Regression based predictor for p53 transactivation

<p>Abstract</p> <p>Background</p> <p>The p53 protein is a master regulator that controls the transcription of many genes in various pathways in response to a variety of stress signals. The extent of this regulation depends in part on the binding affinity of p53 to its response elements (REs). Traditional profile scores for p53 based on position weight matrices (PWM) are only a weak indicator of binding affinity because the level of binding also depends on various other factors such as interaction between the nucleotides and, in case of p53-REs, the extent of the spacer between the dimers.</p> <p>Results</p> <p>In the current study we introduce a novel <it>in-silico </it>predictor for p53-RE transactivation capability based on a combination of multidimensional scaling and multinomial logistic regression. Experimentally validated known p53-REs along with their transactivation capabilities are used for training. Through cross-validation studies we show that our method outperforms other existing methods. To demonstrate the utility of this method we (a) rank putative p53-REs of target genes and target microRNAs based on the predicted transactivation capability and (b) study the implication of polymorphisms overlapping p53-RE on its transactivation capability.</p> <p>Conclusion</p> <p>Taking into account both nucleotide interactions and the spacer length of p53-RE, we have created a novel <it>in-silico </it>regression-based transactivation capability predictor for p53-REs and used it to analyze validated and novel p53-REs and to predict the impact of SNPs overlapping these elements.</p

Intrapersonal and interpersonal dimensions of cancer perception: a confirmatory factor analysis of the cancer experience and efficacy scale (CEES)

Purpose Sociocultural factors influence psychological adjustment to cancer in Asian patients in two major ways: Prioritization of relationships over individual orientations and belief in the efficacy of interpersonal cooperation. We derived and validated among Chinese colorectal cancer (CRC) patients an instrument assessing cancer perceptions to enable the study of the sociocultural processes. Patients and methods Qualitative interviews (n=16) derived 15 items addressing interpersonal experience in Chinese CRC patients' adjustment. These 15 items and 18 corresponding self-referent items were administered to 166 Chinese CRC survivors and subjected to exploratory factor analysis (EFA) to establish the initial scale structure and reliability. The final 29 items, together with other psychometric measures, were administered to a second cohort of 215 CRC patients and subjected to confirmatory factor analysis (CFA). Results EFA (63.35% of the total variance) extracted six factors: Personal strain, socioeconomic strain, emotional strain, personal efficacy, collective efficacy, and proxy efficacy. CFA confirmed the psychometric structure [?2(df)=702.91 (368); Comparative Fit Index=0.95; Nonnormed Fit Index= 0.94; Incremental Fit Index=0.95; standardized root mean square residual=0.08] of the six factors by using a model with two latent factors: Experience and efficacy. All subscales were reliable (a=0.76-0.92). Appropriate correlations with adjustment outcomes (symptom distress, psychological morbidity, and subjective well-being), optimistic personalities, and social relational quality indicated its convergent and divergent validity. Known group comparisons (i.e., age, active treatment, and colostomy) showed its clinical utility. Conclusion The cancer experience and efficacy scale is a valid multidimensional instrument for assessing intrapersonal and interpersonal dimensions of cancer experience in Asian patients, potentiating existing patient-reported outcome measures. © Springer-Verlag 2009.published_or_final_versionSpringer Open Choice, 01 Dec 201

Association between a variation in the phosphodiesterase 4D gene and bone mineral density

BACKGROUND: Fragility fractures caused by osteoporosis are a major cause of morbidity and mortality in aging populations. Bone mineral density (BMD) is a useful surrogate marker for risk of fracture and is a highly heritable trait. The genetic variants underlying this genetic contribution are largely unknown. METHODS: We performed a large-scale association study investigating more than 25,000 single nucleotide polymorphisms (SNPs) located within 16,000 genes. Allele frequencies were estimated in contrasting DNA pools from white females selected for low (<0.87 g/cm(2), n = 319) and high (> 1.11 g/cm(2), n = 321) BMD at the lumbar spine. Significant findings were verified in two additional sample collections. RESULTS: Based on allele frequency differences between DNA pools and subsequent individual genotyping, one of the candidate loci indicated was the phosphodiesterase 4D (PDE4D) gene region on chromosome 5q12. We subsequently tested the marker SNP, rs1498608, in a second sample of 138 white females with low (<0.91 g/cm(2)) and 138 females with high (>1.04 g/cm(2)) lumbar spine BMD. Odds ratios were 1.5 (P = 0.035) in the original sample and 2.1 (P = 0.018) in the replication sample. Association fine mapping with 80 SNPs located within 50 kilobases of the marker SNP identified a 20 kilobase region of association containing exon 6 of PDE4D. In a second, family-based replication sample with a preponderance of females with low BMD, rs1498608 showed an opposite relationship with BMD at different sites (p = 0.00044-0.09). We also replicated the previously reported association of the Ser37Ala polymorphism in BMP2, known to interact biologically with PDE4D, with BMD. CONCLUSION: This study indicates that variants in the gene encoding PDE4D account for some of the genetic contribution to bone mineral density variation in humans. The contrasting results from different samples indicate that the effect may be context-dependent. PDE4 inhibitors have been shown to increase bone mass in normal and osteopenic mice, but up until now there have been no reports implicating any member of the PDE4 gene family in human osteoporosis

Synthesis, magnetic and optical properties of core/shell Co1-xZnxFe2O4/SiO2 nanoparticles

The optical properties of multi-functionalized cobalt ferrite (CoFe2O4), cobalt zinc ferrite (Co0.5Zn0.5Fe2O4), and zinc ferrite (ZnFe2O4) nanoparticles have been enhanced by coating them with silica shell using a modified Stöber method. The ferrites nanoparticles were prepared by a modified citrate gel technique. These core/shell ferrites nanoparticles have been fired at temperatures: 400°C, 600°C and 800°C, respectively, for 2 h. The composition, phase, and morphology of the prepared core/shell ferrites nanoparticles were determined by X-ray diffraction and transmission electron microscopy, respectively. The diffuse reflectance and magnetic properties of the core/shell ferrites nanoparticles at room temperature were investigated using UV/VIS double-beam spectrophotometer and vibrating sample magnetometer, respectively. It was found that, by increasing the firing temperature from 400°C to 800°C, the average crystallite size of the core/shell ferrites nanoparticles increases. The cobalt ferrite nanoparticles fired at temperature 800°C; show the highest saturation magnetization while the zinc ferrite nanoparticles coated with silica shell shows the highest diffuse reflectance. On the other hand, core/shell zinc ferrite/silica nanoparticles fired at 400°C show a ferromagnetic behavior and high diffuse reflectance when compared with all the uncoated or coated ferrites nanoparticles. These characteristics of core/shell zinc ferrite/silica nanostructures make them promising candidates for magneto-optical nanodevice applications

E2F-1 induces melanoma cell apoptosis via PUMA up-regulation and Bax translocation

BACKGROUND: PUMA is a pro-apoptotic Bcl-2 family member that has been shown to be involved in apoptosis in many cell types. We sought to ascertain whether induction of PUMA plays a crucial role in E2F-1-induced apoptosis in melanoma cells. METHODS: PUMA gene and protein expression levels were detected by real-time PCR and Western blot in SK-MEL-2 and HCT116 cell lines after Ad-E2F-1 infection. Activation of the PUMA promoter by E2F-1 overexpression was detected by dual luciferase reporter assay. E2F-1-induced Bax translocation was shown by immunocytochemistry. The induction of caspase-9 activity was measured by caspase-9 colorimetric assay kit. RESULTS: Up-regulation of the PUMA gene and protein by E2F-1 overexpression was detected by real-time PCR and Western blot analysis in the SK-MEL-2 melanoma cell line. In support of this finding, we found six putative E2F-1 binding sites within the PUMA promoter. Subsequent dual luciferase reporter assay showed that E2F-1 expression could increase the PUMA gene promoter activity 9.3 fold in SK-MEL-2 cells. The role of PUMA in E2F-1-induced apoptosis was further investigated in a PUMA knockout cell line. Cell viability assay showed that the HCT116 PUMA-/- cell line was more resistant to Ad-E2F-1-mediated cell death than the HCT116 PUMA+/+ cell line. Moreover, a 2.2-fold induction of the PUMA promoter was also noted in the HCT116 PUMA+/+ colon cancer cell line after Ad-E2F-1 infection. Overexpression of a truncated E2F-1 protein that lacks the transactivation domain failed to up-regulate PUMA promoter, suggesting that PUMA may be a transcriptional target of E2F-1. E2F-1-induced cancer cell apoptosis was accompanied by Bax translocation from the cytosol to mitochondria and the induction of caspase-9 activity, suggesting that E2F-1-induced apoptosis is mediated by PUMA through the cytochrome C/Apaf-1-dependent pathway. CONCLUSION: Our studies strongly demonstrated that E2F-1 induces melanoma cell apoptosis via PUMA up-regulation and Bax translocation. The signaling pathways provided here will further enhance insights on the mechanisms of E2F-1-induced cancer cell apoptosis as a strategy for cancer therapy

The dynamics of human body weight change

An imbalance between energy intake and energy expenditure will lead to a change in body weight (mass) and body composition (fat and lean masses). A quantitative understanding of the processes involved, which currently remains lacking, will be useful in determining the etiology and treatment of obesity and other conditions resulting from prolonged energy imbalance. Here, we show that the long-term dynamics of human weight change can be captured by a mathematical model of the macronutrient flux balances and all previous models are special cases of this model. We show that the generic dynamical behavior of body composition for a clamped diet can be divided into two classes. In the first class, the body composition and mass are determined uniquely. In the second class, the body composition can exist at an infinite number of possible states. Surprisingly, perturbations of dietary energy intake or energy expenditure can give identical responses in both model classes and existing data are insufficient to distinguish between these two possibilities. However, this distinction is important for the efficacy of clinical interventions that alter body composition and mass

Cooperativity Dominates the Genomic Organization of p53-Response Elements: A Mechanistic View

p53-response elements (p53-REs) are organized as two repeats of a palindromic DNA segment spaced by 0 to 20 base pairs (bp). Several experiments indicate that in the vast majority of the human p53-REs there are no spacers between the two repeats; those with spacers, particularly with sizes beyond two nucleotides, are rare. This raises the question of what it indicates about the factors determining the p53-RE genomic organization. Clearly, given the double helical DNA conformation, the orientation of two p53 core domain dimers with respect to each other will vary depending on the spacer size: a small spacer of 0 to 2 bps will lead to the closest p53 dimer-dimer orientation; a 10-bp spacer will locate the p53 dimers on the same DNA face but necessitate DNA looping; while a 5-bp spacer will position the p53 dimers on opposite DNA faces. Here, via conformational analysis we show that when there are 0–2 bp spacers, p53-DNA binding is cooperative; however, cooperativity is greatly diminished when there are spacers with sizes beyond 2 bp. Cooperative binding is broadly recognized to be crucial for biological processes, including transcriptional regulation. Our results clearly indicate that cooperativity of the p53-DNA association dominates the genomic organization of the p53-REs, raising questions of the structural organization and functional roles of p53-REs with larger spacers. We further propose that a dynamic landscape scenario of p53 and p53-REs can better explain the selectivity of the degenerate p53-REs. Our conclusions bear on the evolutionary preference of the p53-RE organization and as such, are expected to have broad implications to other multimeric transcription factor response element organization

FluTE, a Publicly Available Stochastic Influenza Epidemic Simulation Model

Mathematical and computer models of epidemics have contributed to our understanding of the spread of infectious disease and the measures needed to contain or mitigate them. To help prepare for future influenza seasonal epidemics or pandemics, we developed a new stochastic model of the spread of influenza across a large population. Individuals in this model have realistic social contact networks, and transmission and infections are based on the current state of knowledge of the natural history of influenza. The model has been calibrated so that outcomes are consistent with the 1957/1958 Asian A(H2N2) and 2009 pandemic A(H1N1) influenza viruses. We present examples of how this model can be used to study the dynamics of influenza epidemics in the United States and simulate how to mitigate or delay them using pharmaceutical interventions and social distancing measures. Computer simulation models play an essential role in informing public policy and evaluating pandemic preparedness plans. We have made the source code of this model publicly available to encourage its use and further development