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Selective inhibition of the transcription elongation factor (P-TEFb) complex represents a promising approach in cancer therapy, yet CDK9 inhibitors (CDK9i) are currently limited primarily to certain hematological malignancies. Herein, while initial responses to CDK9-targeted therapies are observed in vitro across various KRAS-mutant cancer types, their efficacy is far from satisfactory in nude mouse xenograft models. Mechanistically, CDK9 inhibition leads to compensatory activation of ERK-MYC signaling, accompanied by the recovery of proto-oncogenes, upregulation of immediate early genes (IEGs), stimulation of the complement C1r-C3-C3a cascade, and induction of tumor immunosuppression. The "paradoxical" regulation of PP2Ac activity involving the CDK9/Src interplay contributes to ERK phosphorylation and pause-release of RNA polymerase II (Pol II). Co-targeting of CDK9 and KRAS/MAPK signaling pathways eliminates ERK-MYC activation and prevents feedback activation mediated by receptor tyrosine kinases, leading to more effective control of KRAS-mutant cancers and overcoming KRASi resistance. Moreover, modulating the tumor microenvironment (TME) by complement system intervention enhances the response to CDK9i and potently suppresses tumor growth. Overall, the preclinical investigations establish a robust framework for conducting clinical trials employing KRASi/SOS1i/MEKi or immunomodifiers in combination with CDK9i to simultaneously target cancer cells and their crosstalk with the TME, thereby yielding improved responses in KRAS-mutant patients., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Discrete extreme heat events, deluges, and droughts will become more frequent and disproportionately affect the processes and functions of grassland ecosystems. Here, we compared the responses of CO 2 and heat fluxes to natural extreme events in 2016 in a lower alpine meadow and neighboring upper shrubland on the northeastern Qinghai-Tibetan Plateau. Unlike insensitive sensible heat flux, latent heat flux (LE) increased by 21.8 % in the meadow and by 56.4 % in the shrubland during a dry period and subsequent compound hot-dry period in August. Changes (Δ, data for 2016 minus the corresponding means from other years) in the heat flux at both sites were determined by changes in solar radiation (ΔSwin), as sufficient soil moisture was available. ΔLE was more sensitive to ΔSwin in the open-canopy shrubland, reflecting its greater capacity for evaporative cooling to buffer climate anomalies. CO 2 fluxes responded weakly to extreme wet or dry events but strongly when those events were accompanied by exceptional heat. During single or compound hot events, the mean changes in total ecosystem respiration (ΔTER) increased by about 30 % in both grasslands, although ΔTER was more sensitive to changes in the topsoil temperature in the more productive meadow than in the shrubland. The mean changes in gross primary productivity (ΔGPP) fluctuated by <10 % in the warmer meadow but increased by 29.3 % in the cooler shrubland relative to the respective baseline, probably because of the differences in canopy structure and root depth and the consequent high-temperature stress on vegetation photosynthesis. The changes in net ecosystem CO 2 exchange (ΔNEE) were significantly related to ΔTER in the meadow and increased by 55.8 %, whereas ΔNEE was controlled mainly by ΔGPP in the shrubland and decreased by 22.4 %. Overall, both alpine grasslands were resistant to rainfall anomalies but susceptible to exceptional warmth, with the differential responses being ascribed to canopy structure and root depth. Our results provide helpful insights based on which the carbon sequestration and water-holding functions of alpine grasslands during future climate change can be predicted., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Simulating the carbon-water fluxes at more widely distributed meteorological stations based on the sparsely and unevenly distributed eddy covariance flux stations is needed to accurately understand the carbon-water cycle of terrestrial ecosystems. We established a new framework consisting of machine learning, determination coefficient (R 2 ), Euclidean distance, and remote sensing (RS), to simulate the daily net ecosystem carbon dioxide exchange (NEE) and water flux (WF) of the Eurasian meteorological stations using a random forest model or/and RS. The daily NEE and WF datasets with RS-based information (NEE-RS and WF-RS) for 3774 and 4427 meteorological stations during 2002-2020 were produced, respectively. And the daily NEE and WF datasets without RS-based information (NEE-WRS and WF-WRS) for 4667 and 6763 meteorological stations during 1983-2018 were generated, respectively. For each meteorological station, the carbon-water fluxes meet accuracy requirements and have quasi-observational properties. These four carbon-water flux datasets have great potential to improve the assessments of the ecosystem carbon-water dynamics., (© 2023. Springer Nature Limited.)

The carbon process of the alpine ecosystem is complex and sensitive in the face of continuous global warming. However, the long-term dynamics of carbon budget and its driving mechanism of alpine ecosystem remain unclear. Using the eddy covariance (EC) technique-a fast and direct method of measuring carbon dioxide (CO 2 ) fluxes, we analyzed the dynamics of CO 2 fluxes and their driving mechanism in an alpine wetland in the northeastern Qinghai-Tibet Plateau (QTP) during the growing season (May-September) from 2004-2016. The results show that the monthly gross primary productivity (GPP) and ecosystem respiration (Re) showed a unimodal pattern, and the monthly net ecosystem CO 2 exchange (NEE) showed a V-shaped trend. With the alpine wetland ecosystem being a carbon sink during the growing season, that is, a reservoir that absorbs more atmospheric carbon than it releases, the annual NEE, GPP, and Re reached -67.5 ± 10.2, 473.4 ± 19.1, and 405.9 ± 8.9 gCm -2 , respectively. At the monthly scale, the classification and regression tree (CART) analysis revealed air temperature (Ta) to be the main determinant of variations in the monthly NEE and GPP. Soil temperature (Ts) largely determined the changes in the monthly Re. The linear regression analysis confirmed that thermal conditions (Ta, Ts) were crucial determinants of the dynamics of monthly CO 2 fluxes during the growing season. At the interannual scale, the variations of CO 2 fluxes were affected mainly by precipitation and thermal conditions. The annual GPP and Re were positively correlated with Ta and Ts, and were negatively correlated with precipitation. However, hydrothermal conditions (Ta, Ts, and precipitation) had no significant effect on annual NEE. Our results indicated that climate warming would be beneficial to the improvement of GPP and Re in the alpine wetland, while the increase of precipitation can weaken this effect., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhu, Li, He, Zhang, Yang and Li.)

Biomass temporal stability plays a key role in maintaining sustainable ecosystem functions and services of grasslands, and climate change has exerted a profound impact on plant biomass. However, it remains unclear how the community biomass stability in alpine meadows responds to changes in some climate factors (e.g., temperature and precipitation). Long-term field aboveground biomass monitoring was conducted in four alpine meadows (Haiyan [HY], Henan [HN], Gande [GD], and Qumalai [QML]) on the Qinghai-Tibet Plateau. We found that climate factors and ecological factors together affected the community biomass stability and only the stability of HY had a significant decrease over the study period. The community biomass stability at each site was positively correlated with both the stability of the dominant functional group and functional groups asynchrony. The effect of dominant functional groups on community stability decreased with the increase of the effect of functional groups asynchrony on community stability and there may be a 'trade-off' relationship between the effects of these two factors on community stability. Climatic factors directly or indirectly affect community biomass stability by influencing the stability of the dominant functional group or functional groups asynchrony. Air temperature and precipitation indirectly affected the community stability of HY and HN, but air temperature in the growing season and nongrowing season had direct negative and direct positive effects on the community stability of GD and QML, respectively. The underlying mechanisms varied between community composition and local climate conditions. Our findings highlighted the role of dominant functional group and functional groups asynchrony in maintaining community biomass stability in alpine meadows and we highlighted the importance of the environmental context when exploring the stability influence mechanism. Studies of community stability in alpine meadows along with different precipitation and temperature gradients are needed to improve our comprehensive understanding of the mechanisms controlling alpine meadow stability., Competing Interests: We declare no conflict of interest., (© 2022 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd.)

Changes in ecological processes over time in ambient treatments are often larger than the responses to manipulative treatments in climate change experiments. However, the impacts of human-driven environmental changes on the stability of natural grasslands have been typically assessed by comparing differences between manipulative plots and reference plots. Little is known about whether or how ambient climate regulates the effects of manipulative treatments and their underlying mechanisms. We collected two datasets, one a 36-year long-term observational dataset from 1983 to 2018, and the other a 10-year manipulative asymmetric warming and grazing experiment using infrared heaters with moderate grazing from 2006 to 2015 in an alpine meadow on the Tibetan Plateau. The 36-year observational dataset shows that there was a nonlinear response of community stability to ambient temperature with a positive relationship between them due to an increase in ambient temperature in the first 25 years and then a decrease in ambient temperature thereafter. Warming and grazing decreased community stability with experiment duration through an increase in legume cover and a decrease in species asynchrony, which was due to the decreasing background temperature through time during the 10-year experiment period. Moreover, the temperature sensitivity of community stability was higher under the ambient treatment than under the manipulative treatments. Therefore, our results suggested that ambient climate may control the directional trend of community stability while manipulative treatments may determine the temperature sensitivity of the response of community stability to climate relative to the ambient treatment. Our study emphasizes the importance of the context dependency of the response of community stability to human-driven environmental changes., (© 2021 John Wiley & Sons Ltd.)

The FLUXNET2015 dataset provides ecosystem-scale data on CO 2 , water, and energy exchange between the biosphere and the atmosphere, and other meteorological and biological measurements, from 212 sites around the globe (over 1500 site-years, up to and including year 2014). These sites, independently managed and operated, voluntarily contributed their data to create global datasets. Data were quality controlled and processed using uniform methods, to improve consistency and intercomparability across sites. The dataset is already being used in a number of applications, including ecophysiology studies, remote sensing studies, and development of ecosystem and Earth system models. FLUXNET2015 includes derived-data products, such as gap-filled time series, ecosystem respiration and photosynthetic uptake estimates, estimation of uncertainties, and metadata about the measurements, presented for the first time in this paper. In addition, 206 of these sites are for the first time distributed under a Creative Commons (CC-BY 4.0) license. This paper details this enhanced dataset and the processing methods, now made available as open-source codes, making the dataset more accessible, transparent, and reproducible.

Tibetan permafrost largely formed during the late Pleistocene glacial period and shrank in the Holocene Thermal Maximum period. Quantifying the impacts of paleoclimatic extremes on soil carbon stock can shed light on the vulnerability of permafrost carbon in the future. Here, we synthesize data from 1114 sites across the Tibetan permafrost region to report that paleoclimate is more important than modern climate in shaping current permafrost carbon distribution, and its importance increases with soil depth, mainly through forming the soil's physiochemical properties. We derive a new estimate of modern soil carbon stock to 3 m depth by including the paleoclimate effects, and find that the stock ([Formula: see text] PgC) is triple that predicted by ecosystem models (11.5 ± 4.2 s.e.m PgC), which use pre-industrial climate to initialize the soil carbon pool. The discrepancy highlights the urgent need to incorporate paleoclimate information into model initialization for simulating permafrost soil carbon stocks.