Glioblastoma-derived Macrophage Colony-stimulating Factor (MCSF) Induces Microglial Release of Insulin-like Growth Factor-binding Protein 1 (IGFBP1) to Promote Angiogenesis

Glioblastoma (grade IV glioma/GBM) is the most common primary adult malignant brain tumor with poor prognosis. To characterize molecular determinants of tumor-stroma interaction in GBM, we profiled 48 serum cytokines and identified macrophage colony-stimulating factor (MCSF) as one of the elevated cytokines in sera from GBM patients. Both MCSF transcript and protein were up-regulated in GBM tissue samples through a spleen tyrosine kinase (SYK)-dependent activation of the PI3K-NF kappa B pathway. Ectopic overexpression and silencing experiments revealed that glioma-secreted MCSF has no role in autocrine functions and M2 polarization of macrophages. In contrast, silencing expression of MCSF in glioma cells prevented tube formation of human umbilical vein endothelial cells elicited by the supernatant from monocytes/microglial cells treated with conditioned medium from glioma cells. Quantitative proteomics based on stable isotope labeling by amino acids in cell culture showed that glioma-derived MCSF induces changes in microglial secretome and identified insulin-like growth factor-binding protein 1 (IGFBP1) as one of the MCSF-regulated proteins secreted by microglia. Silencing IGFBP1 expression in microglial cells or its neutralization by an antibody reduced the ability of supernatants derived from microglial cells treated with glioma cell-conditioned medium to induce angiogenesis. In conclusion, this study shows up-regulation of MCSF in GBM via a SYK-PI3K-NF kappa B-dependent mechanism and identifies IGFBP1 released by microglial cells as a novel mediator of MCSF-induced angiogenesis, of potential interest for developing targeted therapy to prevent GBM progression.

Role of Magmas in protein transport and human mitochondria biogenesis

Magmas, a conserved mammalian protein essential for eukaryotic development, is overexpressed in prostate carcinomas and cells exposed to granulocyte-macrophage colony-stimulating factor (GM-CSF). Reduced Magmas expression resulted in decreased proliferative rates in cultured cells. However, the cellular function of Magmas is still elusive. In this report, we have showed that human Magmas is an ortholog of Saccharomyces cerevisiae Pam16 having similar functions and is critical for protein translocation across mitochondrial inner membrane. Human Magmas shows a complete growth complementation of delta pam16 yeast cells at all temperatures. On the basis of our analysis, we report that Magmas localizes into mitochondria and is peripherally associated with inner mitochondrial membrane in yeast and humans. Magmas forms a stable subcomplex with J-protein Pam18 or DnaJC19 through its C-terminal region and is tethered to TIM23 complex of yeast and humans. Importantly, amino acid alterations in Magmas leads to reduced stability of the subcomplex with Pam18 that results in temperature sensitivity and in vivo protein translocation defects in yeast cells. These observations highlight the central role of Magmas in protein import and mitochondria biogenesis. In humans, absence of a functional DnaJC19 leads to dilated cardiac myophathic syndrome (DCM), a genetic disorder with characteristic features of cardiac myophathy and neurodegeneration. We propose that the mutations resulting in decreased stability of functional Magmas:DnaJC19 subcomplex at human TIM23 channel leads to impaired protein import and cellular respiration in DCM patients. Together, we propose a model showing how Magmas:DnaJC19 subcomplex is associated with TIM23 complex and thus regulates mitochondrial import process.

Parallel processor scheduling for minimizing total weighted tardiness using ant colony optimization

In the modern business environment, meeting due dates and avoiding delay penalties are very important goals that can be accomplished by minimizing total weighted tardiness. We consider a scheduling problem in a system of parallel processors with the objective of minimizing total weighted tardiness. Our aim in the present work is to develop an efficient algorithm for solving the parallel processor problem as compared to the available heuristics in the literature and we propose the ant colony optimization approach for this problem. An extensive experimentation is conducted to evaluate the performance of the ACO approach on different problem sizes with the varied tardiness factors. Our experimentation shows that the proposed ant colony optimization algorithm is giving promising results compared to the best of the available heuristics.

Genome-Wide Gene Expression Analysis Reveals a Dynamic Interplay between Luteotropic and Luteolytic Factors in the Regulation of Corpus Luteum Function in the Bonnet Monkey (Macaca radiata)

Although LH is essential for survival and function of the corpus luteum (CL) in higher primates, luteolysis occurs during nonfertile cycles without a discernible decrease in circulating LH levels. Using genome-wide expression analysis, several experiments were performed to examine the processes of luteolysis and rescue of luteal function in monkeys. Induced luteolysis with GnRH receptor antagonist (Cetrorelix) resulted in differential regulation of 3949 genes, whereas replacement with exogenous LH (Cetrorelix plus LH) led to regulation of 4434 genes (1563 down-regulation and 2871 up-regulation). A model system for prostaglandin (PG) F-2 alpha-induced luteolysis in the monkey was standardized and demonstrated that PGF(2 alpha) regulated expression of 2290 genes in the CL. Analysis of the LH-regulated luteal transcriptome revealed that 120 genes were regulated in an antagonistic fashion by PGF(2 alpha). Based on the microarray data, 25 genes were selected for validation by real-time RT-PCR analysis, and expression of these genes was also examined in the CL throughout the luteal phase and from monkeys treated with human chorionic gonadotropin (hCG) to mimic early pregnancy. The results indicated changes in expression of genes favorable to PGF(2 alpha) action during the late to very late luteal phase, and expressions of many of these genes were regulated in an opposite manner by exogenous hCG treatment. Collectively, the findings suggest that curtailment of expression of downstream LH-target genes possibly through PGF(2 alpha) action on the CL is among the mechanisms underlying cross talk between the luteotropic and luteolytic signaling pathways that result in the cessation of luteal function, but hCG is likely to abrogate the PGF(2 alpha)-responsive gene expression changes resulting in luteal rescue crucial for the maintenance of early pregnancy. (Endocrinology 150: 1473-1484, 2009)

Effect of diethylstilbesterol and prolactin on the induction of follicle stimulating hormone receptors in immature and cycling rats

Induction of follicle stimulating hormone receptor in the granulosa cells of intact immature rat ovary by diethylstilbesterol, an estrogen, has been studied. A single injection of 4 mg of diethylstilbesterol produced 72 h later a 3-fold increase in follicle stimulating hormone receptor concentration as monitored by [125I]-oFSH binding to isolated cells. The newly induced receptors were kinetically indistinguishable from the preexisting ones, as determined by Lineweaver-Burk plot of the binding data. The induced receptors were functional as evidenced by increased ability of the granulosa cells to incorporate [3H]-leucine into cellular proteins. Neutralization of endogenous follicle stimulating hormone and luteinizing hormone by administering specific antisera had no effect on the ability of diethylstilbesterol to induce follicle stimulating hormone receptors, whereas blockade of endogenous prolactin secretion by ergobromocryptin administration significantly inhibited (∼ 30 %) the response to diethylstilbesterol; this inhibition could be completely relieved by ovine prolactin treatment. However, ovine prolactin at the dose tried did not by itself enhance follicle stimulating hormone receptor level. Administration of ergobromocryptin to adult cycling rats at noon of proestrus brought about as measured on diestrusII, (a) a reduction of both follicle stimulating hormone (∼ 30 %) and luteinizing hormone (∼ 45 %) receptor concentration in granulosa cells, (b) a drastic reduction in the ovarian tissue estradiol with no change in tissue progesterone and (c) reduction in the ability of isolated granulosa cells to convert testosterone to estradiol in response to follicle stimulating hormone. Ergobromocryptin treatment affected only prolactin and not follicle stimulating hormone or luteinizing hormone surges on the proestrus evening. Treatment of rats with ergobromocryptin at proestrus noon followed by an injection of ovine prolactin (1 mg) at 1700 h of the same day completely reversed the ergobromocryptin induced reduction in ovarian tissue estradiol as well as the aromatase activity of the granulosa cells on diestrus II, thus suggesting a role for proestrus prolactin surge in the follicular maturation process.

Influence of Elastic-Constants on Mode-I Stress-Intensity Factors in 3-Dimensional Crack Problems

Plates with V-through edge notches subjected to pure bending and specimens with rectangular edge-through-notches subjected to combined bending and axial pull were investigated (under live-load and stress-frozen conditions) in a completely nondestructive manner using scattered-light photoelasticity. Stress-intensity factors (SIFs) were evaluated by analysing the singular stress distributions near crack-tips. Improved methods are suggested for the evaluation of SIFs. The thickness-wise variation of SIFs is also obtained in the investigation. The results obtained are compared with the available theoretical solutions.

Ant Colony Optimization Algorithms for Shortest Path Problems

We propose four variants of recently proposed multi-timescale algorithm in [1] for ant colony optimization and study their application on a multi-stage shortest path problem. We study the performance of the various algorithms in this framework. We observe, that one of the variants consistently outperforms the algorithm [1].

Determination of stress-intensity factors for cracks in tubes under torsion

An experimental investigation by two-dimensional photoelastic technique is carried out to study the stress distribution and to determine the stress-intensity factors for arbitrarily oriented cracks in thin cylindrical shells subjected to torsion. A new method is employed to evaluate the pure and mixed-mode SIF's.

Photoelastic parametric studies of mode I stress intensity factors

Results of photoelastic investigations on single edge-notch tension specimens of varying notch angle and crack length are reported. The experimental results of Mode I stress intensity factors are compared with analytical results.

Photoelastic determination of stress intensity factors in patched cracked plates

n this paper, the influence of patch parameters on stress intensity factors in edge cracked plates is studied by employing transmission photoelasticity. Edge cracked plates made of photo-elastic material are patched on one side only by E glass-epoxy and carbon-epoxy unidirectional composites. The patch is located on the crack in such a way that the crack tip is not covered. Magnified isochromatic fringes are obtained by using a projection microscope of magnification 50, converted into a polariscope. Irwin's method is used to compute stress intensity factors from photoelastic data. The reduction in stress intensity factors is presented in graphical form as a function of patch parameters, namely stiffness, location and length. An empirical equation connecting reduction in stress intensity factor and these patch parameters is presented.

On factors influencing the ductile-to-brittle transition in a bulk metallic glass

An experimental study to ascertain the ductile-to-brittle transition (DBT) in a bulk metallic glass (BMG) was conducted. Results of the impact toughness tests conducted at various temperatures on as-cast and structurally relaxed Zr-based BMG show a sharp DBT. The DBT temperature was found to be sensitive to the free-volume content in the alloy. Possible factors that result in the DBT were critically examined. It was found that the postulate of a critical free volume required for the amorphous alloy to exhibit good toughness cannot rationalize the experimental trends. Likewise, the Poisson's ratio-toughness correlations, which suggest a critical Poisson's ratio above which all glasses are tough, were found not to hold good. Viscoplasticity theories, developed using the concept of shear transformation zones and which describe the temperature and strain rate dependence of the crack-tip plasticity in BMGs, appear to be capable of capturing the essence of the experiments. Our results highlight the need for a more generalized theory to understand the origins of toughness in BMGs.

Incidence factors of the tracking systems used in parabolic-cylindrical concentrators

Several orientation and tracking systems employed in parabolic-cylindrical concentrators for focusing the direct solar radiation on the absorber tubes are analyzed from the technical and economic points of view. Case one, where the incidence factor was a function of declination and hour angle, showed that the maximum variations of incident factor from morning to noon was 0.5 at zero angle of declination. Case two, where the incidence factor was a function of declination, hour angle and latitude, showed the maximum variation of the incidence factor to be 0.128, which occurred during noon at the latitude of 30 degrees, corresponding to a change of declination from 0 to 23.5 degrees. In case three, the incidence factor, a function of declination only, showed that the maximum variation of the incidence factor corresponding to the change in declination from 0 to 23.5 degree was 0.0758. It is concluded that system three is the most efficient from the technical and economic point of view.

Analytical estimation of stress intensity factors in patched cracked plates

The fatigue and fracture performance of a cracked plate can be substantially improved by providing patches as reinforcements. The effectiveness of the patches is related to the reduction they cause in the stress intensity factor (SIF) of the crack. So, for reliable design, one needs an accurate evaluation of the SIF in terms of the crack, patch and adhesive parameters. In this investigation, a centrally cracked large plate with a pair of symmetric bonded narrow patches, oriented normally to the crack line, is analysed by a continuum approach. The narrow patches are treated as transversely flexible line members. The formulation leads to an integral equation which is solved numerically using point collocation. The convergence is rapid. It is found that substantial reductions in SIF are possible with practicable patch dimensions and locations. The patch is more effective when placed on the crack than ahead of the crack. The present analysis indicates that a little distance inwards of the crack tip, not the crack tip itself, is the ideal location, for the patch.

Factors affecting the synthesis and distribution of beta-lactamase in Mycobacterium smegmatis SN2 cultures

A high level of extracellular beta-lactamase activity was detected in cultures ofMycobacterium smegmatis SN2. The extracellular distribution of the enzyme varied with growth conditions such as additional carbon source and pH of the medium. Addition of chloramphenicol tothe culture inhibited the increase in the extracellular beta-lactamase activity. Cell wall damage or autolysis may be responsible for the extracellular beta-lactamase activity.