Like all higher organisms, plants have evolved in the context of a microbial world, shaping both their evolution and their contemporary ecology. Interactions between plant roots and soil microorganisms are critical for plant fitness in natural environments. Given this co-evolution and the pivotal importance of plant-microbial interactions, it has been hypothesized, and a growing body of literature suggests, that plants may regulate the composition of their rhizosphere to promote the growth of microorganisms that improve plant fitness in a given ecosystem. Here, using a combination of comparative genomics and exometabolomics, we show that pre-programmed developmental processes in plants (Avena barbata) result in consistent patterns in the chemical composition of root exudates. This chemical succession in the rhizosphere interacts with microbial metabolite substrate preferences that are predictable from genome sequences. Specifically, we observed a preference by rhizosphere bacteria for consumption of aromatic organic acids exuded by plants (nicotinic, shikimic, salicylic, cinnamic and indole-3-acetic). The combination of these plant exudation traits and microbial substrate uptake traits interact to yield the patterns of microbial community assembly observed in the rhizosphere of an annual grass. This discovery provides a mechanistic underpinning for the process of rhizosphere microbial community assembly and provides an attractive direction for the manipulation of the rhizosphere microbiome for beneficial outcomes.
While interactions between roots and microorganisms have been intensively studied, we know little about interactions among root-associated microbes. We used random matrix theory-based network analysis of 16S rRNA genes to identify bacterial networks associated with wild oat (Avena fatua) over two seasons in greenhouse microcosms. Rhizosphere networks were substantially more complex than those in surrounding soils, indicating the rhizosphere has a greater potential for interactions and niche-sharing. Network complexity increased as plants grew, even as diversity decreased, highlighting that community organisation is not captured by univariate diversity. Covariations were predominantly positive (> 80%), suggesting that extensive mutualistic interactions may occur among rhizosphere bacteria; we identified quorum-based signalling as one potential strategy. Putative keystone taxa often had low relative abundances, suggesting low-abundance taxa may significantly contribute to rhizosphere function. Network complexity, a previously undescribed property of the rhizosphere microbiome, appears to be a defining characteristic of this habitat.
This update of pharmacokinetic, pharmacodynamic, and clinical data will provide the necessary guide by which to select between the various PPIs that differ-based on pharmacodynamic assessments-in their relative potencies (e.g., higher doses are needed for pantoprazole and lansoprazole compared with rabeprazole). Despite their well-documented clinical efficacy and safety, there is still a certain number of patients who are refractory to treatment with PPIs (nonresponder), which will leave sufficient space for future drug development and clinical research.
It is well known that rhizosphere microbiomes differ from those of surrounding soil, and yet we know little about how these root-associated microbial communities change through the growing season and between seasons. We analyzed the response of soil bacteria to roots of the common annual grass Avena fatua over two growing seasons using high-throughput sequencing of 16S rRNA genes. Over the two periods of growth, the rhizosphere bacterial communities followed consistent successional patterns as plants grew, although the starting communities were distinct. Succession in the rhizosphere was characterized by a significant decrease in both taxonomic and phylogenetic diversity relative to background soil communities, driven by reductions in both richness and evenness of the bacterial communities. Plant roots selectively stimulated the relative abundance of Alphaproteobacteria, Betaproteobacteria, and Bacteroidetes but reduced the abundance of Acidobacteria, Actinobacteria, and Firmicutes. Taxa that increased in relative abundance in the rhizosphere soil displayed phylogenetic clustering, suggesting some conservation and an evolutionary basis for the response of complex soil bacterial communities to the presence of plant roots. The reproducibility of rhizosphere succession and the apparent phylogenetic conservation of rhizosphere competence traits suggest adaptation of the indigenous bacterial community to this common grass over the many decades of its presence.
Low-molecular-weight organic compounds in root exudates play a key role in plant-microorganism interactions by influencing the structure and function of soil microbial communities. Model exudate solutions, based on organic acids (OAs) (quinic, lactic, maleic acids) and sugars (glucose, sucrose, fructose), previously identified in the rhizosphere of Pinus radiata, were applied to soil microcosms. Root exudate compound solutions stimulated soil dehydrogenase activity and the addition of OAs increased soil pH. The structure of active bacterial communities, based on reverse-transcribed 16S rRNA gene PCR, was assessed by denaturing gradient gel electrophoresis and PhyloChip microarrays. Bacterial taxon richness was greater in all treatments than that in control soil, with a wide range of taxa (88-1043) responding positively to exudate solutions and fewer (<24) responding negatively. OAs caused significantly greater increases than sugars in the detectable richness of the soil bacterial community and larger shifts of dominant taxa. The greater response of bacteria to OAs may be due to the higher amounts of added carbon, solubilization of soil organic matter or shifts in soil pH. Our results indicate that OAs play a significant role in shaping soil bacterial communities and this may therefore have a significant impact on plant growth.
This review summarizes present knowledge of age-related problems in drug action and their clinical implications for an increasingly important population.
Ageing is characterized by a progressive decline in the functional reserve of multiple organs and systems, which can influence drug disposition. In addition, comorbidity and polypharmacy are highly prevalent in the elderly. As ageing is associated with some reduction in first-pass metabolism, bioavailability of a few drugs can be increased. With ageing body fat increases and total body water as well as lean body mass decrease. Consequently, hydrophilic drugs have a smaller apparent volume of distribution (V) and lipophilic drugs have an increased V with a prolonged half-life. Drugs with a high hepatic extraction ratio display some age-related decrease in systemic clearance (CL), but for most drugs with a low hepatic extraction ratio, CL is not reduced with advancing age. In general, activities of cytochrome P450 enzymes are preserved in normal ageing and the genetic influence is much more striking than age effects. Drug transporters play an important role in pharmacokinetic processes, but their function and pharmacology have not yet been fully examined for agerelated effects. One third of elderly persons show no decrease in renal function (GFR > 70 mL/min/1.73 m2). In about two thirds of elderly subjects, the age-related decline of renal function was associated with coexisting cardiovascular diseases and other risk factors. In the elderly a large interindividual variability in drug disposition is particularly prominent. In conclusion, the complexity of interactions between comorbidity, polypharmacy, and age-related changes in pharmacokinetics (and pharmacodynamics) justify the old and well-known dosing aphorism " start low, go slow" for aged individuals.
Selective COX-2 inhibitors (coxibs) are approved for the relief of acute pain and symptoms of chronic inflammatory conditions such as osteoarthritis (OA) and rheumatoid arthritis (RA). They have similar pharmacological properties but a slightly improved gastrointestinal (GI) safety profile if compared to traditional nonsteroidal anti-inflammatory drugs (tNSAIDs). However, long-term use of coxibs can be associated with an increased risk for cardiovascular (CV) adverse events (AEs). For this reason, two coxibs were withdrawn from the market. Currently celecoxib, etoricoxib, and lumiracoxib are used. These three coxibs differ in their chemical structure and selectivity for COX-2, which might explain some of their pharmacological features. Following oral administration, the less lipophilic celecoxib has a lower bioavailability (20-40%) than the other two coxibs (74-100%). All are eliminated by hepatic metabolism involving mainly CYP2C9 (celecoxib, lumiracoxib) and CYP3A4 (etoricoxib). Elimination half-life varies from 5 to 8 h (lumiracoxib), 11 to 16 h (celecoxib) and 19 to 32 h (etoricoxib). In patients with liver disease, plasma levels of celecoxib and etoricoxib are increased about two-fold. Clinical efficacies of the coxibs are comparable to tNSAIDs. There is an ongoing discussion about whether the slightly better GI tolerability (which is lost if acetylsalicylic acid is coadministered) of the coxibs is offset by their elevated risks for CV AEs (also seen with tNSAIDs other than naproxen), which apparently increase with dose and duration of exposure. In addition, the higher costs for coxibs (if compared to tNSAIDs, even when a "gastroprotective" proton pump inhibitor is coadministered) should be taken into consideration, if a coxib will be selected for certain patients with a high risk for GI complications. For such treatment, the lowest effective dose should be used for a limited time. Monitoring of kidney function and blood pressure appears advisable. It is hoped that further controlled studies can better define the therapeutic place of the coxibs.
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