Global warming has led to substantially earlier spring leaf‐out in temperate‐zone deciduous trees. The interactive effects of temperature and daylength underlying this warming response remain unclear. However, they need to be accurately represented by earth system models to improve projections of the carbon and energy balances of temperate forests and the associated feedbacks to the Earth's climate system. We studied the control of leaf‐out by daylength and temperature using data from six tree species across 2,377 European phenological network (http://www.pep725.eu), each with at least 30 years of observations. We found that, in addition to and independent of the known effect of chilling, daylength correlates negatively with the heat requirement for leaf‐out in all studied species. In warm springs when leaf‐out is early, days are short and the heat requirement is higher than in an average spring, which mitigates the warming‐induced advancement of leaf‐out and protects the tree against precocious leaf‐out and the associated risks of late frosts. In contrast, longer‐than‐average daylength (in cold springs when leaf‐out is late) reduces the heat requirement for leaf‐out, ensuring that trees do not leaf‐out too late and miss out on large amounts of solar energy. These results provide the first large‐scale empirical evidence of a widespread daylength effect on the temperature sensitivity of leaf‐out phenology in temperate deciduous trees.

Leaf phenology is one of the most reliable bioindicators of ongoing global warming in temperate and boreal zones because it is highly sensitive to temperature variation. A large number of studies have reported advanced spring leaf‐out due to global warming, yet the temperature sensitivity of leaf‐out has significantly decreased in temperate deciduous tree species over the past three decades. One of the possible mechanisms is that photoperiod is limiting further advance to protect the leaves against potential damaging frosts. However, the “photoperiod limitation” hypothesis remains poorly investigated and experimentally tested. Here, we conducted a photoperiod‐ and temperature‐manipulation experiment in climate chambers on two common deciduous species in Europe: Fagus sylvatica (European beech, a typically late flushing species) and Aesculus hippocastanum (horse chestnut, a typically early flushing species). In agreement with previous studies, we found that the warming significantly advanced the leaf‐out dates by 4.3 and 3.7 days/°C for beech and horse chestnut saplings, respectively. However, shorter photoperiod significantly reduced the temperature sensitivity of beech only (3.0 days/°C) by substantially increasing the heat requirement to avoid leafing‐out too early. Interestingly, the photoperiod limitation only occurs below a certain daylength (photoperiod threshold) when the warming increased above 4°C for beech trees. In contrast, for chestnut, no photoperiod threshold was found even when the ambient air temperature was warmed by 5°C. Given the species‐specific photoperiod effect on leaf phenology, the sequence of the leaf‐out timing among forest tree species may change under future climate warming conditions. Nonphotoperiodic species may benefit from warmer springs by starting the growing season earlier than photoperiodic sensitive species, modifying forest ecosystem structure and functions, but this photoperiod limitation needs to be further investigated experimentally in numerous species.

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Leaf senescence (LS) affects tree fitness, species distribution and ecosystem structure and functioning. The drivers of LS and the processes underlying it have been studied, but the studies have mainly focused on environmental cues and have mainly been based on statistical analyses using in situ data sets. Experimental investigation and field verification of the processes and drivers are thus urgently needed. We conducted a nutrient-addition experiment after a spring-warming experiment in which an ~40-day range of leaf-out (LO) dates was induced in horse chestnut (Aesculus hippocastanum) and beech (Fagus sylvatica) saplings. We found that both increased nutrient supply and advanced LO date significantly affected the timing of LS, but their effects were opposite, as the former delayed and the latter advanced the senescence. The effects of nutrient supply and LO interacted species specifically. In chestnut, the delay of senescence caused by fertilization increased with the delay of LO and was thus stronger for individuals that flushed late in the spring. On the contrary, in beech the delay of senescence caused by fertilization decreased with the delay of LO and was insignificant for individuals with the latest LO. The experimental findings for beech were confirmed with mature trees at a regional scale. The interactive effect between nutrients and LO on senescence may be associated with variable sensitivity to photoperiod, growth sink limitation and/or direct effect of foliar nutrition on the timing of senescence. Our novel results show that the interactive effects of LO and nutrient supply on the timing of LS should be further addressed experimentally in forthcoming studies. It would also be interesting to consider our results in the further development of phenological models used in assessing the effects of climatic change. The differences found in the present study between horse chestnut and beech suggest that the results found for one species cannot necessarily be generalized to other species, so studies with different temperate tree species are called for.

Abbreviations: AR, androgen receptor; ARE, androgen-responsive element; DUB, deubiquitinating enzyme; H3K9, histone H3 on lysine 9; H3K36, histone H3 on lysine 36; HA-ub, HA-tagged ubiquitin; IB, immunoblot; IHC, immunohistochemistry; IP, immunoprecipitation; KDM4A, lysine-specific demethylase 4A; PC, prostate cancer; PTEN, phosphatase and tensin homolog; qPCR, quantitative PCR. AbstractThe histone demethylase lysine-specific demethylase 4A (KDM4A) is reported to be overexpressed and plays a vital in multiple cancers through controlling gene expression by epigenetic regulation of H3K9 or H3K36 methylation marks. However, the biological role and mechanism of KDM4A in prostate cancer (PC) remain unclear.Herein, we reported KDM4A expression was upregulation in phosphatase and tensin homolog knockout mouse prostate tissue. Depletion of KDM4A in PC cells inhibited their proliferation and survival in vivo and vitro. Further studies reveal that USP1 is a deubiquitinase that regulates KDM4A K48-linked deubiquitin and stability.Interestingly, we found c-Myc was a key downstream effector of the USP1-KDM4A/ androgen receptor axis in driving PC cell proliferation. Notably, upregulation of KDM4A expression with high USP1 expression was observed in most prostate tumors and inhibition of USP1 promotes PC cells response to therapeutic agent enzalutamide. Our studies propose USP1 could be an anticancer therapeutic target in PC.

Improved therapeutic approaches are needed for the treatment of recurrent and metastatic endometrial cancer (EC). ECs display hyper-activation of the MAPK and PI3K pathways, the result of somatic aberrations in genes such as FGFR2, KRAS, PTEN, PIK3CA and PIK3R1. FGFR2, as well as the PI3K pathway, have emerged as potential therapeutic targets in EC. Activation of the PI3K pathway is seen in >90% of FGFR2 mutant ECs. This study aimed to examine the efficacy of the pan-FGFR inhibitor BGJ398 with pan-PI3K inhibitors (GDC-0941, BKM120) and the p110α-selective inhibitor BYL719. We assessed synergy in three FGFR2 mutant EC cell lines (AN3CA, JHUEM2 and MFE296) and the combination of BGJ398 and GDC-0941 or BYL719showed strong synergy. A significant increase in cell death and decrease in long-term survival was seen when PI3K inhibitors were combined with BGJ398. Importantly, these effects were seen at low concentrations correlating to only partial inhibition of AKT. The combination of BGJ398 and GDC-0941 showed tumor regressions in vivo, whereas each drug alone only showed moderate tumor growth inhibition. BYL719 alone resulted in increased tumor growth of AN3CA xenografts, but in combination with BGJ398 resulted in tumor regression in b o t h AN3CA and JHUEM2-derived xenografts. These data provide evidence that sub-therapeutic doses of PI3K inhibitors enhance the efficacy of anti-FGFR therapies and a combination therapy may represent a superior therapeutic treatment in FGFR2 mutant EC patients.