An efficient behavioral screening platform classifies natural products and other chemical cues according to their chemosensory valence in C. elegans.

Throughout history, humans have relied on plants as a source of medication, flavoring, and food. Plants synthesize large chemical libraries and release many of these compounds into the rhizosphere and atmosphere where they affect animal and microbe behavior. To survive, nematodes must have evolved the sensory capacity to distinguish plant-made small molecules (SMs) that are harmful and must be avoided from those that are beneficial and should be sought. This ability to classify chemical cues as a function of their value is fundamental to olfaction, and represents a capacity shared by many animals, including humans. Here, we present an efficient platform based on multi-well plates, liquid handling instrumentation, inexpensive optical scanners, and bespoke software that can efficiently determine the valence (attraction or repulsion) of single SMs in the model nematode, Caenorhabditis elegans. Using this integrated hardware-wetware-software platform, we screened 90 plant SMs and identified 37 that attracted or repelled wild-type animals, but had no effect on mutants defective in chemosensory transduction. Genetic dissection indicates that for at least 10 of these SMs, response valence emerges from the integration of opposing signals, arguing that olfactory valence is often determined by integrating chemosensory signals over multiple lines of information. This study establishes that C. elegans is an effective discovery engine for determining chemotaxis valence and for identifying natural products detected by the chemosensory nervous system.

Knockdown of SIX4 inhibits pancreatic cancer cells via apoptosis induction.

Sine oculis homeobox 4 (SIX4), a critical transcription factor modulating organ development, potentially participates in tumorigenesis through numerous pathways. Here, we investigated siRNA-mediated knockdown effects of SIX4 on pancreatic cancer cells and underlying molecular mechanisms. The expression of SIX4 in pancreatic cancer and adjacent tissues were investigated in clinical tissue samples and bioinformatically approved by gene expression omnibus (GEO) database. Appropriate siRNA transfected into PANC1 pancreatic cancer cells in order to SIX4 knockdown. The survival, migration, invasion, colony formation, mitochondrial membrane potential, apoptosis, autophagy, and cell cycle in the cancer cells were investigated after knockdown of SIX4. In addition, expression of genes involved in apoptosis and metastasis were assessed in the transfected cancer cells in mRNA and protein levels. High-throughput analysis using GEO database confirmed the overexpression of SIX4 in pancreatic cancer tissues by six independent pancreatic cancer microarrays. Knockdown of SIX4 by specific siRNA significantly decreased survival, colony formation, and mitochondrial membrane potential of the cancer cells. Further assessments demonstrated that knockdown of SIX4 increases the apoptosis and autophagy rates in the cancer cells through modifying the expression of related genes. Moreover, a significant decrease in migration and invasion rates were observed in SIX4 suppressed group. Furthermore, frequency of the cells transfected with SIX4 siRNA increased slightly in G1 and Sub-G1 phases of cell cycle. Our study suggested that siRNA-mediated knockdown of SIX4 increases the pancreatic cancer cells death and reduces the invasion and migration of the cancer cells through different molecular pathways.

A New Combination: Anti Glypican-3 scFv and Diphtheria Toxin with the Best Flexible Linker.

Along with all cancer treatments, including chemotherapy, radiotherapy, and surgery, targeting therapy is a new treatment manner. Immunotoxins are new recombinant structures that kill cancer cells by targeting specific antigens. Immunotoxins are composed of two parts: toxin moiety, which disrupts protein synthesis process, and antigen binding moiety that bind to antigens on the surface of cancer cells. Glypican 3 (GPC3) is an oncofetal antigen on the surface of Hepatocellular carcinoma (HCC) cells. In this study, truncated Diphtheria toxin (DT389) was fused to humanized scFv YP7 by one, two and three repeats of GGGGS linkers (DT389-(GGGGS)1-3YP7). In-silico and experimental investigation were performed to find out how many repeats of linker between toxin and scFv moieties are sufficient. Results of in-silico investigations revealed that the difference in the number of linkers does not have a significant effect on the main structures of the immunotoxin; however, the three-dimensional structure of two repeats of linker had a more appropriate structure compared to others with one and three linker replications. In addition, with enhancing the number of linkers, the probability of protein solubility has increased. Generally, the bioinformatics results of DT389-(GGGGS)2-YP7 structure showed that expression and folding is suitable; and YP7 scFv has appropriate orientation to bind GPC3. The experimental investigations indicated that the fusion protein was expressed as near to 50% soluble. Due to the high binding affinity of YP7 scFv and the proven potency of diphtheria in inhibiting protein synthesis, the proposed DT389-(GGGGS)2-YP7 immunotoxin is expected to function well in inhibiting HCC.

A novel shiga based immunotoxin against Fn-14 receptor on colorectal and lung cancer.

Immunotoxins are regarded as a type of targeted therapy for killing cells by highly potent bacterial, fungal or plant toxins. Shiga like toxins (SLTs) are a group of bacterial AB5 protein toxins that inhibit host cell protein synthesis through the removal of a single adenine residue from the 28S rRNA and lead to apoptosis. Here, we described the design and usage of a Stx-based immunotoxin that can induce the selective cytotoxicity and apoptosis in Fn-14-positive cells related to the colon and lung cancer. In the present study, the Stx2a-PE15-P4A8 fusion protein was expressed efficiently in E. coli (DE3) system when driven from inclusion bodies by 8 M urea. The Stx2a-PE15-P4A8 fusion protein was expressed efficiently in E. coli (DE3) system and then purified. The purified fusion protein could specifically target Fn-14 receptor existed on colon and lung cancer cell lines and suppress these cells in a dose-dependent manner. In addition, the protein was able to nearly 50 % of apoptotic cell death and maintains about 54 % of its stability after 24 h of incubation in mouse serum at 37 °C. Compared to PE38-P4A8 construct in our previous study, these results showed that the Stx2a-PE15-P4A8 construct can be an efficient therapeutic candidate for cancer immunotherapy.

Simulation of winter wheat response to variable sowing dates and densities in a high-yielding environment.

Crop multi-model ensembles (MME) have proven to be effective in increasing the accuracy of simulations in modelling experiments. However, the ability of MME to capture crop responses to changes in sowing dates and densities has not yet been investigated. These management interventions are some of the main levers for adapting cropping systems to climate change. Here, we explore the performance of a MME of 29 wheat crop models to predict the effect of changing sowing dates and rates on yield and yield components, on two sites located in a high-yielding environment in New Zealand. The experiment was conducted for 6 years and provided 50 combinations of sowing date, sowing density and growing season. We show that the MME simulates seasonal growth of wheat well under standard sowing conditions, but fails under early sowing and high sowing rates. The comparison between observed and simulated in-season fraction of intercepted photosynthetically active radiation (FIPAR) for early sown wheat shows that the MME does not capture the decrease of crop above ground biomass during winter months due to senescence. Models need to better account for tiller competition for light, nutrients, and water during vegetative growth, and early tiller senescence and tiller mortality, which are exacerbated by early sowing, high sowing densities, and warmer winter temperatures.

Uncertainty in climate change impact studies for irrigated maize cropping systems in southern Spain.

This study investigates the main drivers of uncertainties in simulated irrigated maize yield under historical conditions as well as scenarios of increased temperatures and altered irrigation water availability. Using APSIM, MONICA, and SIMPLACE crop models, we quantified the relative contributions of three irrigation water allocation strategies, three sowing dates, and three maize cultivars to the uncertainty in simulated yields. The water allocation strategies were derived from historical records of farmer's allocation patterns in drip-irrigation scheme of the Genil-Cabra region, Spain (2014-2017). By considering combinations of allocation strategies, the adjusted R2 values (showing the degree of agreement between simulated and observed yields) increased by 29% compared to unrealistic assumptions of considering only near optimal or deficit irrigation scheduling. The factor decomposition analysis based on historic climate showed that irrigation strategies was the main driver of uncertainty in simulated yields (66%). However, under temperature increase scenarios, the contribution of crop model and cultivar choice to uncertainty in simulated yields were as important as irrigation strategy. This was partially due to different model structure in processes related to the temperature responses. Our study calls for including information on irrigation strategies conducted by farmers to reduce the uncertainty in simulated yields at field scale.

Prediction of Genes Involved in Lung Cancer with a Systems Biology Approach Based on Comprehensive Gene Information.

Over the past few years, hundreds of genes have been reported in relation to lung cancer. Systems biology studies can help validate this association and find the most valid genes to use in the diagnosis and treatment. We reviewed the candidate genes for lung cancer in 120 published articles from September 1, 1993, to September 1, 2020. We obtained 134 up- and 36 downregulated genes for lung cancer in this article. The genes extracted from the articles were imported to Search Tool for the Retrieval of Interacting genes/proteins (STRING) to construct the protein-protein interaction (PPI) Network and pathway enrichment. GO ontology and Reactome databases were used for describing the genes, average length of survival, and constructing networks. Then, the ClusterONE plugin of Cytoscape software was used to analyze and cluster networks. Hubs and bottleneck nodes were defined based on their degree and betweenness. Common genes between the ClusterONE plugin and network analysis consisted of seven genes (BRCA1-TP53-CASP3-PLK1-VEGFA-MDM2-CCNB1 and PLK1), and two genes (PLK1 and TYMS) were selected as survival factors. Our drug-gene network showed that CASP3, BRCA1, TP53, VEGFA, and MDM2 are common genes that are involved in this network. Also, among the drugs recognized in the drug-gene network, five drugs such as paclitaxel, oxaliplatin, carboplatin, irinotecan, and cisplatin were examined in different studies. It seems that these seven genes, with further studies and confirmatory tests, could be potential markers for lung cancer, especially PLK1 that has a significant effect on the survival of patients. We provide the novel genes into the pathogenesis of lung cancer, and we introduced new potential biomarkers for this malignancy.

Engineering of Cytolethal Distending Toxin B by Its Reducing Immunogenicity and Maintaining Stability as a New Drug Candidate for Tumor Therapy; an In Silico Study.

The cytolethal distending toxin (CDT), Haemophilus ducreyi, is one of the bacterial toxins that have recently been considered for targeted therapies, especially in cancer therapies. CDT is an A-B2 exotoxin. Its catalytic subunit (CdtB) is capable of inducing DNA double strand breaks, cell cycle arrest and apoptosis in host eukaryotic cells. The sequence alignment indicates that the CdtB is structurally homologyr to phosphatases and deoxyribonucleases I (DNase I). Recently, it has been found that CdtB toxicity is mainly related to its nuclease activity. The immunogenicity of CDT can reduce its effectiveness in targeted therapies. However, the toxin can be very useful if its immunogenicity is significantly reduced. Detecting hotspot ectopic residues by computational servers and then mutating them to eliminate B-cell epitopes is a promising approach to reduce the immunogenicity of foreign protein-based therapeutics. By the mentioned method, in this study, we try to reduce the immunogenicity of the CdtB- protein sequence. This study initially screened residue of the CdtB is B-cell epitopes both linearly and conformationally. By overlapping the B-cell epitopes with the excluded conserve residues, and active and enzymatic sites, four residues were allowed to be mutated. There were two mutein options that show reduced antigenicity probability. Option one was N19F, G74I, and S161F with a VaxiJen score of 0.45 and the immune epitope database (IEDB) score of 1.80, and option two was N19F, G74I, and S161W with a VaxiJen score of 0.45 and IEDB score of 1.88. The 3D structure of the proposed sequences was evaluated and refined. The structural stability of native and mutant proteins was accessed through molecular dynamic simulation. The results showed that the mutations in the mutants caused no considerable changes in their structural stability. However, mutant 1 reveals more thermodynamic stability during the simulation. The applied approaches in this study can be used as rough guidelines for finding hot spot immunogen regions in the therapeutic proteins. Our results provide a new version of CdtB that, due to reduced immunogenicity and increased stability, can be used in toxin-based drugs such as immunotoxins.

Drought risk for agricultural systems in South Africa: Drivers, spatial patterns, and implications for drought risk management.

The regular drought episodes in South Africa highlight the need to reduce drought risk by both policy and local community actions. Environmental and socioeconomic factors in South Africa's agricultural system have been affected by drought in the past, creating cascading pressures on the nation's agro-economic and water supply systems. Therefore, understanding the key drivers of all risk components through a comprehensive risk assessment must be undertaken in order to inform proactive drought risk management. This paper presents, for the first time, a national drought risk assessment for irrigated and rainfed systems, that takes into account the complex interaction between different risk components. We use modeling and remote sensing approaches and involve national experts in selecting vulnerability indicators and providing information on human and natural drivers. Our results show that all municipalities have been affected by drought in the last 30 years. The years 1981-1982, 1992, 2016 and 2018 were marked as the driest years during the study period (1981-2018) compared to the reference period (1986-2015). In general, the irrigated systems are remarkably less often affected by drought than rainfed systems; however, most farmers on irrigated land are smallholders for whom drought impacts can be significant. The drought risk of rainfed agricultural systems is exceptionally high in the north, central and west of the country, while for irrigated systems, there are more separate high-risk hotspots across the country. The vulnerability assessment identified potential entry points for disaster risk reduction at the local municipality level, such as increasing environmental awareness, reducing land degradation and increasing total dam and irrigation capacity.

The use of remote sensing to derive maize sowing dates for large-scale crop yield simulations.

One of the major sources of uncertainty in large-scale crop modeling is the lack of information capturing the spatiotemporal variability of crop sowing dates. Remote sensing can contribute to reducing such uncertainties by providing essential spatial and temporal information to crop models and improving the accuracy of yield predictions. However, little is known about the impacts of the differences in crop sowing dates estimated by using remote sensing (RS) and other established methods, the uncertainties introduced by the thresholds used in these methods, and the sensitivity of simulated crop yields to these uncertainties in crop sowing dates. In the present study, we performed a systematic sensitivity analysis using various scenarios. The LINTUL-5 crop model implemented in the SIMPLACE modeling platform was applied during the period 2001-2016 to simulate maize yields across four provinces in South Africa using previously defined scenarios of sowing dates. As expected, the selected methodology and the selected threshold considerably influenced the estimated sowing dates (up to 51 days) and resulted in differences in the long-term mean maize yield reaching up to 1.7 t ha-1 (48% of the mean yield) at the province level. Using RS-derived sowing date estimations resulted in a better representation of the yield variability in space and time since the use of RS information not only relies on precipitation but also captures the impacts of socioeconomic factors on the sowing decision, particularly for smallholder farmers. The model was not able to reproduce the observed yield anomalies in Free State (Pearson correlation coefficient: 0.16 to 0.23) and Mpumalanga (Pearson correlation coefficient: 0.11 to 0.18) in South Africa when using fixed and precipitation rule-based sowing date estimations. Further research with high-resolution climate and soil data and ground-based observations is required to better understand the sources of the uncertainties in RS information and to test whether the results presented herein can be generalized among crop models with different levels of complexity and across distinct field crops.

Effects of soil- and climate data aggregation on simulated potato yield and irrigation water requirement.

Input data aggregation affects crop model estimates at the regional level. Previous studies have focused on the impact of aggregating climate data used to compute crop yields. However, little is known about the combined data aggregation effect of climate (DAEc) and soil (DAEs) on irrigation water requirement (IWR) in cool-temperate and spatially heterogeneous environments. The aims of this study were to quantify DAEc and DAEs of model input data and their combined impacts for simulated irrigated and rainfed yield and IWR. The Agricultural Production Systems sIMulator Next Generation model was applied for the period 1998-2017 across areas suitable for potato (Solanum tuberosum L.) in Tasmania, Australia, using data at 5, 15, 25 and 40 km resolution. Spatial variances of inputs and outputs were evaluated by the relative absolute difference (rAD¯) between the aggregated grids and the 5 km grids. Climate data aggregation resulted in a rAD¯ of 0.7-12.1%, with high values especially for areas with pronounced differences in elevation. The rAD¯ of soil data was higher (5.6-26.3%) than rAD¯ of climate data and was mainly affected by aggregation of organic carbon and maximum plant available water capacity (i.e. the difference between field capacity and wilting point in the effective root zone). For yield estimates, the difference among resolutions (5 km vs. 40 km) was more pronounced for rainfed (rAD¯ = 14.5%) than irrigated conditions (rAD¯ = 3.0%). The rAD¯ of IWR was 15.7% when using input data at 40 km resolution. Therefore, reliable simulations of rainfed yield require a higher spatial resolution than simulation of irrigated yields. This needs to be considered when conducting regional modelling studies across Tasmania. This study also highlights the need to separately quantify the impact of input data aggregation on model outputs to inform about data aggregation errors and identify those variables that explain these errors.

Global wheat production with 1.5 and 2.0°C above pre-industrial warming.

Efforts to limit global warming to below 2°C in relation to the pre-industrial level are under way, in accordance with the 2015 Paris Agreement. However, most impact research on agriculture to date has focused on impacts of warming >2°C on mean crop yields, and many previous studies did not focus sufficiently on extreme events and yield interannual variability. Here, with the latest climate scenarios from the Half a degree Additional warming, Prognosis and Projected Impacts (HAPPI) project, we evaluated the impacts of the 2015 Paris Agreement range of global warming (1.5 and 2.0°C warming above the pre-industrial period) on global wheat production and local yield variability. A multi-crop and multi-climate model ensemble over a global network of sites developed by the Agricultural Model Intercomparison and Improvement Project (AgMIP) for Wheat was used to represent major rainfed and irrigated wheat cropping systems. Results show that projected global wheat production will change by -2.3% to 7.0% under the 1.5°C scenario and -2.4% to 10.5% under the 2.0°C scenario, compared to a baseline of 1980-2010, when considering changes in local temperature, rainfall, and global atmospheric CO2 concentration, but no changes in management or wheat cultivars. The projected impact on wheat production varies spatially; a larger increase is projected for temperate high rainfall regions than for moderate hot low rainfall and irrigated regions. Grain yields in warmer regions are more likely to be reduced than in cooler regions. Despite mostly positive impacts on global average grain yields, the frequency of extremely low yields (bottom 5 percentile of baseline distribution) and yield inter-annual variability will increase under both warming scenarios for some of the hot growing locations, including locations from the second largest global wheat producer-India, which supplies more than 14% of global wheat. The projected global impact of warming <2°C on wheat production is therefore not evenly distributed and will affect regional food security across the globe as well as food prices and trade.

Climate change impact and adaptation for wheat protein.

Wheat grain protein concentration is an important determinant of wheat quality for human nutrition that is often overlooked in efforts to improve crop production. We tested and applied a 32-multi-model ensemble to simulate global wheat yield and quality in a changing climate. Potential benefits of elevated atmospheric CO2 concentration by 2050 on global wheat grain and protein yield are likely to be negated by impacts from rising temperature and changes in rainfall, but with considerable disparities between regions. Grain and protein yields are expected to be lower and more variable in most low-rainfall regions, with nitrogen availability limiting growth stimulus from elevated CO2 . Introducing genotypes adapted to warmer temperatures (and also considering changes in CO2 and rainfall) could boost global wheat yield by 7% and protein yield by 2%, but grain protein concentration would be reduced by -1.1 percentage points, representing a relative change of -8.6%. Climate change adaptations that benefit grain yield are not always positive for grain quality, putting additional pressure on global wheat production.

Multimodel ensembles improve predictions of crop-environment-management interactions.

A recent innovation in assessment of climate change impact on agricultural production has been to use crop multimodel ensembles (MMEs). These studies usually find large variability between individual models but that the ensemble mean (e-mean) and median (e-median) often seem to predict quite well. However, few studies have specifically been concerned with the predictive quality of those ensemble predictors. We ask what is the predictive quality of e-mean and e-median, and how does that depend on the ensemble characteristics. Our empirical results are based on five MME studies applied to wheat, using different data sets but the same 25 crop models. We show that the ensemble predictors have quite high skill and are better than most and sometimes all individual models for most groups of environments and most response variables. Mean squared error of e-mean decreases monotonically with the size of the ensemble if models are added at random, but has a minimum at usually 2-6 models if best-fit models are added first. Our theoretical results describe the ensemble using four parameters: average bias, model effect variance, environment effect variance, and interaction variance. We show analytically that mean squared error of prediction (MSEP) of e-mean will always be smaller than MSEP averaged over models and will be less than MSEP of the best model if squared bias is less than the interaction variance. If models are added to the ensemble at random, MSEP of e-mean will decrease as the inverse of ensemble size, with a minimum equal to squared bias plus interaction variance. This minimum value is not necessarily small, and so it is important to evaluate the predictive quality of e-mean for each target population of environments. These results provide new information on the advantages of ensemble predictors, but also show their limitations.

Climate change effect on wheat phenology depends on cultivar change.

Changing crop phenology is considered an important bio-indicator of climate change, with the recent warming trend causing an advancement in crop phenology. Little is known about the contributions of changes in sowing dates and cultivars to long-term trends in crop phenology, particularly for winter crops such as winter wheat. Here, we analyze a long-term (1952-2013) dataset of phenological observations across western Germany and observations from a two-year field experiment to directly compare the phenologies of winter wheat cultivars released between 1950 and 2006. We found a 14-18% decline in the temperature sum required from emergence to flowering for the modern cultivars of winter wheat compared with the cultivars grown in the 1950s and 1960s. The trends in the flowering day obtained from a phenology model parameterized with the field observations showed that changes in the mean temperature and cultivar properties contributed similarly to the trends in the flowering day, whereas the effects of changes in the sowing day were negligible. We conclude that the single-cultivar concept commonly used in climate change impact assessments results in an overestimation of winter wheat sensitivity to increasing temperature, which suggests that studies on climate change effects should consider changes in cultivars.

Author Correction: The uncertainty of crop yield projections is reduced by improved temperature response functions.

Nature Plants 3, 17102 (2017); published online 17 July 2017; corrected online 27 September 2017.

Erratum: The uncertainty of crop yield projections is reduced by improved temperature response functions.

This corrects the article DOI: 10.1038/nplants.2017.102.

Erratum: The uncertainty of crop yield projections is reduced by improved temperature response functions.

This corrects the article DOI: 10.1038/nplants.2017.102.

The uncertainty of crop yield projections is reduced by improved temperature response functions.

Increasing the accuracy of crop productivity estimates is a key element in planning adaptation strategies to ensure global food security under climate change. Process-based crop models are effective means to project climate impact on crop yield, but have large uncertainty in yield simulations. Here, we show that variations in the mathematical functions currently used to simulate temperature responses of physiological processes in 29 wheat models account for >50% of uncertainty in simulated grain yields for mean growing season temperatures from 14 °C to 33 °C. We derived a set of new temperature response functions that when substituted in four wheat models reduced the error in grain yield simulations across seven global sites with different temperature regimes by 19% to 50% (42% average). We anticipate the improved temperature responses to be a key step to improve modelling of crops under rising temperature and climate change, leading to higher skill of crop yield projections.