Algorithms for reconstruction and analysis of metabolic networks, with an application to Neurospora crassa

In this work, I have developed optimization-based algorithms to reconstruct and analyze metabolic network models, and I have applied them to the metabolism of the filamentous fungus Neurospora crassa. The developed algorithms are: (1) LInear MEtabolite Dilution Flux Balance Analysis (limed-FBA), which predicts flux while linearly accounting for metabolite dilution; (2) One-step functional Pruning (OnePrune), which removes blocked reactions with a single compact linear program; and (3) Consistent Reproduction Of growth/no-growth Phenotype (CROP), which reconciles differences between in silico and experimental gene essentiality faster than previous approaches. Together, these algorithms comprise Fast Automated Reconstruction of Metabolism (FARM). FARM was applied to reconstruct the first genome-scale model of N. crassa metabolism. This organism has played a central role in the development of twentieth-century genetics, biochemistry and molecular biology, and continues to serve as a model organism for eukaryotic biology. The N. crassa model consists of 836 metabolic genes, 257 pathways, 6 cellular compartments, and is supported by extensive manual curation of 491 literature citations. Against an independent test set of more than 300 essential/non-essential genes that were not used to train the model, it displays 93% sensitivity and specificity. The model was also used to simulate the biochemical genetics experiments originally performed on N. crassa by comprehensively predicting nutrient rescue of essential genes and synthetic lethal interactions, and providing detailed pathway-based mechanistic explanations of the predictions. The model provides a reliable computational framework for the integration and interpretation of ongoing experimental efforts in N. crassa, and the algorithms will enhance reconstruction and analysis of high-quality genome-scale metabolic models in general

Symplectic No-core Shell-model Approach to Intermediate-mass Nuclei

We present a microscopic description of nuclei in an intermediate-mass region, including the proximity to the proton drip line, based on a no-core shell model with a schematic many-nucleon long-range interaction with no parameter adjustments. The outcome confirms the essential role played by the symplectic symmetry to inform the interaction and the winnowing of shell-model spaces. We show that it is imperative that model spaces be expanded well beyond the current limits up through fifteen major shells to accommodate particle excitations that appear critical to highly-deformed spatial structures and the convergence of associated observables.Comment: 9 pages, 8 figure

Meta-analysis of glioblastoma multiforme versus anaplastic astrocytoma identifies robust gene markers

<p>Abstract</p> <p>Background</p> <p>Anaplastic astrocytoma (AA) and its more aggressive counterpart, glioblastoma multiforme (GBM), are the most common intrinsic brain tumors in adults and are almost universally fatal. A deeper understanding of the molecular relationship of these tumor types is necessary to derive insights into the diagnosis, prognosis, and treatment of gliomas. Although genomewide profiling of expression levels with microarrays can be used to identify differentially expressed genes between these tumor types, comparative studies so far have resulted in gene lists that show little overlap.</p> <p>Results</p> <p>To achieve a more accurate and stable list of the differentially expressed genes and pathways between primary GBM and AA, we performed a meta-analysis using publicly available genome-scale mRNA data sets. There were four data sets with sufficiently large sample sizes of both GBMs and AAs, all of which coincidentally used human U133 platforms from Affymetrix, allowing for easier and more precise integration of data. After scoring genes and pathways within each data set, we combined the statistics across studies using the nonparametric rank sum method to identify the features that differentiate GBMs and AAs. We found >900 statistically significant probe sets after correction for multiple testing from the >22,000 tested. We also used the rank sum approach to select >20 significant Biocarta pathways after correction for multiple testing out of >175 pathways examined. The most significant pathway was the hypoxia-inducible factor (HIF) pathway. Our analysis suggests that many of the most statistically significant genes work together in a <it>HIF1A</it>/<it>VEGF</it>-regulated network to increase angiogenesis and invasion in GBM when compared to AA.</p> <p>Conclusion</p> <p>We have performed a meta-analysis of genome-scale mRNA expression data for 289 human malignant gliomas and have identified a list of >900 probe sets and >20 pathways that are significantly different between GBM and AA. These feature lists could be utilized to aid in diagnosis, prognosis, and grade reduction of high-grade gliomas and to identify genes that were not previously suspected of playing an important role in glioma biology. More generally, this approach suggests that combined analysis of existing data sets can reveal new insights and that the large amount of publicly available cancer data sets should be further utilized in a similar manner.</p

Foodborne or pandemic: An analysis of the transmission of norovirus-associated gastroenteritis and the role of food handlers

This study examined the strength of association between food workers and food to norovirus in comparison to bacteria associated with foodborne-related gastroenteritis by whether norovirus had a direct (physical evidence), indirect (statistical evidence), or suspect (neither of the two) association with food or food handlers. The Centers for Disease Control and Prevention considers norovirus to cause the largest number of foodborne-related gastroenteritis cases in the United States. The association of norovirus with foodborne outbreaks through its information data collection form focuses on the food worker as the typical source. Yet, many outbreaks are not foodborne in nature. The gap in the research is the evidence supporting the theory that norovirus transmission is the same as bacterial transmission. A secondary data anaylsis was conducted on the data from the electronic Foodborne Outbreak Reporting System between 1998 and 2006. An odds ratio analysis showed no similarity between proportion of the implicated and nonimplicated numbers of outbreaks from norovirus and those from Salmonella. The odds ratios also showed a stronger similarity between proportions of food handler implicated outbreaks from norovirus than from Salmonella. An analysis showed, though, a significant emphasis was not placed on the food handler but on other indirect routes of transmission of norovirus in outbreaks. The analysis also indicated that norovirus transmission was not mainly through food. Norovirus transmission appeared to be through person-to-person rather than food and had more similarities with pandemic influenza than gastroenteritis-associated bacteria. A change in approach to norovirus by local, state, and federal agencies could have social change implications for prevention, surveillance, and public health programs to reduce infection and outbreaks

Zygapophysial joint blocks in chronic low back pain: a test of Revel's model as a screening test

BACKGROUND: Only controlled blocks are capable of confirming the zygapophysial joints (ZJ) as the pain generator in LBP patients. However, previous workers have found that a cluster of clinical signs ("Revel's criteria"), may be valuable in predicting the results of an initial screening ZJ block. It was suggested that these clinical findings are unsuitable for diagnosis, but may be of value in selecting patients for diagnostic blocks of the lumbar ZJ's. To constitute evidence in favour of a clinical management strategy, these results need confirmation. This study evaluates the utility of 'Revel's criteria' as a screening tool for selection of chronic low back pain patients for controlled ZJ diagnostic blocks. METHODS: This study utilized a prospective blinded concurrent reference standard related validity design. Consecutive chronic LBP patients completed pain drawings, psychosocial distress and disability questionnaires, received a clinical examination and lumbar zygapophysial blocks. Two reference standards were evaluated simultaneously: 1. 75% reduction of pain on a visual analogue scale (replication of previous work), and 2. abolition of the dominant or primary pain. Using "Revel's criteria" as predictors, logistic regression analyses were used to test the model. Estimates of sensitivity, specificity, predictive values and likelihood ratios for selected variables were calculated for the two proposed clinical strategies. RESULTS: Earlier results were not replicated. Sensitivity of "Revel's criteria" was low sensitivity (<17%), and specificity high (approximately 90%). Absence of pain with cough or sneeze just reached significance (p = 0.05) within one model. CONCLUSIONS: "Revel's criteria" are unsuitable as a clinical screening test to select chronic LBP patients for initial ZJ blocks. However, the criteria may have use in identifying a small subset (11%) of patients likely to respond to the initial block (specificity 93%)

Two sequential outbreaks caused by multidrug-resistant Acinetobacter baumannii isolates producing OXA-58 or OXA-72 oxacillinase in an intensive care unit in France

International audienc

Incidence and impact on clinical outcome of infections with piperacillin/tazobactam resistant Escherichia coli in ICU: A retrospective study

Escherichia coli infections are frequent in ICU patients. The increased resistance to fluoroquinolones and amoxicillin/clavulanate of this pathogen mandates the prescription of broad-spectrum antibiotics such as piperacillin/tazobactam (PIP-TAZ) or third generation cephalosporins (3GC)