Additive functions in boolean models of gene regulatory network modules.

Gene-on-gene regulations are key components of every living organism. Dynamical abstract models of genetic regulatory networks help explain the genome's evolvability and robustness. These properties can be attributed to the structural topology of the graph formed by genes, as vertices, and regulatory interactions, as edges. Moreover, the actual gene interaction of each gene is believed to play a key role in the stability of the structure. With advances in biology, some effort was deployed to develop update functions in Boolean models that include recent knowledge. We combine real-life gene interaction networks with novel update functions in a Boolean model. We use two sub-networks of biological organisms, the yeast cell-cycle and the mouse embryonic stem cell, as topological support for our system. On these structures, we substitute the original random update functions by a novel threshold-based dynamic function in which the promoting and repressing effect of each interaction is considered. We use a third real-life regulatory network, along with its inferred Boolean update functions to validate the proposed update function. Results of this validation hint to increased biological plausibility of the threshold-based function. To investigate the dynamical behavior of this new model, we visualized the phase transition between order and chaos into the critical regime using Derrida plots. We complement the qualitative nature of Derrida plots with an alternative measure, the criticality distance, that also allows to discriminate between regimes in a quantitative way. Simulation on both real-life genetic regulatory networks show that there exists a set of parameters that allows the systems to operate in the critical region. This new model includes experimentally derived biological information and recent discoveries, which makes it potentially useful to guide experimental research. The update function confers additional realism to the model, while reducing the complexity and solution space, thus making it easier to investigate.

Modelling world investment markets using threshold conditional correlation models

In this paper we propose a parsimonious regime-switching approach to model the correlations between assets, the threshold conditional correlation (TCC) model. This method allows the dynamics of the correlations to change from one state (or regime) to another as a function of observable transition variables. Our model is similar in spirit to Silvennoinen and Teräsvirta (2009) and Pelletier (2006) but with the appealing feature that it does not suffer from the course of dimensionality. In particular, estimation of the parameters of the TCC involves a simple grid search procedure. In addition, it is easy to guarantee a positive definite correlation matrix because the TCC estimator is given by the sample correlation matrix, which is positive definite by construction. The methodology is illustrated by evaluating the behaviour of international equities, govenrment bonds and major exchange rates, first separately and then jointly. We also test and allow for different parts in the correlation matrix to be governed by different transition variables. For this, we estimate a multi-threshold TCC specification. Further, we evaluate the economic performance of the TCC model against a constant conditional correlation (CCC) estimator using a Diebold-Mariano type test. We conclude that threshold correlation modelling gives rise to a significant reduction in portfolio´s variance.

Correlation of intra- and extraepidermal CD8 T cell numbers with development of psoriatic epidermal pathology

The development of psoriatic plaques is T cell dependent. Recently, Th17 CD4 T cells have been proposed to be the main effector cells. However, development of psoriasis is critically dependent on accumulation of epidermal T cells, among the majority express CD8. Here we show that numbers of epidermal CD8 T cells correlated with development of psoriasis in human biopsies, and that blockade of CD8 T cells by depleting antibodies inhibited development of psoriasis in the AGR xenotransplantation mouse model. In human dermis, both CD4 and CD8 T cell numbers correlated significantly with epidermal pathology, indicating a role for dermal CD4 T cells in orchestrating the development of psoriasiform changes induced by epidermis-infiltrating CD8 T cells.

Correlations between motor and intellectual functions in normally developing children between 7 and 18 years.

The relationship between motor and intellectual functions was examined in 252 healthy children from 7 to 18 years using the Zurich Neuromotor Assessment and standardized intelligence tests. The magnitude of Spearman correlations between neuromotor and intellectual scores was generally weak (r = 0.15-0.37). The strongest correlations were found between performance in the pegboard task and visuomotor intelligence (r = 0.35) and between contralateral associated movements and intelligence in boys (r = 0.37). We conclude that specific connections between motor and intellectual functions may exist. However, because the magnitude of correlations is generally weak, we suggest that motor and intellectual domains in healthy children are largely independent.

Predictive accuracy and usefulness of calibration of the ESC SCORE in Switzerland.

BACKGROUND: Prevention of cardiovascular disease (CVD) at the individual level should rely on the assessment of absolute risk using population-specific risk tables. OBJECTIVE: To compare the predictive accuracy of the original and the calibrated SCORE functions regarding 10-year cardiovascular risk in Switzerland. DESIGN: Cross-sectional, population-based study (5773 participants aged 35-74 years). METHODS: The SCORE equation for low-risk countries was calibrated based on the Swiss CVD mortality rates and on the CVD risk factor levels from the study sample. The predicted number of CVD deaths after a 10-year period was computed from the original and the calibrated equations and from the observed cardiovascular mortality for 2003. RESULTS: According to the original and calibrated functions, 16.3 and 15.8% of men and 8.2 and 8.9% of women, respectively, had a 10-year CVD risk > or =5%. Concordance correlation coefficient between the two functions was 0.951 for men and 0.948 for women, both P<0.001. Both risk functions adequately predicted the 10-year cumulative number of CVD deaths: in men, 71 (original) and 74 (calibrated) deaths for 73 deaths when using the CVD mortality rates; in women, 44 (original), 45 (calibrated) and 45 (CVD mortality rates), respectively. Compared to the original function, the calibrated function classified more women and fewer men at high-risk. Moreover, the calibrated function gave better risk estimates among participants aged over 65 years. CONCLUSION: The original SCORE function adequately predicts CVD death in Switzerland, particularly for individuals aged less than 65 years. The calibrated function provides more reliable estimates for older individuals.

Dissecting TCR-MHC/peptide complex interactions with A2/peptide multimers incorporating tumor antigen peptide variants: crucial role of interaction kinetics on functional outcomes.

Soluble peptide/MHC-class-I (pMHC) multimers have recently emerged as unique reagents for the study of specific interactions between the pMHC complex and the TCR. Here, we assessed the relative binding efficiency of a panel of multimers incorporating single-alanine-substituted variants of the tumor-antigen-derived peptide MAGE-A10(254-262) to specific CTL clones displaying different functional avidity. For each individual clone, the efficiency of binding of multimers incorporating MAGE-A10 peptide variants was, in most cases, in good although not linear correlation with the avidity of recognition of the corresponding variant. In addition, we observed two types of discrepancies between efficiency of recognition and multimer binding. First, for some peptide variants, efficient multimer binding was detected in the absence of measurable effector functions. Some of these peptide variants displayed antagonist activity. Second, when comparing different clones we found clear discrepancies between the dose of peptide required to obtain half-maximal lysis in CTL assays and the binding efficiency of the corresponding multimers. These discrepancies, however, were resolved when the differential stability of the TCR/pMHC complexes was determined. For individual clones, decreased recognition correlated with increased TCR/pMHC off-rate. TCR/pMHC complexes formed by antagonist ligands displayed off-rates faster than those of TCR/pMHC complexes formed with weak agonists. In addition, when comparing different clones, the efficiency of multimer staining correlated better with relative multimer off-rates than with half-maximal lysis values. Altogether, the data presented here reconcile and extend our previous results on the impact of the kinetics of interaction of TCR with pMHC complexes on multimer binding and underline the crucial role of TCR/pMHC off-rates for the functional outcome of such interactions.

Correlation between TH1 response standard cytokines as biomarkers in patients with the delta virus in the western Brazilian Amazon

Hepatitis D virus (HDV) is endemic in the Amazon Region and its pathophysiology is the most severe among viral hepatitis. Treatment is performed with pegylated interferon and the immune response appears to be important for infection control. HDV patients were studied: untreated and polymerase chain reaction (PCR) positive (n = 9), anti-HDV positive and PCR negative (n = 8), and responders to treatment (n = 12). The cytokines, interleukin (IL)-2 (p = 0.0008) and IL-12 (p = 0.02) were differentially expressed among the groups and were also correlated (p = 0.0143). Future studies will be conducted with patients at different stages of treatment, associating the viral load with serum cytokines produced, thereby attempting to establish a prognostic indicator of the infection.

Lack of correlation between the optimal glycaemic control and coronary micro vascular dysfunction in patients with diabetes mellitus: a cross sectional study.

Background Coronary microvascular dysfunction (CMD) is associated with cardiovascular events in type 2 diabetes mellitus (T2DM). Optimal glycaemic control does not always preclude future events. We sought to assess the effect of the current target of HBA1c level on the coronary microcirculatory function and identify predictive factors for CMD in T2DM patients. Methods We studied 100 patients with T2DM and 214 patients without T2DM. All of them with a history of chest pain, non-obstructive angiograms and a direct assessment of coronary blood flow increase in response to adenosine and acetylcholine coronary infusion, for evaluation of endothelial independent and dependent CMD. Patients with T2DM were categorized as having optimal (HbA1c < 7 %) vs. suboptimal (HbA1c ≥ 7 %) glycaemic control at the time of catheterization. Results Baseline characteristics and coronary endothelial function parameters differed significantly between T2DM patients and control group. The prevalence of endothelial independent CMD (29.8 vs. 39.6 %, p = 0.40) and dependent CMD (61.7 vs. 62.2 %, p = 1.00) were similar in patients with optimal vs. suboptimal glycaemic control. Age (OR 1.10; CI 95 % 1.04–1.18; p < 0.001) and female gender (OR 3.87; CI 95 % 1.45–11.4; p < 0.01) were significantly associated with endothelial independent CMD whereas glomerular filtrate (OR 0.97; CI 95 % 0.95–0.99; p < 0.05) was significantly associated with endothelial dependent CMD. The optimal glycaemic control was not associated with endothelial independent (OR 0.60, CI 95 % 0.23–1.46; p 0.26) or dependent CMD (OR 0.99, CI 95 % 0.43–2.24; p = 0.98). Conclusions The current target of HBA1c level does not predict a better coronary microcirculatory function in T2DM patients. The appropriate strategy for prevention of CMD in T2DM patients remains to be addressed. Keywords: Endothelial dysfunction; Diabetes mellitus; Coronary microcirculation

Undertreatment of acute pain (oligoanalgesia) and medical practice variation in prehospital analgesia of adult trauma patients: a 10 yr retrospective study.

BACKGROUND: Prehospital oligoanalgesia is prevalent among trauma victims, even when the emergency medical services team includes a physician. We investigated if not only patients' characteristics but physicians' practice variations contributed to prehospital oligoanalgesia. METHODS: Patient records of conscious adult trauma victims transported by our air rescue helicopter service over 10 yr were reviewed retrospectively. Oligoanalgesia was defined as a numeric rating scale (NRS) >3 at hospital admission. Multilevel logistic regression analysis was used to predict oligoanalgesia, accounting first for patient case-mix, and then physician-level clustering. The intraclass correlation was expressed as the median odds ratio (MOR). RESULTS: A total of 1202 patients and 77 physicians were included in the study. NRS at the scene was 6.9 (1.9). The prevalence of oligoanalgesia was 43%. Physicians had a median of 5.7 yr (inter-quartile range: 4.2-7.5) of post-graduate training and 27% were female. In our multilevel analysis, significant predictors of oligoanalgesia were: no analgesia [odds ratio (OR) 8.8], National Advisory Committee for Aeronautics V on site (OR 4.4), NRS on site (OR 1.5 per additional NRS unit >4), female physician (OR 2.0), and years of post-graduate experience [>4.0 to ≤5.0 (OR 1.3), >3.0 to ≤4.0 (OR 1.6), >2.0 to ≤3.0 (OR 2.6), and ≤2.0 yr (OR 16.7)]. The MOR was 2.6, and was statistically significant. CONCLUSIONS: Physicians' practice variations contributed to oligoanalgesia, a factor often overlooked in analyses of prehospital pain management. Further exploration of the sources of these variations may provide innovative targets for quality improvement programmes to achieve consistent pain relief for trauma victims.

Modulation of Higher-Order Olfaction Components on Executive Functions in Humans.

The prefrontal (PFC) and orbitofrontal cortex (OFC) appear to be associated with both executive functions and olfaction. However, there is little data relating olfactory processing and executive functions in humans. The present study aimed at exploring the role of olfaction on executive functioning, making a distinction between primary and more cognitive aspects of olfaction. Three executive tasks of similar difficulty were used. One was used to assess hot executive functions (Iowa Gambling Task-IGT), and two as a measure of cold executive functioning (Stroop Colour and Word Test-SCWT and Wisconsin Card Sorting Test-WCST). Sixty two healthy participants were included: 31 with normosmia and 31 with hyposmia. Olfactory abilities were assessed using the ''Sniffin' Sticks'' test and the olfactory threshold, odour discrimination and odour identification measures were obtained. All participants were female, aged between 18 and 60. Results showed that participants with hyposmia displayed worse performance in decision making (IGT; Cohen's-d = 0.91) and cognitive flexibility (WCST; Cohen's-d between 0.54 and 0.68) compared to those with normosmia. Multiple regression adjusted by the covariates participants' age and education level showed a positive association between odour identification and the cognitive inhibition response (SCWT-interference; Beta = 0.29; p = .034). The odour discrimination capacity was not a predictor of the cognitive executive performance. Our results suggest that both hot and cold executive functions seem to be associated with higher-order olfactory functioning in humans. These results robustly support the hypothesis that olfaction and executive measures have a common neural substrate in PFC and OFC, and suggest that olfaction might be a reliable cognitive marker in psychiatric and neurologic disorders.

CREB-2, a cellular CRE-dependent transcription repressor, functions in association with Tax as an activator of the human T-cell leukemia virus type 1 promoter.

The Tax protein of the human T-cell leukemia virus type 1 (HTLV-1) has been implicated in human T-cell immortalization. The primary function of Tax is to transcriptionally activate the HTLV-1 promoter, but Tax is also known to stimulate expression of cellular genes. It has been reported to associate with several transcription factors, as well as proteins not involved in transcription. To better characterize potential cellular targets of Tax present in infected cells, a Saccharomyces cerevisiae two-hybrid screening was performed with a cDNA library constructed from the HTLV-1-infected MT2 cell line. From this study, we found 158 positive clones representing seven different cDNAs. We focused our attention on the cDNA encoding the transcription factor CREB-2. CREB-2 is an unconventional member of the ATF/CREB family in that it lacks a protein kinase A (PKA) phosphorylation site and has been reported to negatively regulate transcription from the cyclic AMP response element of the human enkephalin promoter. In this study, we demonstrate that CREB-2 cooperates with Tax to enhance viral transcription and that its basic-leucine zipper C-terminal domain is required for both in vitro and in vivo interactions with Tax. Our results confirm that the activation of the HTLV-1 promoter through Tax and factors of the ATF/CREB family is PKA independent.

Pooling of dentin microtensile bond strength data improves clinical correlation.

Purpose: To evaluate whether the correlation between in vitro bond strength data and estimated clinical retention rates of cervical restorations after two years depends on pooled data obtained from multicenter studies or single-test data. Materials and Methods: Pooled mean data for six dentin adhesive systems (Adper Prompt L-Pop, Clearfil SE, OptiBond FL, Prime & Bond NT, Single Bond, and Scotchbond Multipurpose) and four laboratory methods (macroshear, microshear, macrotensile and microtensile bond strength test) (Scherrer et al, 2010) were correlated to estimated pooled two-year retention rates of Class V restorations using the same adhesive systems. For bond strength data from a single test institute, the literature search in SCOPUS revealed one study that tested all six adhesive systems (microtensile) and two that tested five of the six systems (microtensile, macroshear). The correlation was determined with a database designed to perform a meta-analysis on the clinical performance of cervical restorations (Heintze et al, 2010). The clinical data were pooled and adjusted in a linear mixed model, taking the study effect, dentin preparation, type of isolation and bevelling of enamel into account. A regression analysis was carried out to evaluate the correlation between clinical and laboratory findings. Results: The results of the regression analysis for the pooled data revealed that only the macrotensile (adjusted R2 = 0.86) and microtensile tests (adjusted R2 = 0.64), but not the shear and the microshear tests, correlated well with the clinical findings. As regards the data from a single-test institute, the correlation was not statistically significant. Conclusion: Macrotensile and microtensile bond strength tests showed an adequate correlation with the retention rate of cervical restorations after two years. Bond strength tests should be carried out by different operators and/or research institutes to determine the reliability and technique sensitivity of the material under investigation.

Photosensitizing effects of m-tetrahydroxyphenylchlorin on human tumor xenografts: correlation with sensitizer uptake, tumor doubling time and tumor histology.

The photodynamic effects of m-tetrahydroxyphenylchlorin (mTHPC) were assessed on human malignant mesothelioma, squamous cell carcinoma and adenocarcinoma xenografts grown in nude mice and were correlated with mTHPC uptake, histology and doubling time of the tumors. Non-thermal laser light was delivered to the tumor as surface radiation 4 days after intraperitoneal administration of 0.1 and 0.3 mg mTHPC/kg body weight, respectively. The extent of tumor necrosis was measured by histomorphometry. The mTHPC concentration in non-irradiated tumors was assessed by high-performance liquid chromatography (HPLC). The tumors were graded according to their doubling time and their vascular architecture as assessed by histology. The 0.1 mg/kg dose of mTHPC resulted in an equal uptake for all 3 tumor types but revealed a larger extent of photosensitized necrosis for adenocarcinoma, which displayed a delicate tumor stroma with numerous small capillary vessels, than for mesothelioma and squamous cell carcinoma, which were both poor in stroma and vessels. The 0.3 mg/kg dose of mTHPC resulted in a 2-fold higher tumor uptake for all 3 tumor types and in a larger extent of necrosis for mesothelioma and squamous cell carcinoma, but not for adenocarcinoma xenografts, compared with the lower drug dose. Our results demonstrate that different tumor xenografts respond differently to mTHPC-PDT for a given drug-light condition. In this setting, the photosensitizing effect was more closely related to the vascular architecture of the tumors than to the sensitizer uptake and doubling time of the different tumors

Correlation between vasoconstrictor roles and mRNA expression of alpha1-adrenoceptor subtypes in blood vessels of genetically engineered mice.

We examined the contribution of each alpha(1)-adrenoceptor (AR) subtype in noradrenaline (NAd)-evoked contraction in the thoracic aortas and mesenteric arteries of mice. Compared with the concentration-response curves (CRCs) for NAd in the thoracic aortas of wild-type (WT) mice, the CRCs of mutant mice showed a significantly lower sensitivity. The pD(2) value in rank order is as follows: WT mice (8.21) > alpha(1B)-adrenoceptor knockout (alpha(1B)-KO) (7.77) > alpha(1D)-AR knockout (alpha(1D)-KO) (6.44) > alpha(1B)- and alpha(1D)-AR double knockout (alpha(1BD)-KO) (5.15). In the mesenteric artery, CRCs for NAd did not differ significantly between either WT (6.52) and alpha(1B)-KO mice (7.12) or alpha(1D)-KO (6.19) and alpha(1BD)-KO (6.29) mice. However, the CRC maximum responses to NAd in alpha(1D)- and alpha(1BD)-KO mice were significantly lower than those in WT and alpha(1B)-KO mice. Except in the thoracic aortas of alpha(1BD)-KO mice, the competitive antagonist prazosin inhibited the contraction response to NAd with high affinity. However, prazosin produced shallow Schild slopes in the vessels of mice lacking the alpha(1D)-AR gene. In the thoracic aorta, pA(2) values in WT mice for KMD-3213 and BMY7378 were 8.25 and 8.46, respectively, and in alpha(1B)-KO mice they were 8.49 and 9.13, respectively. In the mesenteric artery, pA(2) values in WT mice for KMD-3213 and BMY7378 were 8.34 and 7.47, respectively, and in alpha(1B)-KO mice they were 8.11 and 7.82, respectively. These pharmacological findings were in fairly good agreement with findings from comparison of CRCs, with the exception of the mesenteric arteries of WT and alpha(1B)-KO mice, which showed low affinities to BMY7378. We performed a quantitative analysis of the mRNA expression of each alpha(1)-AR subtype in these vessels in order to examine the correlation between mRNA expression level and the predominance of each alpha(1)-AR subtype in mediating vascular contraction. The rank order of each alpha(1)-AR subtype in terms of its vasoconstrictor role was in fairly good agreement with the level of expression of mRNA of each subtype, that is, alpha(1D)-AR > alpha(1B)-AR > alpha(1A)-AR in the thoracic aorta and alpha(1D)-AR > alpha(1A)-AR > alpha(1B)-AR in the mesenteric artery. No dramatic compensatory change of alpha(1)-AR subtype in mutant mice was observed in pharmacological or quantitative mRNA expression analysis.

Mitotic functions for SNAP45, a subunit of the small nuclear RNA-activating protein complex SNAPc.

The small nuclear RNA-activating protein complex SNAP(c) is required for transcription of small nuclear RNA genes and binds to a proximal sequence element in their promoters. SNAP(c) contains five types of subunits stably associated with each other. Here we show that one of these polypeptides, SNAP45, also known as PTF delta, localizes to centrosomes during parts of mitosis, as well as to the spindle midzone during anaphase and the mid-body during telophase. Consistent with localization to these mitotic structures, both down- and up-regulation of SNAP45 lead to a G(2)/M arrest with cells displaying abnormal mitotic structures. In contrast, down-regulation of SNAP190, another SNAP(c) subunit, leads to an accumulation of cells with a G(0)/G(1) DNA content. These results are consistent with the proposal that SNAP45 plays two roles in the cell, one as a subunit of the transcription factor SNAP(c) and another as a factor required for proper mitotic progression.