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Duloxetine, a potent reuptake inhibitor of serotonin (5-HT) and norepinephrine, is effective for the treatment of major depressive disorder, diabetic neuropathic pain, stress urinary incontinence, generalized anxiety disorder and fibromyalgia. Duloxetine achieves a maximum plasma concentration (C max ) of approximately 47ng/mL (40 mg twice-daily dosing) to 110ng/mL (80 mg twice-daily dosing) approximately 6 hours after dosing. The elimination half-life of duloxetine is approximately 10–12 hours and the volume of distribution is approximately 1640 L. The goal of this paper is to provide a review of the literature on intrinsic and extrinsic factors that may impact the pharmacokinetics of duloxetine with a focus on concomitant medications and their clinical implications. Patient demographic characteristics found to influence the pharmacokinetics of duloxetine include sex, smoking status, age, ethnicity, cytochrome P450 (CYP) 2D6 genotype, hepatic function and renal function. Of these, only impaired hepatic function or severely impaired renal function warrant specific warnings or dose recommendations. Pharmacokinetic results from drug interaction studies show that activated charcoal decreases duloxetine exposure, and that CYP1A2 inhibition increases duloxetine exposure to a clinically significant degree. Specifically, following oral administration in the presence of fluvoxamine, the area under the plasma concentration-time curve and C max of duloxetine significantly increased by 460% (90% CI 359, 584) and 141% (90% CI 93, 200), respectively. In addition, smoking is associated with a 30% decrease in duloxetine concentration. The exposure of duloxetine with CYP2D6 inhibitors or in CYP2D6 poor metabolizers is increased to a lesser extent than that observed with CYP1A2 inhibition and does not require a dose adjustment. In addition, duloxetine increases the exposure of drugs that are metabolized by CYP2D6, but not CYP1A2. Pharmacodynamic study results indicate that duloxetine may enhance the effects of benzodiazepines, but not alcohol or warfarin. An increase in gastric pH produced by histamine H 2 -receptor antagonists or antacids did not impact the absorption of duloxetine. While duloxetine is generally well tolerated, it is important to be knowledgeable about the potential for pharmacokinetic interactions between duloxetine and drugs that inhibit CYP1A2 or drugs that are metabolized by CYP2D6 enzymes.

Duloxetine is a serotonin and norepinephrine reuptake inhibitor that possesses antidepressant and pain-relieving properties. Compared with other antidepressants, it has a high affinity for both norepinephrine and serotonin reuptake transporters, which are relatively balanced. Analgesic onset has been observed within the first week of administration in randomized controlled trials and is likely obtained by enhancing the tone of the descending pain inhibition pathways of the central nervous system. Randomized trials have documented significant analgesic effects for managing chronic pain associated with fibromyalgia and diabetic peripheral neuropathic pain. Studies have also suggested that pain associated with major depressive disorder can be reduced with this medication. Modest effects for headache, osteoarthritic pain, and pain secondary to Parkinson disease have also been documented, but data are obtained from single-blinded or open-label trials that require further corroboration with larger randomized studies. Duloxetine has not yet been directly compared with other antidepressants or anticonvulsants for the treatment of pain syndromes.

From recent developments on how roots affect soil organic carbon (SOC) an apparent paradox has emerged where roots drive SOC stabilization causing SOC accrual, but also SOC destabilization causing SOC loss. We synthesize current results and propose the new Rhizo-Engine framework consisting of two linked components: microbial turnover and the soil physicochemical matrix. The Rhizo-Engine is driven by rhizodeposition, root turnover, and plant uptake of nutrients and water, thereby accelerating SOC turnover through both stabilization and destabilization mechanisms. This Rhizo-Engine framework emphasizes the need for a more holistic approach to study root-driven SOC dynamics. This framework would provide better understanding of plant root effects on soil carbon sequestration and the sensitivity of SOC stocks to climate and land-use changes.

Although clinicians frequently add a second medication to an ineffective antidepressant, randomized trials comparing augmentation medications are lacking. In this study, adult outpatients with nonpsychotic major depressive disorder who had not had a remission during citalopram therapy were assigned to sustained-release bupropion or buspirone and had similar remission rates on the basis of clinician and self-reports. Several important secondary measures favored citalopram plus bupropion over citalopram plus buspirone. Adult outpatients with nonpsychotic major depressive disorder who had not had a remission during citalopram therapy were assigned to bupropion or buspirone and had similar remission rates. Several important secondary measures favored citalopram plus bupropion over citalopram plus buspirone. Numerous studies, 1 – 7 including one by Rush et al. 8 reported elsewhere in this issue of the Journal, have shown that major depressive disorder often requires more than one step of treatment to elicit a remission of symptoms. Frequently, a second medication is added to augment the first. 4 , 6 Augmentations of an initial selective serotonin-reuptake inhibitor (SSRI) with sustained-release bupropion, buspirone, mirtazapine, or dopamine agonists (e.g., pramipexole, dextroamphetamine, and methylphenidate) have been evaluated largely in open case series conducted in symptomatic volunteers with few psychiatric or general medical coexisting illnesses. 9 No randomized, controlled, prospective trials have directly compared two or more . . .

The classic model of nitrogen (N) flux into roots is as a Michaelis–Menten (MM) function of soil-N concentration at root surfaces. Furthermore, soil-N transport processes that determine soil-N concentration at root surfaces are seen as a bottleneck for plant nutrition. Yet, neither the MM relationship nor soil-N transport mechanisms are represented in current terrestrial biosphere models. Processes governing N supply to roots – diffusion, mass flow, N immobilization by soil microbes – are incorporated in a model of root-N uptake. We highlight a seldom considered interaction between these processes: nutrient traverses the rhizosphere more quickly in the presence of mass flow, reducing the probability of its immobilization before reaching the root surface. Root-N uptake is sensitive to the rate of mass flow for widely spaced roots with high N uptake capacity, but not for closely spaced roots or roots with low uptake capacity. The results point to a benefit of root switching from high- to low-affinity N transport systems in the presence of mass flow. Simulations indicate a strong impact of soil water uptake on N delivery to widely spaced roots through transpirationally driven mass flow. Furthermore, a given rate of N uptake per unit soil volume may be achieved by lower root biomass in the presence of mass flow.

Mineral phosphorus (P) fertilizers support high crop yields and contribute to feeding the teeming global population. However, complex edaphic processes cause P to be immobilized in soil, hampering its timely and sufficient availability for uptake by plants. The resultant low use efficiency of current water-soluble P fertilizers creates significant environmental and human health problems. Current practices to increase P use efficiency have been inadequate to curtail these problems. We advocate for the understanding of plant physiological processes, such as physiological P requirement, storage of excess P as phytate, and plant uptake mechanisms, to identify novel ways of designing and delivering P fertilizers to plants for improved uptake. We note the importance and implications of the contrasting role of micronutrients such as zinc and iron in stimulating P availability under low soil P content, while inhibiting P uptake under high P fertilization; this could provide an avenue for managing P for plant use under different P fertilization regimes. We argue that the improvement of the nutritional value of crops, especially cereals, through reduced phytic acid and increased zinc and iron contents should be among the most important drivers toward the development of innovative fertilizer products and fertilization technologies. In this paper, we present various pathways in support of this argument. Retuning P fertilizer products and application strategies will contribute to fighting hunger and micronutrient deficiencies in humans. Moreover, direct soil P losses will be reduced as a result of improved P absorption by plants.

Rationale High levels of impulsivity are a core symptom of psychiatric disorders such as ADHD, mania, personality disorders and drug addiction. The effectiveness of drugs targeting dopamine (DA), noradrenaline (NA) and/or serotonin (5-HT) in the treatment of impulse control disorders emphasizes the role of monoaminergic neurotransmission in impulsivity. However, impulsive behavior is behaviorally and neurally heterogeneous, and several caveats remain in our understanding of the role of monoamines in impulse control. Objectives This study aims to investigate the role of DA, NA and 5-HT in two main behavioral dimensions of impulsivity. Methods The effects of selective DA (GBR12909; 2.5–10 mg/kg), NA (atomoxetine; 0.3–3.0 mg/kg) and 5-HT (citalopram; 0.3–3.0 mg/kg) reuptake inhibitors as well as amphetamine (0.25–1.0 mg/kg) were evaluated on impulsive action in the five-choice serial reaction time task (5-CSRTT) and impulsive choice in the delayed reward task (DRT). In the 5-CSRTT, neuropharmacological challenges were performed under baseline and long intertrial interval (ITI) conditions to enhance impulsive behavior in the task. Results Amphetamine and GBR12909 increased impulsive action and perseverative responding and decreased accuracy and response latency in the 5-CSRTT. Atomoxetine increased errors of omission and response latency under baseline conditions in the 5-CSRTT. Under a long ITI, atomoxetine also reduced premature and perseverative responding and increased accuracy. Citalopram improved impulse control in the 5-CSRTT. Amphetamine and GBR12909, but not citalopram or atomoxetine, reduced impulsive choice in the DRT. Conclusions Elevation of DA neurotransmission increases impulsive action and reduces impulsive choice. Increasing NA or 5-HT neurotransmission reduces impulsive action.

• A growing number of field studies report isotopic offsets between stem water and its potential sources that prevent the unambiguous identification of plant water origin using water isotopes. We explored the causes of this isotopic offset by conducting a controlled experiment on the temperate tree species Fagus sylvatica. • We measured δ²H and δ18O of soil and stem water from potted saplings growing on three soil substrates and subjected to two watering regimes. • Regardless of substrate, soil and stem water δ²H were similar only near permanent wilting point. Under moister conditions, stem water δ²H was 11 ± 3‰ more negative than soil water δ²H, coherent with field studies. Under drier conditions, stem water δ²H became progressively more enriched than soil water δ²H. Although stem water δ18O broadly reflected that of soil water, soil–stem δ²H and δ18O differences were correlated (r = 0.76) and increased with transpiration rates indicated by proxies. • Soil–stem isotopic offsets are more likely to be caused by water isotope heterogeneities within the soil pore and stem tissues, which would be masked under drier conditions as a result of evaporative enrichment, than by fractionation under root water uptake. Our results challenge our current understanding of isotopic signals in the soil–plant continuum.

• Root access to bedrock water storage or groundwater is an important trait allowing plant survival in seasonally dry environments. However, the degree of coordination between water uptake depth, leaf-level water-use efficiency (WUEi) and water potential in drought-prone plant communities is not well understood. • We conducted a 135-d rainfall exclusion experiment in a subtropical karst ecosystem with thin skeletal soils to evaluate the responses of 11 co-occurring woody species of contrasting life forms and leaf habits to a severe drought during the wet growing season. • Marked differences in xylem water isotopic composition during drought revealed distinct ecohydrological niche separation among species. The contrasting behaviour of leaf water potential in coexisting species during drought was largely explained by differences in root access to deeper, temporally stable water sources. Smaller-diameter species with shallower water uptake, more negative water potentials and lower WUEi showed extensive drought-induced canopy defoliation and/or mortality. By contrast, larger-diameter species with deeper water uptake, higher leaf-level WUEi and more isohydric behaviour survived drought with only moderate canopy defoliation. • Severe water limitation imposes strong environmental filtering and/or selective pressures resulting in tight coordination between tree diameter, water uptake depth, iso/anisohydric behaviour, WUEi and drought vulnerability in karst plant communities

59 I. 59 II. 62 III. 69 IV. 73 73 References 73 SUMMARY: There is wide breadth of root function within ecosystems that should be considered when modeling the terrestrial biosphere. Root structure and function are closely associated with control of plant water and nutrient uptake from the soil, plant carbon (C) assimilation, partitioning and release to the soils, and control of biogeochemical cycles through interactions within the rhizosphere. Root function is extremely dynamic and dependent on internal plant signals, root traits and morphology, and the physical, chemical and biotic soil environment. While plant roots have significant structural and functional plasticity to changing environmental conditions, their dynamics are noticeably absent from the land component of process‐based Earth system models used to simulate global biogeochemical cycling. Their dynamic representation in large‐scale models should improve model veracity. Here, we describe current root inclusion in models across scales, ranging from mechanistic processes of single roots to parameterized root processes operating at the landscape scale. With this foundation we discuss how existing and future root functional knowledge, new data compilation efforts, and novel modeling platforms can be leveraged to enhance root functionality in large‐scale terrestrial biosphere models by improving parameterization within models, and introducing new components such as dynamic root distribution and root functional traits linked to resource extraction.