Neutron structure of type-III antifreeze protein allows the reconstruction of AFP-ice interface.

Antifreeze proteins (AFPs) inhibit ice growth at sub-zero temperatures. The prototypical type-III AFPs have been extensively studied, notably by X-ray crystallography, solid-state and solution NMR, and mutagenesis, leading to the identification of a compound ice-binding surface (IBS) composed of two adjacent ice-binding sections, each which binds to particular lattice planes of ice crystals, poisoning their growth. This surface, including many hydrophobic and some hydrophilic residues, has been extensively used to model the interaction of AFP with ice. Experimentally observed water molecules facing the IBS have been used in an attempt to validate these models. However, these trials have been hindered by the limited capability of X-ray crystallography to reliably identify all water molecules of the hydration layer. Due to the strong diffraction signal from both the oxygen and deuterium atoms, neutron diffraction provides a more effective way to determine the water molecule positions (as D(2) O). Here we report the successful structure determination at 293 K of fully perdeuterated type-III AFP by joint X-ray and neutron diffraction providing a very detailed description of the protein and its solvent structure. X-ray data were collected to a resolution of 1.05 Å, and neutron Laue data to a resolution of 1.85 Å with a "radically small" crystal volume of 0.13 mm(3). The identification of a tetrahedral water cluster in nuclear scattering density maps has allowed the reconstruction of the IBS-bound ice crystal primary prismatic face. Analysis of the interactions between the IBS and the bound ice crystal primary prismatic face indicates the role of the hydrophobic residues, which are found to bind inside the holes of the ice surface, thus explaining the specificity of AFPs for ice versus water.

Part III. Iowa railroad resource guide, 2009

This section of the 2009 Iowa Railroad System Plan provides background information for the plan, grouped by topic. The resource guide also provides users with important information about the railroad industry and Iowa’s railroad system. The major topics covered below include: • Iowa’s railroad system and carriers. • Railroad freight and Iowa’s economy. • Rail passenger service and Iowa’s economy. • The safety of Iowa’s railroad system, including network safety and security, and railroad and communication interaction.

The past, present and future of renin-angiotensin aldosterone system inhibition.

The renin-angiotensin aldosterone system (RAAS) is central to the pathogenesis of cardiovascular disease. RAAS inhibition can reduce blood pressure, prevent target organ damage in hypertension and diabetes, and improve outcomes in patients with heart failure and/or myocardial infarction. This review presents the history of RAAS inhibition including a summary of key heart failure, myocardial infarction, hypertension and atrial fibrillation trials. Recent developments in RAAS inhibition are discussed including implementation and optimization of current drug therapies. Finally, ongoing clinical trials, opportunities for future trials and issues related to the barriers and approvability of novel RAAS inhibitors are highlighted.

Laboratory Performance Evaluation of CIR-Emulsion and it Comparison Against CIR-Form Test Result from Phase II, Final Report TR-578 Phase III, December 2009

Currently, no standard mix design procedure is available for CIR-emulsion in Iowa. The CIR-foam mix design process developed during the previous phase is applied for CIR-emulsion mixtures with varying emulsified asphalt contents. Dynamic modulus test, dynamic creep test, static creep test and raveling test were conducted to evaluate the short- and long-term performance of CIR-emulsion mixtures at various testing temperatures and loading conditions. A potential benefit of this research is a better understanding of CIR-emulsion material properties in comparison with those of CIR-foam material that would allow for the selection of the most appropriate CIR technology and the type and amount of the optimum stabilization material. Dynamic modulus, flow number and flow time of CIR-emulsion mixtures using CSS-h were generally higher than those of HFMS-2p. Flow number and flow time of CIR-emulsion using RAP materials from Story County was higher than those from Clayton County. Flow number and flow time of CIR-emulsion with 0.5% emulsified asphalt was higher than CIR-emulsion with 1.0% or 1.5%. Raveling loss of CIR-emulsion with 1.5% emulsified was significantly less than those with 0.5% and 1.0%. Test results in terms of dynamic modulus, flow number, flow time and raveling loss of CIR-foam mixtures are generally better than those of CIR-emulsion mixtures. Given the limited RAP sources used for this study, it is recommended that the CIR-emulsion mix design procedure should be validated against several RAP sources and emulsion types.

Clinical benefit and quality of life in patients with advanced pancreatic cancer receiving gemcitabine plus capecitabine versus gemcitabine alone: a randomized multicenter phase III clinical trial--SAKK 44/00-CECOG/PAN.1.3.001.

PURPOSE: To compare clinical benefit response (CBR) and quality of life (QOL) in patients receiving gemcitabine (Gem) plus capecitabine (Cap) versus single-agent Gem for advanced/metastatic pancreatic cancer. PATIENTS AND METHODS: Patients were randomly assigned to receive GemCap (oral Cap 650 mg/m(2) twice daily on days 1 through 14 plus Gem 1,000 mg/m(2) in a 30-minute infusion on days 1 and 8 every 3 weeks) or Gem (1,000 mg/m(2) in a 30-minute infusion weekly for 7 weeks, followed by a 1-week break, and then weekly for 3 weeks every 4 weeks) for 24 weeks or until progression. CBR criteria and QOL indicators were assessed over this period. CBR was defined as improvement from baseline for >or= 4 consecutive weeks in pain (pain intensity or analgesic consumption) and Karnofsky performance status, stability in one but improvement in the other, or stability in pain and performance status but improvement in weight. RESULTS: Of 319 patients, 19% treated with GemCap and 20% treated with Gem experienced a CBR, with a median duration of 9.5 and 6.5 weeks, respectively (P < .02); 54% of patients treated with GemCap and 60% treated with Gem had no CBR (remaining patients were not assessable). There was no treatment difference in QOL (n = 311). QOL indicators were improving under chemotherapy (P < .05). These changes differed by the time to failure, with a worsening 1 to 2 months before treatment failure (all P < .05). CONCLUSION: There is no indication of a difference in CBR or QOL between GemCap and Gem. Regardless of their initial condition, some patients experience an improvement in QOL on chemotherapy, followed by a worsening before treatment failure.

Salt-dependent renal effects of an angiotensin II antagonist in healthy subjects.

This study was designed to evaluate in healthy volunteers the renal hemodynamic and tubular effects of the orally active angiotensin II receptor antagonist losartan (DuP 753 or MK 954). Losartan or a placebo was administered to 23 subjects maintained on a high-sodium (200 mmol/d) or a low-sodium (50 mmol/d) diet in a randomized, double-blind, crossover study. The two 6-day diet periods were separated by a 5-day washout period. On day 6, the subjects were water loaded, and blood pressure, renal hemodynamics, and urinary electrolyte excretion were measured for 6 hours after a single 100-mg oral dose of losartan (n = 16) or placebo (n = 7). Losartan induced no significant changes in blood pressure, glomerular filtration rate, or renal blood flow in these water-loaded subjects, whatever the sodium diet. In subjects on a low-salt diet, losartan markedly increased urinary sodium excretion from 115 +/- 9 to 207 +/- 21 mumol/min (P < .05). The fractional excretion of endogenous lithium was unchanged, suggesting no effect of losartan on the early proximal tubule in our experimental conditions. Losartan also increased urine flow rate (from 10.5 +/- 0.4 to 13.1 +/- 0.6 mL/min, P < .05); urinary potassium excretion (from 117 +/- 6.9 to 155 +/- 11 mumol/min); and the excretion of chloride, magnesium, calcium, and phosphate. In subjects on a high-salt diet, similar effects of losartan were observed, but the changes induced by the angiotensin II antagonist did not reach statistical significance. In addition, losartan demonstrated significant uricosuric properties with both sodium diets.(ABSTRACT TRUNCATED AT 250 WORDS)

Bioavailability of repeated oral administration of MDL 100,240, a dual inhibitor of angiotensin-converting enzyme and neutral endopeptidase in healthy volunteers.

BACKGROUND: MDL 100,240 (pyrido[2,1-a] [2]benzazepine-4-carboxylic acid,7-[[2-(acetylthio)-1-oxo-3-phenylpropyl]amino]-1,2,3,4,6,7,8, 12b-octahydro-6-oxo, [4S-[4alpha,7alpha(R(*)),12bbeta]]-) is a molecule possessing an inhibiting ability on both angiotensin converting enzyme (ACE) and neutral endopeptidase, the enzyme responsible for atrial natriuretic peptide (ANP) degradation. Such a dual mechanism of action presents a potential clinical interest for the treatment of hypertension and congestive heart failure. OBJECTIVES: To evaluate the bioavailability of MDL 100,240 and its accumulation over repeated oral administration, using ACE inhibition as a surrogate for plasma drug level and determining its profile after oral and i.v. administration. METHODS: First, in an open, one-period, single-dose study, the ACE inhibition profile was characterised following a 12.5 mg MDL 100,240 i.v. infusion. Second, in a three-group, parallel, randomised, double-blind study, each group of four subjects received q.d., over 8 days, 2.5, 10 or 20 mg of MDL 100,240 orally. The ACE inhibition profile was determined on day 1 and day 8. Trough plasma ACE was measured on days 2, 3 and 4. The recovery of ACE activity was monitored up to 72 h after the last dose of MDL 100,240. RESULTS: ACE inhibition profile was similar on day 1 and day 8, and trough inhibition remained unchanged after the 8 days of treatment with 10 mg or 20 mg. Following repeated 2.5-mg ingestion, trough inhibition increased from 33% to 44% after the eighth dose. The oral bioavailability of MDL 100,240 was estimated at 85%, not statistically different from 100%. The accumulation ratio at steady state was estimated at 112%. Expressing the accumulation ratio in terms of half-life, a t(1/2) of 0.31 days or 7. 5 h was estimated. CONCLUSION: MDL 100,240 (oral solution) has a good bioavailability, as estimated by ACE inhibition, and no drug accumulation seems to occur over 8 days with the 10-mg and 20-mg doses, but a slight rise in the trough level is observed with the 2. 5-mg dose.

Antagonistes de l'angiotensine II et cancer: un bilan rassurant [Angiotensin II receptor blockers (ARBs) and cancer: a reassuring balance].

The effects of drugs on new cancer and cancer-related death are a major concern. Recently, a meta-analysis raised the possibility that ARBs might have an adverse impact in this respect. This point of view was highly debated until the publication of two other meta-analyses which did not demonstrate any increased risk of new cancer occurrence as well as of cancer related-death with the use of ARBs in patients with hypertension, heart failure and/or nephropathy. This illustrates that the results of meta-analyses should be interpreted cautiously and critically in order to avoid biased conclusions. Overall the bulk of evidence today indicates that ARBs are not associated with an increased cancer risk.

Simulations in Evolution. III. Randomness as a Generator of Opportunities.

In Neo-Darwinism, variation and natural selection are the two evolutionary mechanisms which propel biological evolution. Our previous reports presented a histogram model to simulate the evolution of populations of individuals classified into bins according to an unspecified, quantifiable phenotypic character, and whose number in each bin changed generation after generation under the influence of fitness, while the total population was maintained constant. The histogram model also allowed Shannon entropy (SE) to be monitored continuously as the information content of the total population decreased or increased. Here, a simple Perl (Practical Extraction and Reporting Language) application was developed to carry out these computations, with the critical feature of an added random factor in the percent of individuals whose offspring moved to a vicinal bin. The results of the simulations demonstrate that the random factor mimicking variation increased considerably the range of values covered by Shannon entropy, especially when the percentage of changed offspring was high. This increase in information content is interpreted as facilitated adaptability of the population.

Contenidos de isomeros trans de los acidos grasos en productos carnicos. (III) Tejido adiposo y grasa intramuscular de vacuno

Se presentan los resultados obtenidos para la determinación de ácidos grasos en una serie de muestras de tejidos subcutáneo y muscular, procedentes de canales de vacuno, por aplicación de la cromatografía en fase gaseosa, para los que se obtuvieron unos valores medios de 58.7% de ácidos saturados, 39.1 % de monoinsaturados y 2.7% de polinsaturados, en el tejido adiposo, y de 44.7% de saturados, 46.1% de monoinsaturados y 9.4% de polinsaturados, en el tejido muscular. Los contenidos de ácidos grasos trans muestran diferencias significativas entre ambos tejidos (medias del 7% de ácidos trans totales en grasa intramuscular y 10.5% en grasa de depósito). El C18: 1t presenta una distribución paralela a la del total de ácidos trans, mientras que para el C16: 1 trans se observa un comportamiento claramente diferente, ya que no se presentan estas diferencias significativas entre ambos tejidos. En cuanto a los factores estudiados que pueden influir en el contenido de isómeros trans, cabe destacar que la raza fue aquél que ofrecía más diferencias, mientras que entre los diversos orígenes (explotaciones ganaderas) y entre categorías de canal se presentaron menos diferencias en relación a los contenidos de estos isómeros. También es importante destacar que las correlaciones que se han observado entre los contenidos de ácidos trans y los totales de ácidos saturados, mono y polinsaturados presentan un signo contrario, según el tipo de tejido. Así, un aumento del % de ácidos trans va aparejado con un aumento de saturados y una disminución de polinsaturados en el tejido muscular, mientras que va aparejado con una disminución de saturados y un aumento de mono y polinsaturados en el tejido adiposo.

A multiplicity of factors contributes to selective RNA polymerase III occupancy of a subset of RNA polymerase III genes in mouse liver.

The genomic loci occupied by RNA polymerase (RNAP) III have been characterized in human culture cells by genome-wide chromatin immunoprecipitations, followed by deep sequencing (ChIP-seq). These studies have shown that only ∼40% of the annotated 622 human tRNA genes and pseudogenes are occupied by RNAP-III, and that these genes are often in open chromatin regions rich in active RNAP-II transcription units. We have used ChIP-seq to characterize RNAP-III-occupied loci in a differentiated tissue, the mouse liver. Our studies define the mouse liver RNAP-III-occupied loci including a conserved mammalian interspersed repeat (MIR) as a potential regulator of an RNAP-III subunit-encoding gene. They reveal that synteny relationships can be established between a number of human and mouse RNAP-III genes, and that the expression levels of these genes are significantly linked. They establish that variations within the A and B promoter boxes, as well as the strength of the terminator sequence, can strongly affect RNAP-III occupancy of tRNA genes. They reveal correlations with various genomic features that explain the observed variation of 81% of tRNA scores. In mouse liver, loci represented in the NCBI37/mm9 genome assembly that are clearly occupied by RNAP-III comprise 50 Rn5s (5S RNA) genes, 14 known non-tRNA RNAP-III genes, nine Rn4.5s (4.5S RNA) genes, and 29 SINEs. Moreover, out of the 433 annotated tRNA genes, half are occupied by RNAP-III. Transfer RNA gene expression levels reflect both an underlying genomic organization conserved in dividing human culture cells and resting mouse liver cells, and the particular promoter and terminator strengths of individual genes.