus on Russell Island, Moreton Bay, Queensland

Abstract We used a network of 20 carbon dioxide- and octenol-supplemented light traps to sample adult mosquitoes throughout Russell Island in southern Moreton Bay, south-east Queensland. Between February and April 2001, an estimated 1365 564 adult female mosquitoes were collected. In contrast to an average catch of 9754 female mosquitoes per trap night on Russell Island, reference traps set on Macleay Island and on the mainland returned average catches of 3172 and 222, respectively. On Russell Island, Ochlerotatus vigilax (Skuse), Coquillettidia linealis (Skuse), Culex annulirostris Skuse and Verrallina funerea (Theobald), known or suspected vectors of Ross River (RR) and/or Barmah Forest (BF) viruses, comprised 89.6% of the 25 taxa collected. When the spatial distributions of the above species were mapped and analysed using local spatial statistics, all were found to be present in highest numbers towards the southern end of the island during most of the 7 weeks. This indicated the presence of more suitable adult harbourage sites and/or suboptimal larval control efficacy. As immature stages and the breeding habitat of Cq. linealis are as yet undescribed, this species in particular presents a considerable impediment to proposed development scenarios. The method presented here of mapping the numbers of mosquitoes throughout a local government area allows specific areas that have high vector numbers to be defined.     

Sequence, organization, and evolution of the A+T region of Drosophila melanogaster mitochondrial DNA

The long (4.6-kb) A+T region of Drosophila melanogaster mitochondrial DNA has been cloned and sequenced. The A+T region is organized in two large arrays of tandemly repeated DNA sequence elements, with nonrepetitive intervening and flanking sequences comprising only 22% of its length. The first repeat array consists of five repeats of 338-373 bp. The second consists of four intact 464-bp repeats and a fifth partial repeat of 137 bp. Three DNA sequence elements are found to be highly conserved in D. melanogaster and in several Drosophila species with short A+T regions. These include a 300-bp DNA sequence element that overlaps the DNA replication origin and two thymidylate stretches identified on opposite DNA strands. We conclude that the length heterogeneity observed in the A+T regulatory region in mitochondrial DNAs from the genus Drosophila results from the expansion (and contraction) of the number of repeated DNA sequence elements. We also propose that the 300-bp conserved DNA sequence element, in conjunction with another primary sequence determinant, perhaps the adjacent thymidylate stretch, functions in the regulation of mitochondrial DNA replication.      

Purification of galectin-3 from ovine placenta: developmentally regulated expression and immunological relevance

Galectins, beta-galactoside-binding lectins, are extensively distributed in the animal kingdom and share some basic molecular properties. Galectin-3, a member of this family, is generally associated with differentiation, morphogenesis, and metastasis. In this study, galectin-3 was isolated from ovine placental cotyledons round the middle of the gestation period by lactose extraction followed by affinity chromatography on lactosyl-agarose, and separated from galectin-1 by size exclusion chromatography on a Superose 12 column. Under native conditions this lectin behaved as a monomer with an apparent molecular weight of approximately 29,000 and an isoelectric point of 9.0. The partial amino acid sequence of the peptides obtained by tryptic digestion of this protein followed by HPLC separation showed striking homology with other members of the galectin-3 subfamily. Furthermore, ovine placental galectin-3 exhibited specific mitogenic activity toward rat spleen mononuclear cells. Besides, this protein strongly reacted with a rabbit antiserum raised against a chicken galectin. Results obtained by Western blot analysis showed that its expression was greatly decreased in term placenta with respect to the middle of the gestation period, suggesting a regulated expression throughout development.