Stem cells must balance self-renewal and differentiation; thus, their activities are precisely controlled. In plants, the control circuits that underlie division and differentiation within meristems have been well studied, but those that underlie feedback on meristems from lateral organs remain largely unknown. Here we show that long-distance auxin transport mediates this feedback in a non-cell-autonomous manner. A low-auxin zone is associated with the shoot apical meristem (SAM) organization center, and auxin levels negatively affect SAM size. Using computational model simulations, we show that auxin transport from lateral organs can inhibit auxin transport from the SAM through an auxin transport switch and thus maintain SAM auxin homeostasis and SAM size. Genetic and microsurgical analyses confirmed the model's predictions. In addition, the model explains temporary change in SAM size of yabby mutants. Our study suggests that the canalization-based auxin flux can be widely adapted as a feedback control mechanism in plants.

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21 has become a leading strategy in curing HIV. Recently, single-cell screening experiments 22 have shown the drug synergy between two categories of biomolecules, Activators (AC) 23 and Noise Enhancers (NE): NE can amplify the reactivation of latent HIV induced by AC, 24 although NE itself cannot reactivate HIV latency. Based on an established LTR-two-state 25 effective model, we uncover two necessary conditions for this type of drug synergy: The 26 decreasing of the turning-on rate of LTR induced by NE is highly inhibited when 27 presented with AC; The timescale of LTR turning off without AC/NE presented should be 28 no slower than the timescale of Tat transactivation. Then we propose a detailed LTR-29 four-state mechanistic model with both AC/NE regulation kinetics and Tat transactivation 30 circuit. We show that, in order to achieve drug synergy, the system of HIV gene state 31 transition must operate out of thermodynamic equilibrium, which is caused by energy 32 input. The direction of energy input determines whether the inhibition of NE upon the 33 reactivation rate of LTR-off states (unbinding of RNAP) can be successfully prevented in 34 the presence of AC. The drug synergy can also be significantly enhanced if the energy 35input is appropriately distributed to more than one reaction. Our model reveals a generic 36 nonequilibrium mechanism underpinning the noise enhanced drug synergy, which may 37 apply to identify the same drug synergy on reactivating a diverse class of lentivirus 38 latency. 39Keywords: HIV latency reactivation, drug synergy, nonequilibrium mechanism, 40 Tat transactivation, Markov jump process 41 Significance Statement 42The "kick and kill" strategy has become a promising way to cure HIV by eliminating latent 43 HIV reservoirs, the main barrier to a clinical cure. Two categories of biomolecules, 44 Activators (AC) and Noise Enhancers (NE), have been found to have synergy on 45 reactivating latent HIV (kick strategy). We uncover the underlying non-equilibrium 46 mechanism of such drug synergy by developing mathematical models based on genetic 47 regulatory kinetics. We find that controlling the magnitude and direction of energy input 48 into genetic regulatory kinetics can prevent NE from reducing the turn-on rate of the 49 inactivated gene state in the presence of AC, which produces the synergy. This general 50 nonequilibrium mechanism can be useful for identifying other drug synergies on lentivirus 51 latency reactivation.

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Due to intense anthropogenic impacts, river networks in co-urbanized areas are severely degraded and fragmented, and their ability to supply multiple ecosystem services is greatly reduced. This study aimed to provide a novel technical approach to identify spatial priorities for complex and special linear water spaces in a co-urbanized area. This approach fully considers the features of river networks with multiple levels and multiple functions. We first identified two spatial configurations of river networks based on the river density: river cluster patches and river corridors, which were each divided into four spatial levels. We then assessed and mapped the multiple ecosystem services provided by each river level through a coupling evaluation model. Finally, based on the evaluation results and spatial clustering analysis, we identified priorities of linear water spaces using six priority grades. This priority identification method based on multiple levels and multiple ecosystem services of linear water spaces shows how a holistic catchment perspective can be applied to the practice of integrated river management in co-urbanized areas. Selecting conservation strategies for linear water spaces on the basis of their structural level and ecological contribution is a more targeted measure.

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