EXAMINE: a computational approach to reconstructing gene regulatory networks

Reverse-engineering of gene networks using linear models often results in an underdetermined system because of excessive unknown parameters. In addition, the practical utility of linear models has remained unclear. We address these problems by developing an improved method, EXpression Array MINing Engine (EXAMINE), to infer gene regulatory networks from time-series gene expression data sets. EXAMINE takes advantage of sparse graph theory to overcome the excessive-parameter problem with an adaptive-connectivity model and fitting algorithm. EXAMINE also guarantees that the most parsimonious network structure will be found with its incremental adaptive fitting process. Compared to previous linear models, where a fully connected model is used, EXAMINE reduces the number of parameters by O(N), thereby increasing the chance of recovering the underlying regulatory network. The fitting algorithm increments the connectivity during the fitting process until a satisfactory fit is obtained. We performed a systematic study to explore the data mining ability of linear models. A guideline for using linear models is provided: If the system is small (3-20 elements), more than 90% of the regulation pathways can be determined correctly. For a large-scale system, either clustering is needed or it is necessary to integrate information in addition to expression profile. Coupled with the clustering method, we applied EXAMINE to rat central nervous system development (CNS) data with 112 genes. We were able to efficiently generate regulatory networks with statistically significant pathways that have been predicted previously.     

Evolutionary conservation suggests a regulatory function of AUG triplets in 5'-UTRs of eukaryotic genes

By comparing sequences of human, mouse and rat orthologous genes, we show that in 5′-untranslated regions (5′-UTRs) of mammalian cDNAs but not in 3′-UTRs or coding sequences, AUG is conserved to a significantly greater extent than any of the other 63 nt triplets. This effect is likely to reflect, primarily, bona fide evolutionary conservation, rather than cDNA annotation artifacts, because the excess of conserved upstream AUGs (uAUGs) is seen in 5′-UTRs containing stop codons in-frame with the start AUG and many of the conserved AUGs are found in different frames, consistent with the location in authentic non-coding sequences. Altogether, conserved uAUGs are present in at least 20–30% of mammalian genes. Qualitatively similar results were obtained by comparison of orthologous genes from different species of the yeast genus Saccharomyces. Together with the observation that mammalian and yeast 5′-UTRs are significantly depleted in overall AUG content, these findings suggest that AUG triplets in 5′-UTRs are subject to the pressure of purifying selection in two opposite directions: the uAUGs that have no specific function tend to be deleterious and get eliminated during evolution, whereas those uAUGs that do serve a function are conserved. Most probably, the principal role of the conserved uAUGs is attenuation of translation at the initiation stage, which is often additionally regulated by alternative splicing in the mammalian 5′-UTRs. Consistent with this hypothesis, we found that open reading frames starting from conserved uAUGs are significantly shorter than those starting from non-conserved uAUGs, possibly, owing to selection for optimization of the level of attenuation.     

S434F in NrdE generates the thermosensitive phenotype of corynebacterium ammoniagenes CH31 and enhances thermolability by increasing the surface hydrophobicity of the NrdE(Ts) protein

The thermosensitive phenotype of strain CH31, a derivative of Corynebacterium ammoniagenes ATCC 6872, was allocated by cloning, sequencing, and genetic complementation to a single C-->T exchange in the nrdE (nucleotide reduction) gene at nucleotide 1301. Protein modeling indicates the impaired surface hydrophobicity of NrdE(Ts) due to the S434F transition.     

The validity of summing lower extremity individual joint kinetic measures

In the analysis of human movement, researchers often sum individual joint kinetics to obtain a single measure of lower extremity function. The extent to which these summed measures relate to the mechanical objectives of the task has not been formally validated. The criterion validity of these measures was established with comparisons to the mechanical objective of two multiple-joint tasks. For the Work task 18 participants performed a loaded barbell squat using 4 resistances while instrumented for biomechanical analysis. For the Power they performed 2 predetermined amounts of work at both self-selected and fast speeds. Using inverse dynamics techniques, the peak net joint moment (PM) was calculated bilaterally in the sagittal plane at the ankle, knee, and hip and was summed into a single measure. This measure was correlated with the task objectives using simple linear regression. Similar procedures were used for the average net joint moment (AM), peak (PP), and average (AP) net joint moment power, and the net joint moment impulse (IM) and work (IP). For the Work task all 6 measures were significantly correlated with the task objective, but only AM, PM, and IP had correlation coefficients above 0.90. For the Power task, IM was not significantly correlated with the task objective, and only AP had a correlation coefficient above 0.90. These findings indicate that the validity of summing individual kinetic measures depends on both the measure chosen and the mechanical objective of the task.     

Analysis of the human <Emphasis Type="Italic">Alu</Emphasis> Ye lineage

Background  

Alu elements are short (~300 bp) interspersed elements that amplify in primate genomes through a process termed retroposition. The expansion of these elements has had a significant impact on the structure and function of primate genomes. Approximately 10 % of the mass of the human genome is comprised of Alu elements, making them the most abundant short interspersed element (SINE) in our genome. The majority of Alu amplification occurred early in primate evolution, and the current rate of Alu retroposition is at least 100 fold slower than the peak of amplification that occurred 30–50 million years ago. Alu elements are therefore a rich source of inter- and intra-species primate genomic variation.     

Licorice: A possible anti-inflammatory and anti-ulcer drug

The purpose of this investigation was to study the anti-inflammatory activities of both glycerrhitinic acid (GA) and the aqueous licorice extract (ALE) in comparison with diclofenac sodium (DS) (10 mg/kg), using the carrageenan-induced paw edema model in male albino rats. In addition, the anti-ulcer activities of ALE, famotidine (FT), and a combination of ALE and FT using indomethacin-induced ulceration technique in rat stomach were investigated. Conventional DS tablets containing GA, as well as DS chewable tablets containing either GA or ALE with different tastes were prepared. Also, rapidly disintegrating FT tablets were prepared using direct compression and camphor sublimation methods. ALE or GA produced significant anti-inflammatory activity similar to DS, and when taken concomitantly, there is no possible antagonism. The anti-ulcer activity of licorice was found to be similar to that of FT in indomethacin-induced ulceration technique in rat stomach. Combination therapy of both FT and licorice showed higher anti-ulcer activity than either of them alone. Generally, tablets containing the crosslinked sodium carboxymethyl cellulose (AcDisol) showed more rapidly disintegrating effect than those including Sodium starch glycolate (Primojel). The oral disintegration was very rapid for all the tested formulations. Also, the amount of FT absorbed from the oral cavity was nearly 9 from 10 mg theoretically present in each formula. It could be concluded that both GA and ALE have anti-inflammatory activity comparable with DS. It may be recommended to add ALE to either FT or diclofinac for more effective anti-inflammatory or anti-ulcer formulations, respectively.     

Sports-anthropological analysis of Tunisian elite karateka

This study is based on a careful sport anthropological investigation (ca. 15 min) of 25 Tunisian athletes of the Karate team (aged 18 - 31 years) with special permission of the Tunisian Ministry of Youth and Sports. Considering the height of the Tunisian elite athletes (175.6 +/- 4.9 cm), heavier kareteka are bigger (178.9 +/- 2.2 cm vs. 171.4 +/- 3.9 cm). The mean weight was 73.1 +/- 8.2 kg (heavier athletes 78.7 +/- 5.9 kg vs. lighter athletes 66.0 +/- 4.1 kg). On Conrad's chessboard diagram all the Tunisian karateka were placed in the leptomorph half, only two in the metromorph corridor, but most of them in the middle between hypoplastic and hyperplastic poles. The AKS index diagram demonstrates a faint diagonal positioning of the single weight categories, with progression of body mass from the lower to the upper right area. None of the athletes surpasses a body height of 184 cm. The variation of the AKS index is higher than the variation of body height. The constitutional analysis according to Knussmann (1961) reveals an orientation of heavier weight classes towards macrosomia and pyknomorphism. The proportional figures of the athletes show a small variation of joint heights in lower extremities. In Parnell's somatochart (1954, 1958) the concentration of Tunisian karateka is found in the mesoectomorph third as well as in the somatochart of Heath & Carter (1967). Further sport anthropological karate studies should focus on adolescents and females as well as on physiological and biomechanic parameters.     

Influence of interleukin-2 and interferon-gamma in murine schistosomiasis

Schistosoma mansoni-infected mice were administered at the time of parasite residency in the lung with recombinant murine interleukin (IL)-2 or interferon-gamma (IFN-gamma), to evaluate the impact of cytokines in host responses to primary schistosomiasis. S. mansoni lung-stage schistosomula did not affect plasma lipids levels in BALB/c, while elicited significant (p<0.05) increase in free fatty acids (FA) and decrease in cholesterol plasma levels in C57BL/6 and CD1 mice, and stimulated expression of mRNA for Th2 cytokines in BALB/c and Th1 cytokines in C57BL/6 and CD1 mice. Production of specific antibodies was negligible in the 3 strains. Interleukin-2 treatment elicited significant (p<0.001) decrease in triglycerides (TG) in CD1, and decrease in TG and cholesterol plasma levels and down-regulation of TNF-alpha mRNA expression in C57BL/6 mice. Induction of type 2 cytokines and/or IFN-gamma mRNA expression did not lead to increase in percentage of specific antibody responders in any mouse strain. Exogenous IL-2-related reduction in cholesterol plasma levels and TNF-alpha mRNA expression in C57BL/6 mice was associated with significant (p<0.05) decrease in adult worm recovery and egg count. Treatment with IFN-gamma elicited significant (p<0.05) free FA plasma levels increase in BALB/c and C57BL/6 and decrease in CD1 mice. Expression of type 2 cytokines mRNA was stimulated in BALB/c and CD1 mice, yet was not accompanied with increase in humoral responses. Exogenous IFN-gamma-related reduction in free FA plasma levels and IFN-gamma mRNA response, and up-regulation of TNF-alpha mRNA expression in CD1 mice were associated with significant increase in adult worm burden and egg load. The data were discussed in an attempt to define host factors predictive of resistance to schistosome infection.