A semilinear in-slide model is introduced to remove the intensity effect in the scanning process. It is demonstrated that the intensity effect can be estimated accurately and removed effectively. This normalization step is vital for Affymetrix arrays to reveal relevant biological results when comparing gene expression in multiple arrays. The normalized expression ratios are analyzed further by a modified two-sample <i>t</i> test along with a sieved permutation scheme for computing <i>P</i> values. The improved specificity and sensitivity are demonstrated by using a study on the impact of macrophage migration inhibitory factor (MIF) reduction in neuroblastoma cells. With semilinear in-slide model analysis, expression of 166 genes was altered with a <i>P</i> value no greater than 0.001. Among those genes, 44 were altered &gt;2-fold. MIF-regulated genes associated with tumor development including IL-8 and <i>C</i>-<i>met</i>, which are overexpressed

Feedback modules, which appear ubiquitously in biological regulations, are often subject to disturbances from the input, leading to fluctuations in the output. Thus, the question becomes how a feedback system can produce a faithful response with a noisy input. We employed multiple time scale analysis, Fluctuation Dissipation Theorem, linear stability, and numerical simulations to investigate a module with one positive feedback loop driven by an external stimulus, and we obtained a critical quantity in noise attenuation, termed as signed activation time. We then studied the signed activation time for a system of two positive feedback loops, a system of one positive feedback loop and one negative feedback loop, and six other existing biological models consisting of multiple components along with positive and negative feedback loops. An inverse relationship is found between the noise amplification rate and the signed activation time, defined as the difference between the deactivation and activation time scales of the noise-free system, normalized by the frequency of noises presented in the input. Thus, the combination of fast activation and slow deactivation provides the best noise attenuation, and it can be attained in a single positive feedback loop system. An additional positive feedback loop often leads to a marked decrease in activation time, decrease or slight increase of deactivation time and allows larger kinetic rate variations for slow deactivation and fast activation. On the other hand, a negative feedback loop may increase the activation and deactivation times. The negative relationship between the noise amplification rate and the signed

Macrophages play an important role in the inflammatory responses involved with spinal cord injury (SCI). We have previously demonstrated that infiltrated bone marrow-derived macrophages (BMDMs) engulf myelin debris, forming myelin-laden macrophages (mye-M). These mye-M promote disease progression through their pro-inflammatory phenotype, enhanced neurotoxicity, and impaired phagocytic capacity for apoptotic cells. We thus hypothesize that the excessive accumulation of mye-M is the root of secondary injury, and that targeting mye-M represents an efficient strategy to improve the local inflammatory microenvironment in injured spinal cords and to further motor neuron function recovery. In this study, we administer murine embryonic stem cell conditioned media (ESC-M) as a cell-free stem cell based therapy to treat a mouse model of SCI. We showed that BMDMs, but not microglial cells, engulf myelin debris generated at the injury site. Phagocytosis of myelin debris leads to the formation of mye-M in the injured spinal cord, which are surrounded by activated microglia cells. These mye-M are pro-inflammatory and lose the normal macrophage phagocytic capacity for apoptotic cells. We therefore focus on how to trigger lipid efflux from mye-M and thus restore their function. Using ESC-M as an immune modulating treatment for inflammatory damage after SCI, we rescued mye-M function and improved functional locomotor recovery. ESC-M treatment on mye-M resulted in improved exocytosis of internalized lipids and a normal capacity for apoptotic cell phagocytosis. Furthermore, when ESC-M was administered