Phenotypic plasticity, the ability for a single genotype to generate different phenotypes in response to environmental conditions, is biologically ubiquitous, and yet almost nothing is known of the developmental mechanisms that regulate the extent of a plastic response. In particular, it is unclear why some traits or individuals are highly sensitive to an environmental variable while other traits or individuals are less so. Here we elucidate the developmental mechanisms that regulate the expression of a particularly important form of phenotypic plasticity: the effect of developmental nutrition on organ size. In all animals, developmental nutrition is signaled to growing organs via the insulin-signaling pathway. Drosophila organs differ in their size response to developmental nutrition and this reflects differences in organ-specific insulin-sensitivity. We show that this variation in insulin-sensitivity is regulated at the level of the forkhead transcription factor FOXO, a negative growth regulator that is activated when nutrition and insulin signaling are low. Individual organs appear to attenuate growth suppression in response to low nutrition through an organ-specific reduction in FOXO expression, thereby reducing their nutritional plasticity. We show that FOXO expression is necessary to maintain organ-specific differences in nutritional-plasticity and insulin-sensitivity, while organ-autonomous changes in FOXO expression are sufficient to autonomously alter an organ's nutritional-plasticity and insulin-sensitivity. These data identify a gene (FOXO) that modulates a plastic response through variation in its expression. FOXO is recognized as a key player in the response of size, immunity, and longevity to changes in developmental nutrition, stress, and oxygen levels. FOXO may therefore act as a more general regulator of plasticity. These data indicate that the extent of phenotypic plasticity may be modified by changes in the expression of genes involved in signaling environmental information to developmental processes.

The role of juvenile hormone (JH) in regulating the timing and nature of insect molts is well-established. Increasing evidence suggests that JH is also involved in regulating final insect size. Here we elucidate the developmental mechanism through which JH regulates body size in developing Drosophila larvae by genetically ablating the JH-producing organ, the corpora allata (CA). We found that larvae that lack CA pupariated at smaller sizes than control larvae due to a reduced larval growth rate. Neither the timing of the metamorphic molt nor the duration of larval growth was affected by the loss of JH. Further, we show that the effects of JH on growth rate are dependent on the forkhead box O transcription factor (FOXO), which is negatively regulated by the insulinsignaling pathway. Larvae that lacked the CA had elevated levels of FOXO activity, whereas a loss-of-function mutation of FOXO rescued the effects of CA ablation on final body size. Finally, the effect of JH on growth appears to be mediated, at least in part, via ecdysone synthesis in the prothoracic gland. These results indicate a role of JH in regulating growth rate via the ecdysone-and insulin-signaling pathways.T o correctly regulate their body size, animals control both the rate and duration of their growth. Canonically, growth rate and growth duration have been thought of as separate processes regulated by independent signaling pathways. In insects, the hormones ecdysone and juvenile hormone (JH) control the timing of the metamorphic transition and hence growth duration (1). The conserved insulin/insulin-like growth factor signaling (IIS) and target of rapamycin (TOR) pathways regulate growth rate (1). Recent evidence in Drosophila melanogaster indicates, however, that IIS and TOR signaling regulate ecdysone synthesis (2-5), whereas ecdysone antagonizes IIS (2, 6). This interaction between the mechanisms that regulate growth duration and those that control growth rate appears to coordinate the two processes, and may be a general feature of size regulation. To test this hypothesis, we explored whether JH also regulates growth rate in Drosophila.In the tobacco hornworm Manduca sexta, JH regulates growth duration by regulating the hormonal response to critical weight, a size checkpoint used to determine when to end growth and begin metamorphosis (7). A decline in circulating JH initiates the first step in the hormonal cascade that begins with attainment of critical weight, and ends, after a terminal growth period (TGP), in the rise in circulating ecdysone that stops body growth (8-10). Starvation maintains high rates of JH synthesis in the JH-producing tissue, the corpora allata (CA) (9), and delays the critical weight transition (8). Removal of the CA (CAX) causes larvae to reach critical weight earlier than normal and at a smaller size (8, 11). Application of JH suppresses the critical weight transition and delays metamorphosis, resulting in larger size (8).Intriguingly, recent studies show that, like CAX Manduca, CAX Drosophila larvae are smaller ...

Cyclooxygenase (COX) isoforms catalyze the committed step in prostaglandin biosynthesis. The primary structures of COX-1 and COX-2 are very similar except that COX-2 has a 19-amino acid (19-AA) segment of unknown function located just inside its C terminus. Here we provide evidence that the major role of the 19-AA cassette is to mediate entry of COX-2 into the ERassociated degradation system that transports ER proteins to the cytoplasm. COX-1 is constitutively expressed in many cells, whereas COX-2 is usually expressed inducibly and transiently. In murine NIH/3T3 fibroblasts, we find that COX-2 protein is degraded with a half-life (t1 ⁄ 2 ) of about 2 h, whereas COX-1 is reasonably stable (t1 ⁄ 2 >12 h); COX-2 degradation is retarded by 26 S proteasome inhibitors. Similarly, COX-1 expressed heterologously in HEK293 cells is quite stable (t1 ⁄ 2 > 24 h), whereas COX-2 expressed heterologously is degraded with a t1 ⁄ 2 of ϳ5 h, and its degradation is slowed by proteasome inhibitors. A deletion mutant of COX-2 was prepared lacking 18 residues of the 19-AA cassette. This mutant retains native COX-2 activity but, unlike native COX-2, is stable in HEK293 cells. Conversely, inserting the COX-2 19-AA cassette near the C terminus of COX-1 yields a mutant ins594 -612 COX-1 that is unstable (t1 ⁄ 2 ϳ3 h). Mutation of Asn-594, an N-glycosylation site at the beginning of the 19-AA cassette, stabilizes both COX-2 and ins594 -612 COX-1; nonetheless, COX mutants that are glycosylated at Asn-594 but lack the remainder of the 19-amino acid cassette (i.e. del597-612 COX-2 and ins594 -596 COX-1) are stable. Thus, although glycosylation of Asn-594 is necessary for COX-2 degradation, at least part of the remainder of the 19-AA insert is also required. Finally, kifunensine, a mannosidase inhibitor that can block entry of ER proteins into the ER-associated degradation system, retards COX-2 degradation.Prostanoids are an important class of lipid mediators that are synthesized in almost all mammalian tissues. Prostanoids act in an autocrine and paracrine fashion through G protein-coupled receptors to elicit a variety of physiological and pathological responses (1-7). The committed step in the prostanoid biosynthetic pathway is catalyzed by the cyclooxygenase isozymes COX-1 2 and COX-2 (1, 3, 4, 8). Within a species, COX-1 and COX-2 exhibit ϳ60% amino acid sequence identity. Both isoforms are membrane-bound, ER-resident, heme-containing glycoproteins that function as homodimers (1, 3, 4, 9). Structural and biochemical studies have shown that COX-1 and COX-2 are unusual integral membrane proteins in that the enzymes associate monotopically with the luminal surfaces of the ER and the contiguous inner membrane of the nuclear envelope (10 -15).Despite their close similarities in structure, catalytic function, and subcellular localization, COX-1 and COX-2 differ markedly in their profiles of expression. COX-1 is constitutively expressed in resting cells of many tissues (16). COX-2 expression can be induced in fibroblast, epithelial, endothelia...

Summary Nitrogen (N) is one of the key essential macronutrients that affects rice growth and yield. Inorganic N fertilizers are excessively used to boost yield and generate serious collateral environmental pollution. Therefore, improving crop N use efficiency (NUE) is highly desirable and has been a major endeavour in crop improvement. However, only a few regulators have been identified that can be used to improve NUE in rice to date. Here we show that the rice NIN‐like protein 4 (OsNLP4) significantly improves the rice NUE and yield. Field trials consistently showed that loss‐of‐OsNLP4 dramatically reduced yield and NUE compared with wild type under different N regimes. In contrast, the OsNLP4 overexpression lines remarkably increased yield by 30% and NUE by 47% under moderate N level compared with wild type. Transcriptomic analyses revealed that OsNLP4 orchestrates the expression of a majority of known N uptake, assimilation and signalling genes by directly binding to the nitrate‐responsive cis‐element in their promoters to regulate their expression. Moreover, overexpression of OsNLP4 can recover the phenotype of Arabidopsis nlp7 mutant and enhance its biomass. Our results demonstrate that OsNLP4 plays a pivotal role in rice NUE and sheds light on crop NUE improvement.

Nitrogen is essential for plant survival and growth. Excessive application of nitrogenous fertilizer has generated serious environment pollution and increased production cost in agriculture. To deal with this problem, tremendous efforts have been invested worldwide to increase the nitrogen use ability of crops. However, only limited success has been achieved to date. Here we report that NLP7 (NIN-LIKE PROTEIN 7) is a potential candidate to improve plant nitrogen use ability. When overexpressed in Arabidopsis, NLP7 increases plant biomass under both nitrogen-poor and -rich conditions with better-developed root system and reduced shoot/root ratio. NLP7–overexpressing plants show a significant increase in key nitrogen metabolites, nitrogen uptake, total nitrogen content, and expression levels of genes involved in nitrogen assimilation and signalling. More importantly, overexpression of NLP7 also enhances photosynthesis rate and carbon assimilation, whereas knockout of NLP7 impaired both nitrogen and carbon assimilation. In addition, NLP7 improves plant growth and nitrogen use in transgenic tobacco (Nicotiana tabacum). Our results demonstrate that NLP7 significantly improves plant growth under both nitrogen-poor and -rich conditions by coordinately enhancing nitrogen and carbon assimilation and sheds light on crop improvement.

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2D numerical simulations of flows generated by a synthetic jet actuator with a circular orifice were conducted at two different diaphragm displacement settings, one representing a typical laminar case and the other a fully turbulent case. The flow in the cavity was included in the computation in order to provide more accurate predictions. A velocity boundary condition was applied at the neutral position of the diaphragm to account for its temporal deformation. Comparisons were made between the computational results and existing PIV and hot-wire data in terms of the time sequence of the velocity vector field, velocity variations in space and with time. It is found that computational results for the laminar case agree well with the experimental data. Four turbulent models were tested for the fully turbulent case. It was found that the predictions using the RNG κ-ε and Standard κ-ε models were reasonably close to the experimental data. This initial study has produced some encouraging evidence for the capacity of FLUENT in simulating the key features of synthetic jets. THE AERONAUTICAL JOURNAL FEBRUARY 2005 89 Paper No. 2938. Manuscript NOMENCLATURE

Machine learning has recently become a promising technique in fluid mechanics, especially for active flow control (AFC) applications. A recent work [Rabault et al., J. Fluid Mech. 865, 281-302 (2019)] has demonstrated the feasibility and effectiveness of deep reinforcement learning (DRL) in performing AFC over a circular cylinder at Re ¼ 100, i.e., in the laminar flow regime. As a follow-up study, we investigate the same AFC problem at an intermediate Reynolds number, i.e., Re ¼ 1000, where the weak turbulence in the flow poses great challenges to the control. The results show that the DRL agent can still find effective control strategies, but requires much more episodes in the learning. A remarkable drag reduction of around 30% is achieved, which is accompanied by elongation of the recirculation bubble and reduction of turbulent fluctuations in the cylinder wake. Furthermore, we also perform a sensitivity analysis on the learnt control strategies to explore the optimal layout of sensor network. To our best knowledge, this study is the first successful application of DRL to AFC in weakly turbulent conditions. It therefore sets a new milestone in progressing toward AFC in strong turbulent flows.