In response to recommendations to redefine statistical significance to p ≤ .005, we propose that researchers should transparently report and justify all choices they make when designing a study, including the alpha level.

Idiopathic pulmonary fibrosis (IPF) is a progressive and terminal lung disease with no known cure. IPF is a disease of aging, with median age of diagnosis over 65 years. Median survival is between 3 and 5 years after diagnosis. IPF is characterized primarily by excessive deposition of extracellular matrix (ECM) proteins by activated lung fibroblasts and myofibroblasts, resulting in reduced gas exchange and impaired pulmonary function. Growing evidence supports the concept of a pro-fibrotic environment orchestrated by underlying factors such as genetic predisposition, chronic injury and aging, oxidative stress, and impaired regenerative responses may account for disease development and persistence. Currently, two FDA approved drugs have limited efficacy in the treatment of IPF. Many of the genes and gene networks associated with lung development are induced or activated in IPF. In this review, we analyze current knowledge in the field, gained from both basic and clinical research, to provide new insights into the disease process, and potential approaches to treatment of pulmonary fibrosis.

This study was undertaken to compare the ability of two guanidine compounds (aminoguanidine and methylguanidine), with different in vitro effects on NO synthase activity and AGE formation, to inhibit diabetic vascular dysfunction developing early after the onset of diabetes. In rats with STZ-induced diabetes of 5-wk duration, regional vascular [125I]albumin permeation was increased about two- to threefold in ocular tissues, sciatic nerve, and aorta; in general, both guanidine compounds normalized albumin permeation in diabetic rats without affecting it in controls. Methylguanidine was only approximately 7% as effective as aminoguanidine as an inhibitor of AGE formation from L-lysine and G6P; both compounds were poor inhibitors of AR. Methylguanidine was approximately 1-5% as potent as aminoguanidine and L-NMMA as an inhibitor of the cytokine- and endotoxin-inducible isoform of NO synthase. In contrast, the potency of methylguanidine as an inhibitor of the constitutive isoform of NO synthase was comparable to that of aminoguanidine, and both guanidine compounds were much less effective than L-NMMA. These observations suggest a role for a relative or absolute increase in NO production in the pathogenesis of early diabetic vascular dysfunction and raise the possibility that inhibition of diabetic vascular functional changes by aminoguanidine may reflect inhibition of NO synthase activity rather than, or in addition to, prevention of AGE formation.

No abstract

g Anaerobic digesters rely on the diversity and distribution of parallel metabolic pathways mediated by complex syntrophic microbial communities to maintain robust and optimal performance. Using mesophilic swine waste digesters, we experimented with increased ammonia loading to induce a shift from aceticlastic methanogenesis to an alternative acetate-consuming pathway of syntrophic acetate oxidation. In comparison with control digesters, we observed shifts in bacterial 16S rRNA gene content and in functional gene repertoires over the course of the digesters' 3-year operating period. During the first year, under identical startup conditions, all bioreactors mirrored each other closely in terms of bacterial phylotype content, phylogenetic structure, and evenness. When we perturbed the digesters by increasing the ammonia concentration or temperature, the distribution of bacterial phylotypes became more uneven, followed by a return to more even communities once syntrophic acetate oxidation had allowed the experimental bioreactors to regain stable operation. The emergence of syntrophic acetate oxidation coincided with a partial shift from aceticlastic to hydrogenotrophic methanogens. Our 16S rRNA gene analysis also revealed that acetatefed enrichment experiments resulted in communities that did not represent the bioreactor community. Analysis of shotgun sequencing of community DNA suggests that syntrophic acetate oxidation was carried out by a heterogeneous community rather than by a specific keystone population with representatives of enriched cultures with this metabolic capacity.

. 2000. Development and evaluation of grazing-tolerant alfalfa cultivars: A review. Can. J. Plant Sci. 80: 503-512. Plant breeders have long sought to improve grazing tolerance of alfalfa without sacrificing the beneficial yield and quality attributes of this species. Most efforts have focussed on selecting for traits (e.g., creeping rootedness) related to grazing tolerance and/or simulated grazing, but these efforts failed to account for the multiple stresses caused by grazing animals. Trait selection often led to sacrifices in yield and other desirable characteristics resulting in cultivars that were not robust across grazing management systems and environments. An innovative selection procedure was recently developed at the University of Georgia which incorporated intensive grazing with continuous stocking by beef cattle. The development of "Alfagraze" using this procedure showed that grazing tolerance and high yields can be incorporated into the same cultivar, along with consistent performance across grazing management systems and environments. Subsequent research has shown that grazing tolerance can be improved within elite, high-yielding, multiple-pest-resistant cultivars and breeding populations. Selection using intensive grazing with continuous stocking has been summarised in a "Standard Test Protocol" that is now being successfully used by public and private alfalfa breeders and in cultivar evaluation programs in the USA, Canada, and other countries. Les sélectionneurs cherchent depuis longtemps à améliorer la tolérance de la luzerne au pâturage, sans compromettre le rendement quantitatif et qualitatif de l'espèce. On s'est essentiellement attaché jusqu'ici à la recherche de caractères particuliers, p. ex. l'enracinement traçant, liés à la tolérance au pâturage ou à la paissance simulée, mais cela n'a pas été suffisant pour contrer les multiples stress causés par les animaux à l'herbe. La sélection axée sur un caractère particulier s'est souvent faite aux dépens des autres caractères désirables, notamment le rendement, ce qui a produit des cultivars ne pouvant persister que dans certains systèmes pastoraux et dans certains milieux de culture. Une technique de sélection originale a été mise au point dernièrement à l'Université de Géorgie (E.U), qui incorpore le pâturage intensif sous à chargement animal continu par des bovins à viande. L'obtention du cultivar Alfagraze par cette méthode démontre que tolérance au pâturage et rendement élevé peuvent être réunis dans un même cultivar, lui assurant ainsi des performances stables, indépendamment du système pastoral utilisé ou des conditions du milieu. Des recherches subséquentes ont montré qu'il est possible d'améliorer la tolérance à la pâture dans des cultivars ou des populations de sélection à haut rendement et à large spectre de résistance aux maladies. La nouvelle méthode, normalisée dans un protocole expérimental standard, est aujourd'hui utilisé avec succès par les sélectionneurs de luzerne, tant privés que ceux du secteur public, ainsi que dans les pr...

These studies were undertaken to examine effects of elevated glucose levels on glycolysis, sorbitol pathway activity, and the cytosolic redox state of NADH/NAD+ in isolated glomeruli. Blood-free glomeruli were isolated from kidneys of male, Sprague-Dawley rats using standard sieving techniques, then incubated for one hour at 37 degrees C, pH 7.4, pO2 approximately 500 torr, in Krebs bicarbonate/Hepes buffer containing 5 or 30 mM glucose. Elevated glucose levels increased glucose 6-phosphate, fructose 6-phosphate, total triose phosphates, lactate, the lactate/pyruvate ratio, sorbitol, and fructose, but did not affect sn-glycerol 3-phosphate, pyruvate, or myo-inositol levels. The more reduced glomerular cytosolic redox state (manifested by the tissue lactate/pyruvate ratio) induced by 30 mM glucose was completely abrogated by aldose reductase inhibitors added to the diet two to seven days prior to glomerular isolation. These observations, coupled with evidence linking glucose- and diabetes-induced glomerular dysfunction to increased sorbitol pathway metabolism, support the hypothesis that metabolic imbalances associated with a more reduced ratio of cytosolic NADH/NAD+ (resulting from increased glucose metabolism via the sorbitol pathway) play an important role in mediating glucose- and diabetes-induced glomerular dysfunction.

Alfalfa (Medicago saliva L.) generally does not persist well under continuous grazing. Experiments were conducted under continuous grazing to compare the persistence and regrowth potential of an alfalfa germplasm (Georgia—Grazed Collection, GA‐GC), selected for continuous grazing, with two hay‐type (Apollo and Florida 77) and two grazing‐type (Travois and Spredor II) cultivars. The germplasm and cultivars were subjected to continuous, heavy grazing by beef cattle for 18 weeks in each of 3 yr to a height of 3 to 5 cm. Wire exclosures rotated at 28‐d intervals on all plots were used to estimate the regrowth potential of each entry during the grazing period. Plant and stem counts were taken before and after grazing each year as estimates of stand persistence. Cultivars differed significantly for stand persistence after 3 yr of continuous grazing with 6 to 9 plants m−2 remaining for the hay‐type cultivars and 40 to 48 plants m−2 remaining for grazing‐type cultivars. The GA‐GC maintained plant densities of 64 plants m−2 while producing the highest forage regrowth compared with all cultivars. Total nonstructural carbohydrates (TNC) in roots at the end of 1986 and 1987 grazing seasons ranged from 256 g kg−1 for Florida 77 to 429 g kg−1 for Travois, suggesting that grazing tolerance may be related to the TNC concentration in roots of alfalfa that had been heavily and continuously grazed. This study indicates that selection for plant persistence under continuous grazing from a broad‐based population improved the grazing tolerance of the resulting germplasm (GA‐GC) while maintaining the potential for good forage yields.