Integrated Analysis of High-Resolution Gene Expression and Copy Number Profiling Identified Biallelic Deletion of CDKN2A/2B Tumor Suppressor Locus As the Most Frequent and Unique Genomic Abnormality in Diffuse Large B-Cell Lymphoma (DLBCL) with Strong Prognostic Value in Both GCB and ABC Subtypes and Not Overcome by a Dose-Intensive Immunochemotherapy Regimen Plus Rituximab. Results of a Prospective GELA Clinical Trial Program

Background and aim of the study: Genomic gains and losses play a crucial role in the development and progression of DLBCL and are closely related to gene expression profiles (GEP), including the germinal center B-cell like (GCB) and activated B-cell like (ABC) cell of origin (COO) molecular signatures. To identify new oncogenes or tumor suppressor genes (TSG) involved in DLBCL pathogenesis and to determine their prognostic values, an integrated analysis of high-resolution gene expression and copy number profiling was performed. Patients and methods: Two hundred and eight adult patients with de novo CD20+ DLBCL enrolled in the prospective multicentric randomized LNH-03 GELA trials (LNH03-1B, -2B, -3B, 39B, -5B, -6B, -7B) with available frozen tumour samples, centralized reviewing and adequate DNA/RNA quality were selected. 116 patients were treated by Rituximab(R)-CHOP/R-miniCHOP and 92 patients were treated by the high dose (R)-ACVBP regimen dedicated to patients younger than 60 years (y) in frontline. Tumour samples were simultaneously analysed by high resolution comparative genomic hybridization (CGH, Agilent, 144K) and gene expression arrays (Affymetrix, U133+2). Minimal common regions (MCR), as defined by segments that affect the same chromosomal region in different cases, were delineated. Gene expression and MCR data sets were merged using Gene expression and dosage integrator algorithm (GEDI, Lenz et al. PNAS 2008) to identify new potential driver genes. Results: A total of 1363 recurrent (defined by a penetrance > 5%) MCRs within the DLBCL data set, ranging in size from 386 bp, affecting a single gene, to more than 24 Mb were identified by CGH. Of these MCRs, 756 (55%) showed a significant association with gene expression: 396 (59%) gains, 354 (52%) single-copy deletions, and 6 (67%) homozygous deletions. By this integrated approach, in addition to previously reported genes (CDKN2A/2B, PTEN, DLEU2, TNFAIP3, B2M, CD58, TNFRSF14, FOXP1, REL...), several genes targeted by gene copy abnormalities with a dosage effect and potential physiopathological impact were identified, including genes with TSG activity involved in cell cycle (HACE1, CDKN2C) immune response (CD68, CD177, CD70, TNFSF9, IRAK2), DNA integrity (XRCC2, BRCA1, NCOR1, NF1, FHIT) or oncogenic functions (CD79b, PTPRT, MALT1, AUTS2, MCL1, PTTG1...) with distinct distribution according to COO signature. The CDKN2A/2B tumor suppressor locus (9p21) was deleted homozygously in 27% of cases and hemizygously in 9% of cases. Biallelic loss was observed in 49% of ABC DLBCL and in 10% of GCB DLBCL. This deletion was strongly correlated to age and associated to a limited number of additional genetic abnormalities including trisomy 3, 18 and short gains/losses of Chr. 1, 2, 19 regions (FDR < 0.01), allowing to identify genes that may have synergistic effects with CDKN2A/2B inactivation. With a median follow-up of 42.9 months, only CDKN2A/2B biallelic deletion strongly correlates (FDR p.value < 0.01) to a poor outcome in the entire cohort (4y PFS = 44% [32-61] respectively vs. 74% [66-82] for patients in germline configuration; 4y OS = 53% [39-72] vs 83% [76-90]). In a Cox proportional hazard prediction of the PFS, CDKN2A/2B deletion remains predictive (HR = 1.9 [1.1-3.2], p = 0.02) when combined with IPI (HR = 2.4 [1.4-4.1], p = 0.001) and GCB status (HR = 1.3 [0.8-2.3], p = 0.31). This difference remains predictive in the subgroup of patients treated by R-CHOP (4y PFS = 43% [29-63] vs. 66% [55-78], p=0.02), in patients treated by R-ACVBP (4y PFS = 49% [28-84] vs. 83% [74-92], p=0.003), and in GCB (4y PFS = 50% [27-93] vs. 81% [73-90], p=0.02), or ABC/unclassified (5y PFS = 42% [28-61] vs. 67% [55-82] p = 0.009) molecular subtypes (Figure 1). Conclusion: We report for the first time an integrated genetic analysis of a large cohort of DLBCL patients included in a prospective multicentric clinical trial program allowing identifying new potential driver genes with pathogenic impact. However CDKN2A/2B deletion constitutes the strongest and unique prognostic factor of chemoresistance to R-CHOP, regardless the COO signature, which is not overcome by a more intensified immunochemotherapy. Patients displaying this frequent genomic abnormality warrant new and dedicated therapeutic approaches.

Exaggerated exercise-induced pulmonary hypertension causes lung water accumulation and right ventricular dysfunction in patients with chronic mountain sickness

Background: Chronic mountain sickness (CMS) is characterized by exaggerated exercise-induced pulmonary hypertension. Evidences suggests that exercise may cause lung fluid accumulation at high altitude. We hypothesized that, in patients with CMS, exercise causes lung fluid accumulation.Methods: In 21 male CMS patients and 20 matched healthy controls born and permanently living in La Paz (Bolivia, 3600m) we assessed with echocardiogram, pulmonary artery pressure (PASP), right and left ventricular function and ultrasoundlung comets (ULCs, a marker of lung fluid accumulation) at rest and during mild bicycle exercise (10 min at 50W).Results: CMS patients presented a more than 2-fold greater exercise-induced increase in pulmonary artery pressure than controls (17.1±8.3 vs 7.2±7.9 mmHg, P=0.003). This exaggerated PASP response to exercise was associated with a roughly 3-fold greater increase in UCLs in patients with CMS than in controls (6.3±5.1 vs. 2.1±5.3, p<0.05), and there existed a significant relationship between PASP and UCLs (r=0.44, p<0.001). Finally, TDI on lateral tricuspid annulus decreased during exercise in patients with CMS (from 13.2±3.2 to 11.5±2.1 cm s-1, p=0.03), but increased in controls (from 13.1±2.9 to 14.9±2.6 cm s-1 , p=0.04). Left ventricular function remained unaltered in the 2 groups.Conclusions: we provide the first direct evidence in CMS patients that exaggerated exercise-induced pulmonary hypertension causes rapid lung fluid accumulation and right ventricular dysfunction. We speculate that in patients with CMS these two phenomena contribute to reduced exercise performances and Figure 1 increased cardiovascular morbidity and mortality that characterise these subjects.

The referent : a new referential methodology and procedure in live drawing

My research in live drawing and new technologies uses a combination of a human figure in live in composition, overlaid with a digital projection of a second human figure. The aim is to explore, to amplify and thoroughly analyse the search for distinctive identities and graphic languages of representation for live and projected models.

Council Bluffs Interstate System (I-29, I-80 and I-480) Improvements Project, February 28, 2005

The Iowa Department of Transportation (Iowa DOT), Nebraska Department of Roads (NDOR), and the Federal Highway Administration (FHWA) are proposing to improve the interstate system around Council Bluffs with improvements extending across the Missouri River on I-80 to east of the I-480 interchange in Omaha, Nebraska, see Figure 1-1. The study considers long-term, broad-based transportation improvements along I-80, I-29, and I-480, including approximately 18 mainline miles of interstate and 14 interchanges (3 system1, 11 service), that would add capacity and correct functional issues along the mainline and interchanges and upgrade the I-80 Missouri River Crossing. These improvements, once implemented, would bring the segments of I-80 and I-29 up to current engineering standards and modernize the roadway to accommodate future traffic needs

Council Bluffs Interstate System (I-29, I-80 and I-480) Final Environment Impact Statement, July, 2005

The Iowa Department of Transportation (Iowa DOT), Nebraska Department of Roads (NDOR), and the Federal Highway Administration (FHWA) are proposing improvements to the interstate system in the Omaha/Council Bluffs metropolitan area, extending across the Missouri River on Interstate 80 (I-80) to east of the Interstate 480 (I-480) interchange in Omaha, Nebraska (see Figure 1-1). The study considers long-term, broad-based transportation improvements along Interstate I-29 (I-29), I-80, and I-480, including approximately 18 mainline miles of interstate and 14 interchanges (3 system1, 11 service), that would add capacity and correct functional issues along the mainline and interchanges and upgrade the I-80 Missouri River Crossing. These improvements, once implemented, would bring the segments of I-80 and I-29 up to current engineering standards and modernize the roadway to accommodate future traffic needs.

Simulations of action of DNA topoisomerases to investigate boundaries and shapes of spaces of knots.

The configuration space available to randomly cyclized polymers is divided into subspaces accessible to individual knot types. A phantom chain utilized in numerical simulations of polymers can explore all subspaces, whereas a real closed chain forming a figure-of-eight knot, for example, is confined to a subspace corresponding to this knot type only. One can conceptually compare the assembly of configuration spaces of various knot types to a complex foam where individual cells delimit the configuration space available to a given knot type. Neighboring cells in the foam harbor knots that can be converted into each other by just one intersegmental passage. Such a segment-segment passage occurring at the level of knotted configurations corresponds to a passage through the interface between neighboring cells in the foamy knot space. Using a DNA topoisomerase-inspired simulation approach we characterize here the effective interface area between neighboring knot spaces as well as the surface-to-volume ratio of individual knot spaces. These results provide a reference system required for better understanding mechanisms of action of various DNA topoisomerases.

Wage cuts and managers' empathy: How a positive emotion can contribute to positive organizational ethics in difficult times

Using the lens of positive organizational ethics, we theorized that empathy affects decisions in ethical dilemmas that concern the well-being of not only the organization but also other stakeholders. We hypothesized and found that empathetic managers were less likely to comply with requests by an authority figure to cut the wages of their employees than were non-empathetic managers. However, when an authority figure requested to hold wages constant, empathy did not affect wage cut decisions. These findings imply that empathy can serve as a safeguard for ethical decision making in organizations during trying times without generally undermining organizational effectiveness. We conclude by discussing the implications of our research.

Tree and Brush Control For County Road Right-of-Way, Ocotober 2002

This manual summarizes the roadside tree and brush control methods used by all of Iowa's 99 counties. It is based on interviews conducted in Spring 2002 with county engineers, roadside managers and others. The target audience of this manual is the novice county engineer or roadside manager. Iowa law is nearly silent on roadside tree and brush control, so individual counties have been left to decide on the level of control they want to achieve and maintain. Different solutions have been developed but the goal of every county remains the same: to provide safe roads for the traveling public. Counties in eastern and southern Iowa appear to face the greatest brush control challenge. Most control efforts can be divided into two categories: mechanical and chemical. Mechanical control includes cutting tools and supporting equipment. A chain saw is the most widely used cutting tool. Tractor mounted boom mowers and brush cutters are used to prune miles of brush but have significant safety and aesthetic limitations and boom mowers are easily broken by inexperienced operators. The advent of tree shears and hydraulic thumbs offer unprecedented versatility. Bulldozers are often considered a method of last resort since they reduce large areas to bare ground. Any chipper that violently grabs brush should not be used. Chemical control is the application of herbicide to different parts of a plant: foliar spray is applied to leaves; basal bark spray is applied to the tree trunk; a cut stump treatment is applied to the cambium ring of a cut surface. There is reluctance by many to apply herbicide into the air due to drift concerns. One-third of Iowa counties do not use foliar spray. By contrast, several accepted control methods are directed toward the ground. Freshly cut stumps should be treated to prevent resprouting. Basal bark spray is highly effective in sensitive areas such as near houses. Interest in chemical control is slowly increasing as herbicides and application methods are refined. Fall burning, a third, distinctly separate technique is underused as a brush control method and can be effective if timed correctly. In all, control methods tend to reflect agricultural patterns in a county. The use of chain saws and foliar sprays tends to increase in counties where row crops predominate, and boom mowing tends to increase in counties where grassland predominates. For counties with light to moderate roadside brush, rotational maintenance is the key to effective control. The most comprehensive approach to control is to implement an integrated roadside vegetation management (IRVM) program. An IRVM program is usually directed by a Roadside Manager whose duties may be shared with another position. Funding for control programs comes from the Rural Services Basic portion of a county's budget. The average annual county brush control budget is about $76,000. That figure is thought not to include shared expenses such as fuel and buildings. Start up costs for an IRVM program are less if an existing control program is converted. In addition, IRVM budgets from three different northeastern Iowa counties are offered for comparison in this manual. The manual also includes a chapter on temporary traffic control in rural work zones, a summary of the Iowa Code as it relates to brush control, and rules on avoiding seasonal disturbance of the endangered Indiana bat. Appendices summarize survey and forest cover data, an equipment inventory, sample forms for record keeping, a sample brush control policy, a few legal opinions, a literature search, and a glossary.

Congenital disorder of glycosylation type Id (CDG Id) : phenotypic, biochemical and molecular characterization of a new patient

Rapport de synthèseLes troubles de la glycosylation (Congenital Disorders of Glycosylation, CDG) regroupent une famille de maladies multi-systémiques héréditaires causées par des défauts dans la synthèse de glycoconjugés. La glycosylation est une réaction enzymatique consistant à lier de façon covalente un glucide à une chaîne peptidique ou une protéine. Il existe deux types de glycosylation. La N-gjycosylation est l'addition de glucides aux chaînes peptidiques en croissance dès leur entrée dans la lumière du réticulum endoplasmique. Elle s'effectue sur les futures glycoprotéines membranaires et conduit à des chaînes de sucres courtes et ramifiées. La O-glycosylation est l'addition de glucides au niveau des résidus hydroxylés des acides aminés sérine et thréonine des chaînes peptidiques déjà présentes dans la lumière de l'appareil de Golgi. Elle est, dans la plupart des cas, effectuée sur îes protéoglycanes et conduit à des chaînes de sucres longues et non ramifiées. La classification des CDG repose sur le niveau de l'étape limitante de la glycosylation. Les CDG de type 1, plus fréquents, regroupent les déficits enzymatiques se situant en amont du transfert de Poligosaccharide sur la chaîne peptidique. Les CDG de type 2 regroupent ceux ayant lieu en aval de ce transfert. Parmi les nombreux différents sous-types de CDG, le CDG de type ld est causé par une anomalie de la mannosyltransferase, enzyme codée par le gène ALG3 (chromosome 3q27). Jusqu'à ce jour, six patients atteints de CDG ld ont été reportés dans la littérature. Notre travail a permis de décrire un septième patient et d'affiner les caractéristiques cliniques, biologiques, neuroradiologiques et moléculaires du CDG ld. Notre patient est notamment porteur d'une nouvelle mutation de type missense sur le gène ALG3. Tous les patients atteints de CDG ld présentent une encéphalopathie progressive avec microcéphalie, retard psychomoteur sévère et épilepsie. Une ostéopénie marquée est présente chez certains patients. Elle est parfois sous diagnostiquée et révélée uniquement lors de fracture pathologique. Les patients atteints de CDG ld présentent également des traits dysmorphiques typiques, mais aucune atteinte multi-systémique ou anomalie biologique spécifique n'est retrouvée telle que dans les autres types de CDG. Le dépistage biochimique des troubles de la glycosylation se fait par une analyse simple et peu coûteuse qui est l'analyse de la transferrine sérique par isoelectrofocusing ou par électrophorèse capillaire. Un tel dépistage devrait être effectué chez tout patient présentant une encéphalopathie d'origine indéterminée, et cela même en l'absence d'atteinte multi- systémique. Notre travail a été publié sous forme d'article de type « short report », peer-reviewed, dans le Journal of Inherited Metabolic Diseases. Le Journal est une révue spécialisée du domaine des erreirs innées du métabolisme. S'agissant d'un seul patient rapporté, l'article ne montre que très synthétiquement le travail effectué, Pour cette raison un complément à l'article avec matériel, méthodes et résultats figure ci-après et concerne la partie de recherche moléculaire de notre travail. La doctorante a non seulement encadré personnellement le patient au niveau clinique et biochimique, mais a plus particulièrement mis au point l'analyse moléculaire du gène ALG3 dans le laboratoire de Pédiatrie Moléculaire pour la première fois ; cela a impliqué l'étude du gène, le choix des oligonucleotides et l'optimisation des réactions d'amplification et séquençage.

Protein turnover, ureagenesis and gluconeogenesis.

The major processes discussed below are protein turnover (degradation and synthesis), degradation into urea, or conversion into glucose (gluconeogenesis, Figure 1). Daily protein turnover is a dynamic process characterized by a double flux of amino acids: the amino acids released by endogenous (body) protein breakdown can be reutilized and reconverted to protein synthesis, with very little loss. Daily rates of protein turnover in humans (300 to 400 g per day) are largely in excess of the level of protein intake (50 to 80 g per day). A fast growing rate, as in premature babies or in children recovering from malnutrition, leads to a high protein turnover rate and a high protein and energy requirement. Protein metabolism (synthesis and breakdown) is an energy-requiring process, dependent upon endogenous ATP supply. The contribution made by whole-body protein turnover to the resting metabolic rate is important: it represents about 20 % in adults and more in growing children. Metabolism of proteins cannot be disconnected from that of energy since energy balance influences net protein utilization, and since protein intake has an important effect on postprandial thermogenesis - more important than that of fats or carbohydrates. The metabolic need for amino acids is essentially to maintain stores of endogenous tissue proteins within an appropriate range, allowing protein homeostasis to be maintained. Thanks to a dynamic, free amino acid pool, this demand for amino acids can be continuously supplied. The size of the free amino acid pool remains limited and is regulated within narrow limits. The supply of amino acids to cover physiological needs can be derived from 3 sources: 1. Exogenous proteins that release amino acids after digestion and absorption 2. Tissue protein breakdown during protein turnover 3. De novo synthesis, including amino acids (as well as ammonia) derived from the process of urea salvage, following hydrolysis and microflora metabolism in the hind gut. When protein intake surpasses the physiological needs of amino acids, the excess amino acids are disposed of by three major processes: 1. Increased oxidation, with terminal end products such as CO₂ and ammonia 2. Enhanced ureagenesis i. e. synthesis of urea linked to protein oxidation eliminates the nitrogen radical 3. Gluconeogenesis, i. e. de novo synthesis of glucose. Most of the amino groups of the excess amino acids are converted into urea through the urea cycle, whereas their carbon skeletons are transformed into other intermediates, mostly glucose. This is one of the mechanisms, essential for life, developed by the body to maintain blood glucose within a narrow range, (i. e. glucose homeostasis). It includes the process of gluconeogenesis, i. e. de novo synthesis of glucose from non-glycogenic precursors; in particular certain specific amino acids (for example, alanine), as well as glycerol (derived from fat breakdown) and lactate (derived from muscles). The gluconeogenetic pathway progressively takes over when the supply of glucose from exogenous or endogenous sources (glycogenolysis) becomes insufficient. This process becomes vital during periods of metabolic stress, such as starvation.

Council Bluffs Interstate System Improvements Project Pottawatomie County, Iowa and Douglas County, Nebraska Project Number: IM-029-3(62)54-13-78, November 2004

The Iowa Department of Transportation (Iowa DOT), Nebraska Department of Roads (NDOR), and the Federal Highway Administration (FHWA) are proposing to improve the interstate system around Council Bluffs with improvements extending across the Missouri River on I-80 to east of the I-480 interchange in Omaha, Nebraska, see Figure 1-1. The study considers long-term, broad-based transportation improvements along I-80, I-29, and I-480, including approximately 18 mainline miles of interstate and 14 interchanges (3 system1, 11 service), that would add capacity and correct functional issues along the mainline and interchanges and upgrade the I-80 Missouri River Crossing. These improvements, once implemented, would bring the segments of I-80 and I-29 up to current engineering standards and modernize the roadway to accommodate future traffic needs. In 2001, Iowa DOT and FHWA initiated the Council Bluffs Interstate System (CBIS) Improvements Project. The agencies concluded that the environmental study process would be conducted in two stages; that is, a tiered approach would be applied. The project is being conducted pursuant to the National Environmental Policy Act (NEPA) regulations issued by the Council on Environmental Quality (CEQ), 40 Code of Federal Regulations (CFR) Part 1502.20, and FHWA 23 CFR Part 771.111, that permit tiering for large, complex NEPA studies. Tier 1 is an examination of the overall interstate system improvement needs, including a clear explanation of the area’s transportation needs, a study of alternatives to satisfy them, and broad consideration of potential environmental and social impacts. The Tier 1 evaluation is at a sufficient level of engineering and environmental detail to assist decision makers in selecting a preferred transportation strategy. Tier 1 includes preparation of a draft and final Environmental Impact Statement (EIS) that would disclose the potential environmental and social effects (evaluated at a planning level that considers a variety of conceptual designs) of the proposed improvements. The final EIS will conclude with a Record of Decision (ROD) that states the preferred plan for improvements to be implemented. Essentially, the Tier 1 document will establish the planning framework for the needed improvements. Because the scope of the overall system improvements is large, the interstate improvements would be implemented as a series of individual projects that fit into the overall planning framework. The Tier 1 Area of Potential Impact, which is discussed in detail in Section 4 is an alternative that considers a combination of the most reasonable concepts that have been developed, buffered by approximately 100 or more feet to ensure that any Tier 2 design modifications would remain inside the outer boundary.

Record of Decision Council Bluffs Interstate System (I-29, I-80 and I-480) Improvements Project TIER 1 Environmental Impact Statement Council Bluffs, Iowa to Omaha, Nebraska FHWA-IA- EIS-04-01F Project Number: IM-029-3(62)54—13-78 Submitted Pursuant to 42 USC 4332(2)(c) and 49 USC 303, October 2008

The Federal Highway Administration (FHWA) approves the selection of the Reconstruction of All or Part of the Interstate (Construction Alternative) as the Preferred Alternative to provide improvements to the interstate system in the Omaha/Council Bluffs metropolitan area, extending across the Missouri River on Interstate 80 to east of the Interstate 480 interchange in Omaha, Nebraska. The study considered long-term, broad-based transportation improvements along Interstate I-29 (I-29), I-80, and I-480, including approximately 18 mainline miles of interstate and 14 interchanges (3 system, 11 service), that would add capacity and correct functional issues along the mainline and interchanges and upgrade the I-80 Missouri River Crossing. FHWA also approves the decisions to provide full access between West Broadway and I-29, design the I-80/I-29 overlap section as a dual-divided freeway, and locating the new I-80 Missouri River Bridge north of the existing bridge. Improvements to the interstate system, once implemented, would bring the segments of I-80 and I-29 (see Figure 1) up to current engineering standards and accommodate future traffic needs. This Record of Decision (ROD) concludes Tier 1 of the Council Bluffs Interstate System (CBIS) Improvements Project. Tier 1 included an examination of the area’s transportation needs, a study of alternatives to satisfy them, and broad consideration of potential environmental and social impacts. The Tier 1 evaluation consisted of a sufficient level of engineering and environmental detail to assist decision makers in selecting a preferred transportation strategy. During Tier 1 a Draft EIS (FHWA-IA- EIS-04-01D) was developed which was approved by FHWA, Iowa DOT, and Nebraska Department of Roads (NDOR) in November 2004 with comments accepted through March 15, 2005. The Draft EIS summarized the alternatives that were considered to address the transportation needs around Council Bluffs; identified reconstruction of all or part of the interstate, the “Construction Alternative,” as the Preferred Alternative; identified three system-level decisions that needed to be made at the Tier 1 level; and invited comment on the issues. The Final EIS (FHWA-IA- EIS-04-01F) further documented the Construction Alternative as the Preferred Alternative and identified the recommended decisions for the three system level decisions that needed to be made in Tier 1. This ROD defines the Selected Alternative determined in the Tier 1 studies.

Glutamine synthesis rate in the hyperammonaemic rat brain using simultaneous localized in vivo H-1 and N-15 MRS

Objectives: Glutamine synthetase is a critical step in the glutamate-glutamine cycle, the major mechanism of glutamate neurotransmission and is implicated in the mechanism of ammonia toxicity. 15N MRS is an alternative approach to 13C MRS in studying glutamate- glutamine metabolism. 15N MRS studies allow to measure an apparent glutamine synthesis rate (Vsyn) which reflects a combination of the glutamate- glutamine cycle activity (Vnt) and net glutamine accumulation. The net glutamine synthesis (Vsyn-Vnt) can be directly measured from 1H NMR. Therefore, the aim of this study was to perform in vivo localized 1H MRS interleaved with 15N MRS to directly measure the net glutamine synthesis rate and the apparent glutamine synthesis rate under 15N labeled ammonia infusion in the rat brain, respectively. Methods: 1H and 15N MRS data were acquired interleaved on a 9.4T system (Varian/Magnex Scientific) using 5 rats. 15NH4Cl solution was infused continuously into the femoral vein for up to 10 h (4.5 mmol/h/kg).1 The plasma ammonia concentration was increased to 0.95±0.08 mmol/L (Analox GM7 analyzer). 1H spectra were acquired and quantified as described previously.2 15N unlocalized and localized spectra were acquired using the sequence;3 and quantified using AMARES and an external reference method.4 The metabolic model used to analyze the total Gln and 5-15N labeled Gln time courses is shown on Figure 1A. Results: Glutamine concentration increased from 2.5±0.3 to 15±3.3 mmol/kg whereas the total glutamate concentrations remained unchanged (Figure 1B). The linear fit of the time-evolution of the total Gln from the 1H spectra gave the net synthesis flux (Vsyn-Vnt), which was 0.021± 0.006 mmol/min per g (Figure 1D). The 5-15N Gln peak (_271 ppm) was visible in the first and all subsequent scans, whereas the 2-15N Gln/Glu peak (_342 ppm) appeared after B1.5 h (Figure 1C). From the in vivo 5-15N Gln time course, Vsyn = 0.29±0.1 mmol/min per g and a plasma NH3 fractional enrichment of 71%±6% were calculated. Vnt was 0.26±0.1 mmol/min/g, obtained assuming a negligible Gln efflux.5 Vsyn and Vnt were within the range of 13C NMR measurements.6 Conclusion: The combination of 1H and 15N NMR allowed for the first time a direct and localized measurement of Vnt and apparent glutamine synthesis rate. Vnt is approximately one order of magnitude faster than the net glutamine accumulation.

Council Bluffs Interstate System Improvements Project Pottawattamie County, IA and Douglas County, Nebraska, July 19, 2005

The Iowa Department of Transportation (Iowa DOT), Nebraska Department of Roads (NDOR), and the Federal Highway Administration (FHWA) are proposing improvements to the interstate system in the Omaha/Council Bluffs metropolitan area, extending across the Missouri River on Interstate 80 (I-80) to east of the Interstate 480 (I-480) interchange in Omaha, Nebraska (see Figure 1-1). The study considers long-term, broad-base transportation improvements along Interstate I-29 (I-29), I-80, and I-480, including approximately 18 mainline miles of interstate and 14 interchanges (3 system1, 11 service), that would add capacity and correct functional issues along the mainline and interchanges and upgrade the I-80 Missouri River Crossing. These improvements, once implemented, would bring the segments of I-80 and I-29 up to current engineering standards and modernize the roadway to accommodate future traffic needs.

Council Bluffs Interstate System Improvements Project Pottawattamie County, IA and Douglas County, Nebraska, July 19, 2005

The Iowa Department of Transportation (Iowa DOT), Nebraska Department of Roads (NDOR), and the Federal Highway Administration (FHWA) are proposing improvements to the interstate system in the Omaha/Council Bluffs metropolitan area, extending across the Missouri River on Interstate 80 (I-80) to east of the Interstate 480 (I-480) interchange in Omaha, Nebraska (see Figure 1-1). The study considers long-term, broad-base transportation improvements along Interstate I-29 (I-29), I-80, and I-480, including approximately 18 mainline miles of interstate and 14 interchanges (3 system1, 11 service), that would add capacity and correct functional issues along the mainline and interchanges and upgrade the I-80 Missouri River Crossing. These improvements, once implemented, would bring the segments of I-80 and I-29 up to current engineering standards and modernize the roadway to accommodate future traffic needs.