Short-term extreme heat at flowering amplifies the impacts of climate change on maize production

Extreme weather poses a threat to global crop production, food security and farmer livelihoods. High temperatures have been identified as detrimental to crop yields; however, how heat stress during the critical flowering stage will influence future maize (Zea mays L.) yields remains unclear. Here, we combined statistical and process-based models to assess impacts of short-term extreme heat at flowering on Chinese maize yield under climate change. We showed that heat around flowering has a stronger impact on yields than heat at other times in the growing season, especially for temperatures >30 °C. Heat stress during flowering was responsible for 23% of total yield loss from extreme degree days (EDDs) in 1990–2012. An improved process-based model (Agricultural Production Systems sIMulator (APSIM)-maize) incorporating a grain-temperature function was then applied and indicated that extreme heat at flowering amplified the impacts of climate change on maize production compared to the original model. The improved APSIM-maize predicted an 8.7% yield reduction across the Chinese Maize Belt as EDDs increased more than quadrupled at the end of the century (2070–2099) under a high emissions pathway (SSP585) in comparison with the baseline period (1990–2019). Our study highlights the importance of extreme heat at flowering on maize yield and can inform farmers and policy makers on adaptive measures as well as providing a reference for other crop areas facing similar challenges.


Introduction
Rising average temperature and more frequent extreme weather events from climate change are expected to pose global yield variability, increase yield risk, and raise a challenge for future yield progress (Urban et al 2012, Ray et al 2015, Urban et al 2015, Perry et al 2020. The impact of changing climatic extremes on crop production is an important area of current research, with increasingly severe heat being a particular concern (Battisti and Naylor 2009, Tai et al 2014, Lesk et al 2016. Maize (Zea mays L.) production supplies 38.9% of global cereal grains, and therefore maize systems are central to the world food security and sustainability agenda (Godfray et al 2010, FAO 2021. Previous studies have found increasing sensitivity of maize yield to climate change Field 2007, Tigchelaar et al 2018) and predicted around a 7% global yield loss with each degree-Celsius warming (Lesk et al 2016, Zhao et al 2017. However, the influence of short-term extreme heat at the critical growth stage (e.g. flowering) on maize yields remains scarcely understood and is widely omitted from historical and future analyses, crop models and climate risk projections (Parent et al 2018, which has limited our capability to assess climate change impacts. Greater knowledge around the influence of extreme heat during flowering can inform future breeding efforts and the design of management practices, such as the timing of growing seasons (Minoli et al 2019).
Statistical and process-based crop models are the two distinct tools for integrating the current knowledge and evaluating influence of climate change on crop productivity (Zhao et al 2016). Numerous studies have used statistical models with various regression functions based on observed crop data and historical weather records to assess yield-climate relationships, which often present high level of accuracy (Lobell et al 2011, Butler et al 2018. Yet, a limitation of statistical models is the lack of understanding of the underlying physiological mechanisms under heat stress, especially for the short-term extremes (Roberts et al 2017). In comparison, the processbased crop models integrate plant-scale physiological mechanisms, and produce data of crop growth and development in daily steps (Lobell et al 2013, Asseng et al 2015. However, large uncertainties exist in yield projections among crop models, arising from over-simplification of specific processes and limited measurements needed to calibrate model parameters, especially under extreme weather conditions (Rötter et al 2011, Asseng et al 2013. One important shortcoming is that most crop models do not directly model damage to reproductive organs and process from short-term heat (e.g. flowering), which introduces uncertainty in process-based crop models' projections of future yield changes (Feng et al 2019, Sun et al 2021. Here we used both methods to assess the impacts of short-term extreme heat at flowering on historical and future maize yields in the Chinese Maize Belt (CMB).

Study region and data collection
We focused on the CMB, which accounts for 76.6% and 18.2% of national and global total maize production during the latest decades, respectively (supplementary figure S1). In addition, it covers 77.5% and 17.0% of national and global total maize harvest areas, respectively. Since the regions spans nearly 38 • of longitude and 33 • of latitude (97.5 • -135.1 • E, 21.1 • -53.6 • N), it covers a diversity of climates from southern tropical and sub-tropical systems at low latitudes to cool-temperate systems at high latitudes and therefore serves as an excellent laboratory for investigating the maize yield-climate relationship (Ray et al 2015, Meng et al 2016). The CMB was divided into four maize planting regions from north to south based on geographic locations and cropping systems: Northeast (NE), North China Plain (NCP), Northwest (NW), and Southwest (SW) (figure 1(c)) (Meng et al 2013).
Prefecture-level yield data of 139 cities from 14 provinces in the CMB were extracted from the China Municipal Statistical Yearbook of National Bureau of Statistics (http://data.stats.gov.cn) for 1990-2012. At the same time, maize development data (containing planting, flowering, and maturity dates) were obtained from 94 agro-meteorological experiment stations of China Meteorological Administration (CMA; http://data.cma.cn). Our former study found that maize hybrid Zhengdan958 (ZD958) was widespread planted across major maize regions in China in past decades and could be serve as the representative hybrid of Chinese modern maize (Luo et al 2020). In this study, we collected observed data on phenology (e.g. sowing, flowering, and maturity dates), yield, and field management for ZD958 from 12 experimental sites (figure 1; supplementary table S1), and then used them to calibrate and validate the crop model. Maize phenology data are available for three distinct growing stages: planting, silking and physiological maturity. To investigate yield sensitivities to growing degree days (GDDs) and extreme degree days (EDDs) of different development stage, the maize development stage was split into three phases according to maize phenology: (1) vegetative phase, from planting to the 7th day prior to silking (abbreviate as P1); (2) flowering phase, from the 7th day prior to silking to the 7th day post silking (abbreviate as P2), and (3) grain-filling phase, from the 7th day post silking to physiological maturity (abbreviate as P3). In addition, detailed information on soil properties can be found in supplementary table S2 based on representative soils in the region.
Weather data is critical for both statistical models establishing and process-based crop model running. About 197 weather stations spanning the CMB were considered in this study (figure 1(c)). Observed daily maximum temperature (T max ), minimum temperature (T min ), rainfall (Rain) and sunshine hours (SunHr) data for the period 1990-2019 were directly obtained from National Meteorological Networks of CMA. Daily solar radiation (Radn) data were calculated from observed SunHr using the method of Angstrom (Angstrom 1924).
To simulate maize yield under climate change, future climate scenario data were obtained from global climate models (GCMs), which was provided by the World Climate Research Program of Coupled Model Inter-comparison Project Phase 6 (CMIP6, https://esgf-node.llnl.gov/search/cmip6). Here, we selected climate projections for the CMB from five different GCMs (BCC-CSM2-MR, GISS-E2-1-G, INM-CM5-0, IPSL-CM6A-LR and UKESM1-0-LL) (see supplementary method). Daily weather data (daily temperature, rainfall, and solar radiation) from 1961 to 2100 were downscaled from monthly gridded data obtained from the five GCMs using the statistical downscaling model NWAI-WG (Liu and Zuo 2012).

Panel regression crop model
Using national data for the past 23 years (1990-2012), we first developed a statistical growth model that analyzed the influence of EDDs (>30 • C) (Lobell et al 2013) and GDDs (8 • C-30 • C) on maize yield in three consecutive growth phases (Lobell et al 2011). GDDs and EDDs are heat units used to examine effects of beneficial moderate temperatures and damaging hot temperatures on maize yields, respectively. For each station's daily weather, hourly temperatures were estimated from daily T max and T min using a sinusoidal function (Schlenker and Roberts 2009), and the GDDs was calculated according to the following definition (Lobell et al 2011) (equation (1)): EDDs is defined in a same analogous manner (equation (2)) where t is the hourly time step, and N is the total number of hours in each growing phase. T t is the average temperature during the time step (determined by interpolating between T min and T max with a sin curve). In this study, we used 8 • C for the base temperature and 30 • C as the high temperature threshold (McMaster andWilhelm 1997, Lobell et al 2011).
Aggregating GDD s and EDD s across every growing phase for each year and removing the sample mean across all years, produce anomalies in accumulated temperature measures, GDD ′ y and EDD ′ y , which are combined into a panel regression model for yield (Tack et al 2017b, Butler et al 2018 Y y,c = ε y,c + β 0,c + β 1 y Y y, c is the predicted yield for each city, c, and year, y. The β 0, c term is a city-fixed effect to control for time-invariant heterogeneity, whereas other β terms are various regression coefficients and uniform across each city. β 1 accounts for a time trend to capture technological improvement, while β 2 , β 3 , β 3 and β 4 represents yield response to climate variables. Primes on GDD and EDD indicate that the mean has been removed to prevent interaction with the β 0, c term. Although the estimated β 1 , β 2 , β 3 and β 4 would not change if the magnitude of GDD and EDD were used instead of anomalies, the value of β 0, c would then not be interpretable as the mean county yield (Butler and Huybers 2015). The statistical uncertainties of the regression panel model were calculated using 1000 block-bootstrap resampling, with blocking done at the year level to account for spatial correlation. The 1000 sets of estimated regression coefficients were then used to determine the confidence intervals of the model-estimated coefficients. Time trends in GDDs and EDDs were calculated with an ordinary leastsquares fit. Then, the influence of GDD and EDD trends on yields is obtained by multiplying by the respective sensitivities and summing, using equation (Butler et al 2018), In order to separate the contribution of climate and timing (i.e., growth stage) adjustments to yield, we considered two restricted scenarios following Butler et al (2018). First, planting and growing phase dates were fixed to their average values between 1990 and 2012, while weather data were considered as actual historical values, changing over time. Then, we explore effects of timing changes associated with changes in the growing season by specifying a fixed seasonal climatology and allowing planting and growth phase dates to vary. Likewise, a longterm simulation under five GCMs to investigate the impact of heat stress at flowering on maize yield was conducted in future. Additionally, to explore how temperature-yield relationships vary across different regions of CMB, we divided our sample into four major maize areas and applied the panel regression model in each region.

Improved process-based crop model (Agricultural Production Systems sIMulator (APSIM)-maize)
The APSIM is a cropping systems simulation model, which features a modular structure that can be modified to address specific research questions (Hammer et al 2010, Singh et al 2017. The APSIM model has been widely used for modeling impacts of climate changes on maize growth and yield in CMB (Liu et al 2013, Wang et al 2014, Bu et al 2015, Dai et al 2016. Here we used the latest released version (APSIM 7.10; www.apsim.info.) to simulate maize growth, development and capture effects of heat during flowering on maize yield. In the APSIMmaize module, grain number (GN), a vital component for yield, is a function of plant growth rate per day around flowering and is limited by a temperature threshold when daily cumulative temperatures are above critical values (Messina et al 2019). Utilizing insights from the statistical modeling, we developed a new GN-temperature stress function (GTF) for the process-based model (APSIM-maize) and analyzed the impact of climate change. To incorporate the adverse effects of short-term heat at flowering on GN and final yield for ZD958, we derived the response of seed setting to daily maximum temperature based on a temperature-controlled greenhouse experiment (Hou 2020), which included multiply temperature levels (see text S1). In the APSIM-maize 7.10, we added a stress switch (GN-temperature stress function, hereafter we called 'GTF') to capture temperature effects on GN according to Singh et al (2017) (see text S2).
Here, we first calibrate and validate maize phenology and yield based on the field-experimental data (supplementary table S1) across the CMB. Secondly, we parameterized GTF for ZD958 in maize module using a seed setting-temperature dataset derived from the temperature-controlled experiment (Hou 2020). Then, the calibrated model without the GTF (the 'original model') and the model with the parameterized GTF (the 'improved model') were used to explore the potential impact of the extreme heat on grain yield. Detailed information on genetic parameters for ZD958 can be found in supplementary table S3. The performance of the APSIM-maize model for phenology and yield simulation were shown in the supplementary figure S2.
In this study, we considered two Shared Socioeconomic Pathways (SSP245 and SSP585), which are the middle and high end of the range of future forcing pathways, respectively, covering a wider range of warming responses than the Representative Concentration Pathways (i.e., RCP4.5 and RCP8.5) used in CMIP5 (Tokarska et al 2020). Crop model simulations were run for the historically observed weather (1990-2019) and five GCMs with three climate periods (i.e., baseline period 1990-2019; future periods 2030-2059, abbreviated as 2040s; and 2070-2099, abbreviated as 2080s) using the ZD958 hybrid.
For the management options, maize was sown from 20 March to 13 June of each year with at least 360 kg of N fertilizer according to local managements. Sowing density was set as 7.5 plants m −2 for three regions (NE, NCP and NW). In the SW, the density was 6.0 plants m −2 . The initial soil conditions were reset each year to exclude any 'carry-over' effects from previous seasons. CO 2 concentrations (held at APSIM default, 350 ppm) (Brown et al 2014), soil characteristics and crop management settings were kept constant for all three periods. No stress from diseases, weeds and pests was assumed for the model simulations, and all other options were left as the defaults. The long-term simulations were conducted under rainfed for NE and SW and with full irrigation for NCP and NW according to famer practices (Meng et al 2013).
To translate these impacts into relative yield changes due to yield components (i.e., grain number, abbreviated as GN; grain size, abbreviated as GS) and short-term heat at flowering (EDDs, calculated by 30 • C, 33 • C and 36 • C, respectively, abbreviated as EDD30, EDD33, and EDD36), we normalized each variable as difference between mean value in baseline period and that in every future time series with the principal component analysis (PCA) (Abdi and Williams 2010). We next analyzed the importance of GN and GS to yield change under each scenario using a Random Forest model (Breiman 2001).

Increasing extreme heat during flowering
We found substantial overlap between the maize flowering period and EDD exposure, with 45% of days during the flowering period exceeding 30 • C (figure 1). Historical average EDDs vary considerably among regions, from 2.6 • C day in the NE to 13.8 • C day in the NCP. Over the past 23 years, the CMB has experienced increasing EDDs at flowering (0.5 • C day decade −1 ) with an average increase over the time series of 8.6 • C day. Overall, the EDDs at flowering have increased by 31.5% since 1990, accounting for 16.3% of that in the whole growing season (supplementary table S4).

Historical influence of short-term extreme heat at flowering on maize yields
The model captures about 98% of variation in grain yield for the entire study region (table 1). In general, yield is positively correlated with GDDs and negatively correlated with EDDs. The coefficients of EDDs and GDDs at flowering are larger in magnitude than during the vegetative and grain filling phases, while both vegetative and grain filling have longer duration days than flowering (supplementary table S5), suggesting that heat around flowering has a stronger impact on yields, especially for temperatures >30 • C. The regional analysis showed a relative stable temperature-yield relationship and verified the important role of temperature at flowering on yield across all regions (supplementary  table S6).
Changes in development timing trends make better use of moderate temperature (GDDs) for yield improvements, but could not obviate the negative effects of EDDs, especially during the flowering stage ( figure 2; supplementary figures S3 and S4). Over the 23 years, the increased EDDs over the maize growing season contributed to a 2.6% loss in yield across study region, which was offset by a 6.5% yield improvement associated with GDDs. Yield trends from EDDs trends at flowering was −3.3 kg ha −1 per decade, which contributed 23% of total yield loss from EDDs in growing season (figure 2; supplementary table S7). Given the critical role of EDDs around flowering in driving yield loss, future climate projections showed more severe effects on maize yield by the panel model (supplementary table S8). In the case of SSP585 scenario with current heat sensitivity, climate trends would reduce maize yield by 12.2% over the next 80 years, where yield loss from EDDs around flowering could be as high as 2.9% (supplementary figure S5).

Amplified impacts of climate change on yield by APSIM model with GTF module
Based on insights on historical influence of EDDs at flowering on maize yield from the above statistical model, we further used the process-based crop model (APSIM) to measure future maize yield response to short-term heat stress. With the specified GTF module, the crop model has a better performance on GN and final yield simulation, the coefficient of determination (R 2 ) was increased from 0.02 to 0.4 for GN and from 0.1 to 0.7 for yield.
Larger yield declines were observed for the improved model compared with the original model under future climate, with large variations among regions for most periods (figure 3; supplementary figure S6). Greatest yield loss was observed in SSP585 in 2080s. For the NE, grain yield was projected to no change with the improved model while it was actually projected to increase by 10.3% with the original model. Greater yield losses were seen in the NCP, from 4.1% with the original to 10.4% with the improved model, in the NW, from 0.6% to 12.6%, and for the SW, from 6.1% to 12.0%, respectively. For the whole CMB, yield was projected to decrease by 1.8%-8.7% with the improved model from the baseline to 2080s under SSP245 and SSP585, respectively.
Considering the impacts of the growing shortterm heat stress (figure 4), the improved model  better reflects the impacts of short-term extreme heat on yield under future scenarios. Both the change in EDDs at flowering (∆EDD, compared with baseline EDDs) and change in yield (∆yield, compared with baseline yield) in the improved model were significantly negatively associated with an R 2 of 0.15 (P < 0.000) and 0.35 (P < 0.000) for SSP245 and SSP585 scenarios, respectively (figure 5). On the other hand, the model without the modified GTF showed positive yield increases with elevated EDDs, implying an overestimation of yield under climate change ranging from 3.2% in the baseline period   The proportions of variance explained by the principal components are presented in the axis labels. EDD30, EDD33, EDD36 means the threshold temperature for EDD calculation were 30 • C, 33 • C and 36 • C, respectively. Each variable was normalized as the difference between the mean value in the baseline period and that in every future time series. (d), Relative importance of GN and GS on future yield change. The importance of each variable is expressed as the mean increase in prediction error (that is, the increase in mean square error, %IncMSE) with predictor omitted, scaled to sum to 100% for each analysis.

Discussion and conclusions
Climate warming in China results in changes for beneficial moderate temperature (GDDs) and damaging hot temperature (EDDs) across CMB, which consequently affects maize production (Piao et al 2010). Although researches have paid much attentions to the effects of short-term heat on grain crops (Liu et al 2014, Jin et al 2017, Maiorano et al 2017, no previous studies have examined the impact of extreme heat at flowering for CMB, an important cropping region which contributes nearly one-fifth of global maize production. Previous statistical models, even those examining differential effects of weather by growth stage, still often fail to include the effects of extreme heat at flowering Huybers 2015, Butler et al 2018). While previous research has pointed out that stage-dependent heat sensitivity was more important than magnitude of heat for process-base models' improvement under short-term extreme heat stress (Sun et al 2021), existing studies for most maize models failed to capture the impacts of heat stress around flowering (Jin et al 2016, Huang et al 2021. The approach proposed here provided an inter-comparison of crop models, and improved our insights to climate change impacts. Results show that heat around flowering has strong impacts on maize yield, consistent with a recent study of United States maize systems that showed temperature sensitivity peaks during silking and grain filling (Butler and Huybers 2015). On average, warming weather experienced by CMB accounted for 3.9% of yield trends over the past 23 years , and the extreme heat (>30 • C) around flowering primely drove 23% of yield reduction (table 1; figure 2). Although adaptive improvements in crop timing practices optimized the impacts of rising temperature during the entire growing season and thereby contributed to a net yield gain of 6.7% during 1990-2012 (supplementary table S7), farmer-controlled adjustments did not obviate the negative effects from short-term extreme heat at flowering. Notably, the process-based crop model with improved GTF showed that short-term extreme heat at flowering amplified impacts of warming weather on maize yield, resulting in 1.8% and 8.7% yield declines under SSP245 and SSP585 respectively by 2080s (2070-2099), compared with the baseline (figure 3). These estimated yield declines are comparable to findings in some other regions. For example, Bassu et al (2021) modeled maize yield in Europe and found yield reductions of 14%-17% under future climate conditions. Lesk et al (2016) suggested that a global increase in seasonal mean temperature associated with extreme heat disasters of per 1 • C would lead to 6%-7% declines in yield. In contrast, a different result was reported in Midwest US maize belt, where more beneficial climate trends (e.g. the decreased EDDs) and changes in development timing together explained more than a quarter (28%) of total yield improvement since 1981 (Butler et al 2018).
Since statistical models usually have a high level of accuracy on yield prediction, many researchers have combined observed yield and weather data to capture net effects of the entire range of processes by which climate affects yield (Lobell et al 2011, Tigchelaar et al 2018, Zaveri and Lobell 2019. In contrast to prior work in the CMB, we considered effects of shortterm hot temperature during the key flowering period (15 d around flowering). Although statistical model is a powerful analytical method for detecting effects of historical weather on crops, there are some limits for projecting future yield responses under climate changes (White 2009, Burney et al 2010. Processbased crop model (e.g. APSIM) could address that and simulate the temperature response of yield with insights into underlying mechanisms such as GN (Hammer et al 2010).
Our results indicated considerable damage in the 2080s under SSP585 across CMB, with 10.7%, 12.3% and 11.3% yield declines for NCP, NW and SW and a small increase (0.2%) for NE compared to the baseline period (1990-2019), respectively (figure 3), which mainly results from regional agro-ecological variability (Meng et al 2017). Unlike other regions, the NE experienced a slight improvement in yield except for during the 2080s, mainly due to hybrid ZD958 in our modeling, which is characterized by a relatively slow dehydration rate resulting in harvesting despite incomplete physiological maturation in historical period (Wang et al 2019). Additionally, the current limitation of low temperature at an earlier growth stage together with increasing precipitation partly explain the positive changes in NE (Liu et al 2016). Solar dimming and intensive extreme heat events in NCP and lack of irrigation in NW were related to more serious yield declines under climate change (Wang et al 2014. Likewise, the varying degree of yield loss and a lower level of maize production in the SW is a result of significant elevation-related climatic differences in the karst mountain areas and diverse landforms and ecosystems (Li et al 2012).
Heat stress at flowering could cause irreversible damage to kernel development and final grain yield by affecting cell division, sugar metabolism, and starch biosynthesis (Commuri andJones 2001, Liu et al 2022). Plants have sophisticated adaptive systems at the cellular and molecular levels based on heat shock proteins and new genes transcribing and translating to cope with the extreme heat stress (Dupuis andDumas 1990, Maestri et al 2002). This is difficult to be included in current process-based models to predict the acclimation of plants to the changing climate. Targeted breeding effort with heat-tolerant maize genotypes selection is a potential strategy for the acclimation of plants to climate-related stress (Cairns 2012, Naveed et al 2016, Tack et al 2016. However, researcher found that agricultural outputs could have huge declines even with long-run adaptation considered under future climate due to extreme heat and other stresses (Burke and Emerick 2016). In contrast, the recent work through the implicit estimate under a unifying estimation framework pointed yield benefits associated with growing season adjustments (Mérel and Gammans 2021). Adjusting sowing dates to match the supply and requirements of crops to local climate resources, such as a better solar radiation utilization, a more suitable phenological growing stage for crop production, would eventually buffer climate risks (e.g. heat and drought) and provide economic benefits (Ortiz-Bobea and Just 2013, Kawasaki 2019, Minoli et al 2022. In addition, irrigation, would also be an alternative approach to maintain crop yield with warming temperature (Tack et al 2017a), directly by alleviating crop water stress and indirectly by reducing heat stress through evaporative cooling (Li et al 2020). Irrigation leaded to an average yield increase of 22% across global maize areas (Wang et al 2021a). Nevertheless, we acknowledge that further research on the feasibility of irrigation should take the sustainability and water resource constraint into consideration, given that excessive and unsustainable groundwater consumption had limited crop production in China and other areas (Veeck et al 2020).
There are, of course, many other possible factors that this study cannot address. Analyses with the process-based crop model presented here cover a single, widely planted hybrid-ZD958 (Wang et al 2021b), and therefore is a simplification of real-world temperature responses. Further work on the role of short-term heat stress on yield changes should evaluate multiple regionally-specific varieties that play an important role in crop production adaptation (Zabel et al 2021). It is important to note that better simulating the impacts of extreme heat on GS during the grain filling period could additionally improve yield projections under climate changes (Rezaei et al 2015). For the simulation, irrigation is applied for NCP and NW, which also have effects on the microclimate and result in evaporative cooling, ultimately reduce the impact of actual heat stress (Lobell et al 2008). This process should also be incorporated in the crop modeling. Since irrigation is an effective strategy to mitigate the harmful effects of extreme heat and to cool surface air temperature (Li et al 2020, Zhu andBurney 2022), further research should consider how increasing atmospheric aridity (high vapor pressure deficit, VPD) with global warming would influence rainfed maize.
Our study highlighted the important role of the extreme high temperature at flowering on maize yield. We found that more than half of the CMB experienced increases in short-term heat stress at flowering over the past 23 years. This resulted in damaging yield loss from extreme heat stress, which together accounted for one-third of yield trends from EDDs during maize growing season. Overall, the CMB is projected to face yield declines in the future. These findings emphasize the importance of shortterm heat stress during flowering as an important control on yields under climate change, as well as motivate multi-scale and multi-method crop model assessments to improve our understanding of crop physiological responses to climate change (Sánchez et al 2014).

Data availability statements
All data that support the findings of this study are included within the article (and any supplementary files).

Author contributions
Q M conceived and designed the research; N L and Q M performed research and wrote the manuscript; N D M provided edits and comments on the manuscript; Y Z, P F, S H, D L and P W provided method suggestions and contributed to the interpretation of the results; Y Y and X W helped to analyses data and commented on the manuscript.