Changes in resource partitioning between and within organs support growth adjustment to neighbor proximity in Brassicaceae seedlings.

In shade-intolerant plants, the perception of proximate neighbors rapidly induces architectural changes resulting in elongated stems and reduced leaf size. Sensing and signaling steps triggering this modified growth program have been identified. However, the underlying changes in resource allocation that fuel stem growth remain poorly understood. Through 14CO2 pulse labeling of Brassica rapa seedlings, we show that perception of the neighbor detection signal, low ratio of red to far-red light (R:FR), leads to increased carbon allocation from the major site of photosynthesis (cotyledons) to the elongating hypocotyl. While carbon fixation and metabolite levels remain similar in low R:FR, partitioning to all downstream carbon pools within the hypocotyl is increased. Genetic analyses using Arabidopsis thaliana mutants indicate that low-R:FR-induced hypocotyl elongation requires sucrose transport from the cotyledons and is regulated by a PIF7-dependent metabolic response. Moreover, our data suggest that starch metabolism in the hypocotyl has a growth-regulatory function. The results reveal a key mechanism by which metabolic adjustments can support rapid growth adaptation to a changing environment.

Integration of Phytochrome and Cryptochrome Signals Determines Plant Growth during Competition for Light.

Plants in dense vegetation perceive their neighbors primarily through changes in light quality. Initially, the ratio between red (R) and far-red (FR) light decreases due to reflection of FR by plant tissue well before shading occurs. Perception of low R:FR by the phytochrome photoreceptors induces the shade avoidance response [1], of which accelerated elongation growth of leaf-bearing organs is an important feature. Low R:FR-induced phytochrome inactivation leads to the accumulation and activation of the transcription factors PHYTOCHROME-INTERACTING FACTORs (PIFs) 4, 5, and 7 and subsequent expression of their growth-mediating targets [2, 3]. When true shading occurs, transmitted light is especially depleted in red and blue (B) wavelengths, due to absorption by chlorophyll [4]. Although the reduction of blue wavelengths alone does not occur in nature, long-term exposure to low B light induces a shade avoidance-like response that is dependent on the cryptochrome photoreceptors and the transcription factors PIF4 and PIF5 [5-7]. We show in Arabidopsis thaliana that low B in combination with low R:FR enhances petiole elongation similar to vegetation shade, providing functional context for a low B response in plant competition. Low B potentiates the low R:FR response through PIF4, PIF5, and PIF7, and it involves increased PIF5 abundance and transcriptional changes. Low B attenuates a low R:FR-induced negative feedback loop through reduced gene expression of negative regulators and reduced HFR1 levels. The enhanced response to combined phytochrome and cryptochrome inactivation shows how multiple light cues can be integrated to fine-tune the plant's response to a changing environment.

Light-Mediated Hormonal Regulation of Plant Growth and Development.

Light is crucial for plant life, and perception of the light environment dictates plant growth, morphology, and developmental changes. Such adjustments in growth and development in response to light conditions are often established through changes in hormone levels and signaling. This review discusses examples of light-regulated processes throughout a plant's life cycle for which it is known how light signals lead to hormonal regulation. Light acts as an important developmental switch in germination, photomorphogenesis, and transition to flowering, and light cues are essential to ensure light capture through architectural changes during phototropism and the shade avoidance response. In describing well-established links between light perception and hormonal changes, we aim to give insight into the mechanisms that enable plants to thrive in variable light environments.

Contrasting growth responses in lamina and petiole during neighbor detection depend on differential auxin responsiveness rather than different auxin levels.

Foliar shade triggers rapid growth of specific structures that facilitate access of the plant to direct sunlight. In leaves of many plant species, this growth response is complex because, although shade triggers the elongation of petioles, it reduces the growth of the lamina. How the same external cue leads to these contrasting growth responses in different parts of the leaf is not understood. Using mutant analysis, pharmacological treatment and gene expression analyses, we investigated the role of PHYTOCHROME INTERACTING FACTOR7 (PIF7) and the growth-promoting hormone auxin in these contrasting leaf growth responses. Both petiole elongation and lamina growth reduction are dependent on PIF7. The induction of auxin production is both necessary and sufficient to induce opposite growth responses in petioles vs lamina. However, these contrasting growth responses are not caused by different auxin concentrations in the two leaf parts. Our work suggests that a transient increase in auxin levels triggers tissue-specific growth responses in different leaf parts. We provide evidence suggesting that this may be caused by the different sensitivity to auxin in the petiole vs the blade and by tissue-specific gene expression.

Light intensity modulates the regulatory network of the shade avoidance response in Arabidopsis.

Plants such as Arabidopsis thaliana respond to foliar shade and neighbors who may become competitors for light resources by elongation growth to secure access to unfiltered sunlight. Challenges faced during this shade avoidance response (SAR) are different under a light-absorbing canopy and during neighbor detection where light remains abundant. In both situations, elongation growth depends on auxin and transcription factors of the phytochrome interacting factor (PIF) class. Using a computational modeling approach to study the SAR regulatory network, we identify and experimentally validate a previously unidentified role for long hypocotyl in far red 1, a negative regulator of the PIFs. Moreover, we find that during neighbor detection, growth is promoted primarily by the production of auxin. In contrast, in true shade, the system operates with less auxin but with an increased sensitivity to the hormonal signal. Our data suggest that this latter signal is less robust, which may reflect a cost-to-robustness tradeoff, a system trait long recognized by engineers and forming the basis of information theory.

Prevention and management of adverse events related to regorafenib.

Regorafenib is an oral multikinase inhibitor that has shown antitumor activity in a range of solid tumors. Based on data from phase III clinical trials, regorafenib is indicated for the treatment of adult patients with metastatic colorectal cancer who have previously been treated with, or are not considered candidates for, other available therapies, and in patients with advanced gastrointestinal stromal tumors that cannot be surgically removed and no longer respond to other appropriate treatments. A panel of oncology nurses, research coordinators, and other medical oncology experts, experienced in the care of patients treated with regorafenib, met to discuss the best practice for the management of regorafenib-associated adverse events (AEs). The panel agreed that, in clinical trials and daily practice with regorafenib, AEs are common but mostly manageable. The most common and/or important AEs associated with regorafenib were considered to be hand-foot skin reaction, rash or desquamation, stomatitis, diarrhea, hypertension, liver abnormalities, and fatigue. This manuscript describes the experience and recommendations of the panel for managing these AEs in everyday clinical practice. Appropriate education, monitoring, and management are considered essential for reducing the incidence, duration, and severity of regorafenib-associated AEs.

Auxin-mediated plant architectural changes in response to shade and high temperature.

The remarkable plasticity of their architecture allows plants to adjust growth to the environment and to overcome adverse conditions. Two examples of environmental stresses that drastically affect shoot development are imminent shade and high temperature. Plants in crowded environments and plants in elevated ambient temperature display very similar phenotypic adaptations of elongated hypocotyls in seedlings and elevated and elongated leaves at later developmental stages. The comparable growth responses to shade and high temperature are partly regulated through shared signaling pathways, of which the phytohormone auxin and the phytochrome interacting factors (PIFs) are important components. During both shade- and temperature-induced elongation growth auxin biosynthesis and signaling are upregulated in a PIF-dependent manner. In this review we will discuss recent progress in our understanding of how auxin mediates architectural adaptations to shade and high temperature.

Shade avoidance: phytochrome signalling and other aboveground neighbour detection cues.

Plants compete with neighbouring vegetation for limited resources. In competition for light, plants adjust their architecture to bring the leaves higher in the vegetation where more light is available than in the lower strata. These architectural responses include accelerated elongation of the hypocotyl, internodes and petioles, upward leaf movement (hyponasty), and reduced shoot branching and are collectively referred to as the shade avoidance syndrome. This review discusses various cues that plants use to detect the presence and proximity of neighbouring competitors and respond to with the shade avoidance syndrome. These cues include light quality and quantity signals, mechanical stimulation, and plant-emitted volatile chemicals. We will outline current knowledge about each of these signals individually and discuss their possible interactions. In conclusion, we will make a case for a whole-plant, ecophysiology approach to identify the relative importance of the various neighbour detection cues and their possible interactions in determining plant performance during competition.

Perception of low red:far-red ratio compromises both salicylic acid- and jasmonic acid-dependent pathogen defences in Arabidopsis.

In dense stands of plants, such as agricultural monocultures, plants are exposed simultaneously to competition for light and other stresses such as pathogen infection. Here, we show that both salicylic acid (SA)-dependent and jasmonic acid (JA)-dependent disease resistance is inhibited by a simultaneously reduced red:far-red light ratio (R:FR), the early warning signal for plant competition. Conversely, SA- and JA-dependent induced defences did not affect shade-avoidance responses to low R:FR. Reduced pathogen resistance by low R:FR was accompanied by a strong reduction in the regulation of JA- and SA-responsive genes. The severe inhibition of SA-responsive transcription in low R:FR appeared to be brought about by the repression of SA-inducible kinases. Phosphorylation of the SA-responsive transcription co-activator NPR1, which is required for full induction of SA-responsive transcription, was indeed reduced and may thus play a role in the suppression of SA-mediated defences by low R:FR-mediated phytochrome inactivation. Our results indicate that foraging for light through the shade-avoidance response is prioritised over plant immune responses when plants are simultaneously challenged with competition and pathogen attack.

Plant neighbor detection through touching leaf tips precedes phytochrome signals.

Plants in dense vegetation compete for resources, including light, and optimize their growth based on neighbor detection cues. The best studied of such behaviors is the shade-avoidance syndrome that positions leaves in optimally lit zones of a vegetation. Although proximate vegetation is known to be sensed through a reduced ratio between red and far-red light, we show here through computational modeling and manipulative experiments that leaves of the rosette species Arabidopsis thaliana first need to move upward to generate sufficient light reflection potential for subsequent occurrence and perception of a reduced red to far-red ratio. This early hyponastic leaf growth response is not induced by known neighbor detection cues under both climate chamber and natural sunlight conditions, and we identify a unique way for plants to detect future competitors through touching of leaf tips. This signal occurs before light signals and appears to be the earliest means of above-ground plant-plant signaling in horizontally growing rosette plants.

Low red/far-red ratios reduce Arabidopsis resistance to Botrytis cinerea and jasmonate responses via a COI1-JAZ10-dependent, salicylic acid-independent mechanism.

Light is an important modulator of plant immune responses. Here, we show that inactivation of the photoreceptor phytochrome B (phyB) by a low red/far-red ratio (R:FR), which is a signal of competition in plant canopies, down-regulates the expression of defense markers induced by the necrotrophic fungus Botrytis cinerea, including the genes that encode the transcription factor ETHYLENE RESPONSE FACTOR1 (ERF1) and the plant defensin PLANT DEFENSIN1.2 (PDF1.2). This effect of low R:FR correlated with a reduced sensitivity to jasmonate (JA), thus resembling the antagonistic effects of salicylic acid (SA) on JA responses. Low R:FR failed to depress PDF1.2 mRNA levels in a transgenic line in which PDF1.2 transcription was up-regulated by constitutive expression of ERF1 in a coronatine insensitive1 (coi1) mutant background (35S::ERF1/coi1). These results suggest that the low R:FR effect, in contrast to the SA effect, requires a functional SCFCOI1-JASMONATE ZIM-DOMAIN (JAZ) JA receptor module. Furthermore, the effect of low R:FR depressing the JA response was conserved in mutants impaired in SA signaling (sid2-1 and npr1-1). Plant exposure to low R:FR ratios and the phyB mutation markedly increased plant susceptibility to B. cinerea; the effect of low R:FR was (1) independent of the activation of the shade-avoidance syndrome, (2) conserved in the sid2-1 and npr1-1 mutants, and (3) absent in two RNA interference lines disrupted for the expression of the JAZ10 gene. Collectively, our results suggest that low R:FR ratios depress Arabidopsis (Arabidopsis thaliana) immune responses against necrotrophic microorganisms via a SA-independent mechanism that requires the JAZ10 transcriptional repressor and that this effect may increase plant susceptibility to fungal infection in dense canopies.

Quantitation of pretreatment serum interferon-γ-inducible protein-10 improves the predictive value of an IL28B gene polymorphism for hepatitis C treatment response.

UNLABELLED: Polymorphisms of the IL28B gene are highly associated with sustained virological response (SVR) in patients with chronic hepatitis C treated with peginterferon and ribavirin. Quantitation of interferon-γ-inducible protein-10 (IP-10) may also differentiate antiviral response. We evaluated IP-10 levels in pretreatment serum from 115 nonresponders and 157 sustained responders in the Study of Viral Resistance to Antiviral Therapy of Chronic Hepatitis C cohort, including African American (AA) and Caucasian American (CA) patients. Mean IP-10 was lower in sustained responders compared with nonresponders (437 ± 31 vs 704 ± 44 pg/mL, P < 0.001), both in AA and CA patients. The positive predictive value of low IP-10 levels (<600 pg/mL) for SVR was 69%, whereas the negative predictive value of high IP-10 levels (>600 pg/mL) was 67%. We assessed the combination of pretreatment IP-10 levels with IL28B genotype as predictors of treatment response. The IL28B polymorphism rs12979860 was tested in 210 participants. The CC, CT, and TT genotypes were found in 30%, 49%, and 21% of patients, respectively, with corresponding SVR rates of 87%, 50%, and 39% (P < 0.0001). Serum IP-10 levels within the IL28B genotype groups provided additional information regarding the likelihood of SVR (P < 0.0001). CT carriers with low IP-10 had 64% SVR versus 24% with high IP-10. Similarly, a higher SVR rate was identified for TT and CC carriers with low versus high IP-10 (TT, 48% versus 20%; CC, 89% versus 79%). IL28B genotype and baseline IP-10 levels were additive but independent when predicting SVR in both AA and CA patients. CONCLUSION: When IL28B genotype is combined with pretreatment serum IP-10 measurement, the predictive value for discrimination between SVR and nonresponse is significantly improved, especially in non-CC genotypes. This relationship warrants further investigation to elucidate the mechanisms of antiviral response and prospective validation.

Growth-mediated stress escape: convergence of signal transduction pathways activated upon exposure to two different environmental stresses.

• Plants can escape from specific environmental stresses through active growth strategies. Here, we compared two such stress-escape syndromes to investigate whether plants use conserved signal transduction pathways to escape from different stresses. • Full submergence is a threat to terrestrial plants as it cuts off their access to oxygen and CO(2). Proximate neighbors, in contrast, take away resources such as light. Both submergence and shade can be escaped through rapid shoot elongation. We analysed the precise kinetics and physiological control of petiole elongation responses to shade and submergence in the flood-tolerant species Rumex palustris. • We found that petiole elongation induced by submergence and that induced by shade occurred with similar kinetics, both involving cell expansion. These responses were induced by two different signals, elevated ethylene and a reduced red : far-red light ratio (R : FR), respectively. A downstream target for ethylene was abscisic acid, but low R : FR appeared to act independently of this hormone. Gibberellin, however, appeared to be essential to both ethylene- and low R : FR-induced petiole elongation. • We propose that gibberellin and expansins, a family of cell wall-loosening proteins, represent elements of a conserved growth machinery that is activated by stress-specific signaling events to regulate escape from stress.

Auxin and ethylene regulate elongation responses to neighbor proximity signals independent of gibberellin and della proteins in Arabidopsis.

Plants modify growth in response to the proximity of neighbors. Among these growth adjustments are shade avoidance responses, such as enhanced elongation of stems and petioles, that help plants to reach the light and outgrow their competitors. Neighbor detection occurs through photoreceptor-mediated detection of light spectral changes (i.e. reduced red:far-red ratio [R:FR] and reduced blue light intensity). We recently showed that physiological regulation of these responses occurs through light-mediated degradation of nuclear, growth-inhibiting DELLA proteins, but this appeared to be only part of the full mechanism. Here, we present how two hormones, auxin and ethylene, coregulate DELLAs but regulate shade avoidance responses through DELLA-independent mechanisms in Arabidopsis (Arabidopsis thaliana). Auxin appears to be required for both seedling and mature plant shoot elongation responses to low blue light and low R:FR, respectively. Auxin action is increased upon exposure to low R:FR and low blue light, and auxin inhibition abolishes the elongation responses to these light cues. Ethylene action is increased during the mature plant response to low R:FR, and this growth response is abolished by ethylene insensitivity. However, ethylene is also a direct volatile neighbor detection signal that induces strong elongation in seedlings, possibly in an auxin-dependent manner. We propose that this novel ethylene and auxin control of shade avoidance interacts with DELLA abundance but also controls independent targets to regulate adaptive growth responses to surrounding vegetation.

Binding kinetics of darunavir to human immunodeficiency virus type 1 protease explain the potent antiviral activity and high genetic barrier.

The high incidence of cross-resistance between human immunodeficiency virus type 1 (HIV-1) protease inhibitors (PIs) limits their sequential use. This necessitates the development of PIs with a high genetic barrier and a broad spectrum of activity against PI-resistant HIV, such as tipranavir and darunavir (TMC114). We performed a surface plasmon resonance-based kinetic study to investigate the impact of PI resistance-associated mutations on the protease binding of five PIs used clinically: amprenavir, atazanavir, darunavir, lopinavir, and tipranavir. With wild-type protease, the binding affinity of darunavir was more than 100-fold higher than with the other PIs, due to a very slow dissociation rate. Consequently, the dissociative half-life of darunavir was much higher (>240 h) than that of the other PIs, including darunavir's structural analogue amprenavir. The influence of protease mutations on the binding kinetics was tested with five multidrug-resistant (MDR) proteases derived from clinical isolates harboring 10 to 14 PI resistance-associated mutations with a decreased susceptibility to various PIs. In general, all PIs bound to the MDR proteases with lower binding affinities, caused mainly by a faster dissociation rate. For amprenavir, atazanavir, lopinavir, and tipranavir, the decrease in affinity with MDR proteases resulted in reduced antiviral activity. For darunavir, however, a nearly 1,000-fold decrease in binding affinity did not translate into a weaker antiviral activity; a further decrease in affinity was required for the reduced antiviral effect. These observations provide a mechanistic explanation for darunavir's potent antiviral activity and high genetic barrier to the development of resistance.

DELLA protein function in growth responses to canopy signals.

Plants can sense neighbour competitors through light-quality signals and respond with shade-avoidance responses. These include increased shoot elongation, which enhances light capture and thus competitive power. Such plant-plant interactions therefore profoundly affect plant development in crowded populations. Shade-avoidance responses are tightly coordinated by interactions between light signals and hormones, with essential roles for the phytochrome B photoreceptor [sensing the red:far red (R:FR) ratio] and the hormone gibberellin (GA). The family of growth-suppressing DELLA proteins are targets for GA signalling and are proposed to integrate signals from other hormones. However, the importance of these regulators has not been studied in the ecologically relevant, complex realm of plant canopies. Here we show that DELLA abundance is regulated during growth responses to neighbours in dense Arabidopsis stands. This occurs in a R:FR-dependent manner in petioles, depends on GA, and matches the induction kinetics of petiole elongation. Similar interactions were observed in the growth response of seedling hypocotyls and are general for a second canopy signal, reduced blue light. Enhanced DELLA stability in the gai mutant inhibits shade-avoidance responses, indicating that DELLA proteins constrain shade-avoidance. However, using multiple DELLA knockout mutants, we show that the observed DELLA breakdown is not sufficient to induce shade-avoidance in petioles, but plays a more central role in hypocotyls. These data provide novel information on the regulation of shade-avoidance under ecologically important conditions, defining the importance of DELLA proteins and GA and unravelling the existence of GA- and DELLA-independent mechanisms.

Struggling for light: della regulation during plant-plant interactions.

We recently described how DELLA proteins are involved in plant growth responses to neighbors in dense stands. These responses that are called shade avoidance include enhanced stem and petiole elongation and are a classic example of adaptive phenotypic plasticity. Although much is known about neighbor detection, much less is known about the signal transduction network downstream of these signals. We will discuss here how a group of growth-supressors, called DELLA proteins, are functionally regulated upon the detection of neighbors. DELLA proteins are degraded upon binding of gibberellin (GA) to its receptor, thus releasing the restraint of GA responses. We discuss here that GA positively regulates shade avoidance by reducing DELLA protein levels. Furthermore, we will show that this is an essential step in shade avoidance, but also that reduced DELLA abundance alone is not sufficient to induce these growth responses. It is concluded that GA-dependent DELLA degradation is one essential step in the signal transduction network from light-mediated neighbor detection towards adaptive shoot elongation responses.