A robust measure of correlation between two genes on a microarray

<p>Abstract</p> <p>Background</p> <p>The underlying goal of microarray experiments is to identify gene expression patterns across different experimental conditions. Genes that are contained in a particular pathway or that respond similarly to experimental conditions could be co-expressed and show similar patterns of expression on a microarray. Using any of a variety of clustering methods or gene network analyses we can partition genes of interest into groups, clusters, or modules based on measures of similarity. Typically, Pearson correlation is used to measure distance (or similarity) before implementing a clustering algorithm. Pearson correlation is quite susceptible to outliers, however, an unfortunate characteristic when dealing with microarray data (well known to be typically quite noisy.)</p> <p>Results</p> <p>We propose a resistant similarity metric based on Tukey's biweight estimate of multivariate scale and location. The resistant metric is simply the correlation obtained from a resistant covariance matrix of scale. We give results which demonstrate that our correlation metric is much more resistant than the Pearson correlation while being more efficient than other nonparametric measures of correlation (e.g., Spearman correlation.) Additionally, our method gives a systematic gene flagging procedure which is useful when dealing with large amounts of noisy data.</p> <p>Conclusion</p> <p>When dealing with microarray data, which are known to be quite noisy, robust methods should be used. Specifically, robust distances, including the biweight correlation, should be used in clustering and gene network analysis.</p

Defining and Detecting Malaria Epidemics in the Highlands of Western Kenya

Epidemic detection algorithms are being increasingly recommended for malaria surveillance in sub-Saharan Africa. We present the results of applying three simple epidemic detection techniques to routinely collected longitudinal pediatric malaria admissions data from three health facilities in the highlands of western Kenya in the late 1980s and 1990s. The algorithms tested were chosen because they could be feasibly implemented at the health facility level in sub-Saharan Africa. Assumptions of these techniques about the normal distribution of admissions data and the confidence intervals used to define normal years were also investigated. All techniques identified two “epidemic” years in one of the sites. The untransformed Cullen method with standard confidence intervals detected the two “epidemic” years in the remaining two sites but also triggered many false alarms. The performance of these methods is discussed and comments made about their appropriateness for the highlands of western Keny

Transforaminal endoscopic surgery for symptomatic lumbar disc herniations: a systematic review of the literature

The study design includes a systematic literature review. The objective of the study was to evaluate the effectiveness of transforaminal endoscopic surgery and to compare this with open microdiscectomy in patients with symptomatic lumbar disc herniations. Transforaminal endoscopic techniques for patients with symptomatic lumbar disc herniations have become increasingly popular. The literature has not yet been systematically reviewed. A comprehensive systematic literature search of the MEDLINE and EMBASE databases was performed up to May 2008. Two reviewers independently checked all retrieved titles and abstracts and relevant full text articles for inclusion criteria. Included articles were assessed for quality and outcomes were extracted by the two reviewers independently. One randomized controlled trial, 7 non-randomized controlled trials and 31 observational studies were identified. Studies were heterogeneous regarding patient selection, indications, operation techniques, follow-up period and outcome measures and the methodological quality of these studies was poor. The eight trials did not find any statistically significant differences in leg pain reduction between the transforaminal endoscopic surgery group (89%) and the open microdiscectomy group (87%); overall improvement (84 vs. 78%), re-operation rate (6.8 vs. 4.7%) and complication rate (1.5 vs. 1%), respectively. In conclusion, current evidence on the effectiveness of transforaminal endoscopic surgery is poor and does not provide valid information to either support or refute using this type of surgery in patients with symptomatic lumbar disc herniations. High-quality randomized controlled trials with sufficiently large sample sizes are direly needed to evaluate if transforaminal endoscopic surgery is more effective than open microdiscectomy

Serum paraoxonase and arylesterase activities in patients with lung cancer in a Turkish population

BACKGROUND: Lung cancer (LC) is the leading cause of cancer-related deaths. Oxidative DNA damage may contribute to the cancer risk. The antioxidant paraoxonase (PON1) is an endogenous free radical scavenger in the human body. The aim of this study was to determine serum PON1 and arylesterase (ARE) activities in patients with newly diagnosed LC. METHODS: This case control study involved a total of 39 patients with newly diagnosed LC (untreated) and same number of age- and sex-matched healthy individuals. Serum PON1 and ARE activities in addition to lipid parameters were measured in both groups. RESULTS: Serum PON1 and ARE activities were found to be lower in patients with LC compared to the controls (p = 0.001 and p = 0.018, respectively). The ratio of PON1/high density lipoprotein (HDL) was significantly lower in the LC group compared to the control one (p = 0.009). There were positive correlations between the serum levels of HDL and PON1 in both the control (r = 0.415, p = 0.009) and the LC groups (r = 0.496, p = 0.001), respectively. PON1 enzyme activity was calculated as three different phenotypes in both groups. In regard to lipid parameters, total cholesterol levels were significantly lower (p = 0.014) in the LC group whereas the other lipid parameters such as HDL, LDL, and triglyceride levels were not significantly different among groups. CONCLUSION: Serum PON1 activity is significantly low in the LC group compared with the healthy controls. Metastasis status and cigarette smoking do not affect serum PON1 activity in the LC patients

CaZF, a Plant Transcription Factor Functions through and Parallel to HOG and Calcineurin Pathways in Saccharomyces cerevisiae to Provide Osmotolerance

Salt-sensitive yeast mutants were deployed to characterize a gene encoding a C2H2 zinc finger protein (CaZF) that is differentially expressed in a drought-tolerant variety of chickpea (Cicer arietinum) and provides salinity-tolerance in transgenic tobacco. In Saccharomyces cerevisiae most of the cellular responses to hyper-osmotic stress is regulated by two interconnected pathways involving high osmolarity glycerol mitogen-activated protein kinase (Hog1p) and Calcineurin (CAN), a Ca2+/calmodulin-regulated protein phosphatase 2B. In this study, we report that heterologous expression of CaZF provides osmotolerance in S. cerevisiae through Hog1p and Calcineurin dependent as well as independent pathways. CaZF partially suppresses salt-hypersensitive phenotypes of hog1, can and hog1can mutants and in conjunction, stimulates HOG and CAN pathway genes with subsequent accumulation of glycerol in absence of Hog1p and CAN. CaZF directly binds to stress response element (STRE) to activate STRE-containing promoter in yeast. Transactivation and salt tolerance assays of CaZF deletion mutants showed that other than the transactivation domain a C-terminal domain composed of acidic and basic amino acids is also required for its function. Altogether, results from this study suggests that CaZF is a potential plant salt-tolerance determinant and also provide evidence that in budding yeast expression of HOG and CAN pathway genes can be stimulated in absence of their regulatory enzymes to provide osmotolerance

Phase field approach with anisotropic interface energy and interface stresses: Large strain formulation

A thermodynamically consistent, large-strain, multi-phase field approach (with consequent interface stresses) is generalized for the case with anisotropic interface (gradient) energy (e.g. an energy density that depends both on the magnitude and direction of the gradients in the phase fields). Such a generalization, if done in the “usual” manner, yields a theory that can be shown to be manifestly unphysical. These theories consider the gradient energy as anisotropic in the deformed configuration, and, due to this supposition, several fundamental contradictions arise. First, the Cauchy stress tensor is non-symmetric and, consequently, violates the moment of momentum principle, in essence the Herring (thermodynamic) torque is imparting an unphysical angular momentum to the system. In addition, this non-symmetric stress implies a violation of the principle of material objectivity. These problems in the formulation can be resolved by insisting that the gradient energy is an isotropic function of the gradient of the order parameters in the deformed configuration, but depends on the direction of the gradient of the order parameters (is anisotropic) in the undeformed configuration. We find that for a propagating nonequilibrium interface, the structural part of the interfacial Cauchy stress is symmetric and reduces to a biaxial tension with the magnitude equal to the temperature- and orientation-dependent interface energy. Ginzburg–Landau equations for the evolution of the order parameters and temperature evolution equation, as well as the boundary conditions for the order parameters are derived. Small strain simplifications are presented. Remarkably, this anisotropy yields a first order correction in the Ginzburg–Landau equation for small strains, which has been neglected in prior works. The next strain-related term is third order. For concreteness, specific orientation dependencies of the gradient energy coefficients are examined, using published molecular dynamics studies of cubic crystals. In order to consider a fully specified system, a typical sixth order polynomial phase field model is considered. Analytical solutions for the propagating interface and critical nucleus are found, accounting for the influence of the anisotropic gradient energy and elucidating the distribution of components of interface stresses. The orientation-dependence of the nonequilibrium interface energy is first suitably defined and explicitly determined analytically, and the associated width is also found. The developed formalism is applicable to melting/solidification and crystal-amorphous transformation and can be generalized for martensitic and diffusive phase transformations, twinning, fracture, and grain growth, for which interface energy depends on interface orientation of crystals from either side

Absence of CD34 on Murine Skeletal Muscle Satellite Cells Marks a Reversible State of Activation during Acute Injury

Background: Skeletal muscle satellite cells are myogenic progenitors that reside on myofiber surface beneath the basal lamina. In recent years satellite cells have been identified and isolated based on their expression of CD34, a sialomucin surface receptor traditionally used as a marker of hematopoietic stem cells. Interestingly, a minority of satellite cells lacking CD34 has been described. Methodology/Principal Findings: In order to elucidate the relationship between CD34+ and CD34- satellite cells we utilized fluorescence-activated cell sorting (FACS) to isolate each population for molecular analysis, culture and transplantation studies. Here we show that unless used in combination with a7 integrin, CD34 alone is inadequate for purifying satellite cells. Furthermore, the absence of CD34 marks a reversible state of activation dependent on muscle injury. Conclusions/Significance: Following acute injury CD34- cells become the major myogenic population whereas the percentage of CD34+ cells remains constant. In turn activated CD34- cells can reverse their activation to maintain the pool of CD34+ reserve cells. Such activation switching and maintenance of reserve pool suggests the satellite cell compartment is tightly regulated during muscle regeneration

A Factor Graph Nested Effects Model To Identify Networks from Genetic Perturbations

Complex phenotypes such as the transformation of a normal population of cells into cancerous tissue result from a series of molecular triggers gone awry. We describe a method that searches for a genetic network consistent with expression changes observed under the knock-down of a set of genes that share a common role in the cell, such as a disease phenotype. The method extends the Nested Effects Model of Markowetz et al. (2005) by using a probabilistic factor graph to search for a network representing interactions among these silenced genes. The method also expands the network by attaching new genes at specific downstream points, providing candidates for subsequent perturbations to further characterize the pathway. We investigated an extension provided by the factor graph approach in which the model distinguishes between inhibitory and stimulatory interactions. We found that the extension yielded significant improvements in recovering the structure of simulated and Saccharomyces cerevisae networks. We applied the approach to discover a signaling network among genes involved in a human colon cancer cell invasiveness pathway. The method predicts several genes with new roles in the invasiveness process. We knocked down two genes identified by our approach and found that both knock-downs produce loss of invasive potential in a colon cancer cell line. Nested effects models may be a powerful tool for inferring regulatory connections and genes that operate in normal and disease-related processes