SynergyFinder (https://synergyfinder.fimm.fi) is a stand-alone web-application for interactive analysis and visualization of drug combination screening data. Since its first release in 2017, SynergyFinder has become a widely used web-tool both for the discovery of novel synergistic drug combinations in pre-clinical model systems (e.g. cell lines or primary patient-derived cells), and for better understanding of mechanisms of combination treatment efficacy or resistance. Here, we describe the latest version of SynergyFinder (release 2.0), which has extensively been upgraded through the addition of novel features supporting especially higher-order combination data analytics and exploratory visualization of multi-drug synergy patterns, along with automated outlier detection procedure, extended curve-fitting functionality and statistical analysis of replicate measurements. A number of additional improvements were also implemented based on the user requests, including new visualization and export options, updated user interface, as well as enhanced stability and performance of the web-tool. With these improvements, SynergyFinder 2.0 is expected to greatly extend its potential applications in various areas of multi-drug combinatorial screening and precision medicine.

SynergyFinder 2.0: visual analytics of multi-drug combination synergies.

Fungi interact with plants in various ways, with each interaction giving rise to different alterations in both partners. While fungal pathogens have detrimental effects on plant physiology, mutualistic fungi augment host defence responses to pathogens and/or improve plant nutrient uptake. Tropic growth towards plant roots or stomata, mediated by chemical and topographical signals, has been described for several fungi, with evidence of species-specific signals and sensing mechanisms. Fungal partners secrete bioactive molecules such as small peptide effectors, enzymes and secondary metabolites which facilitate colonization and contribute to both symbiotic and pathogenic relationships. There has been tremendous advancement in fungal molecular biology, omics sciences and microscopy in recent years, opening up new possibilities for the identification of key molecular mechanisms in plant–fungal interactions, the power of which is often borne out in their combination. Our fragmentary knowledge on the interactions between plants and fungi must be made whole to understand the potential of fungi in preventing plant diseases, improving plant productivity and understanding ecosystem stability. Here, we review innovative methods and the associated new insights into plant–fungal interactions.

Friends or foes? Emerging insights from fungal interactions with plants

Macrophomina phaseolina is a generalist soil-borne fungus present all over the world. It cause diseases such as stem and root rot, charcoal rot and seedling blight. Under high temperatures and low soil moisture, this fungus can cause substantial yield losses in crops such as soybean, sorghum and groundnut. The wide host range and high persistence of M. phaseolina in soil as microsclerotia make disease control challenging. Therefore, understanding the basis of the pathogenicity mechanisms as well as its interactions with host plants is crucial for controlling the pathogen. In this work, we aim to describe the general characteristics and pathogenicity mechanisms of M. phaseolina, as well as the hosts defense response. We also review the current methods and most promising forecoming ones to reach a responsible control of the pathogen, with minimal impacts to the environment and natural resources.

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Macrophomina phaseolina: General Characteristics of Pathogenicity and Methods of Control

Edible plant oil (EPO) is an indispensable nutritional resource for human health. Various cultivars of oil-bearing plants are grown worldwide, and the chemical compositions of different plant oils are diverse. The extremely complex components in oils lead to diverse standards for evaluating the quality and safety of different EPOs. The environment poses great challenges to the EPO safety and quality during the entire industrial chain, including plant cultivation, harvesting, oil processing, and storage. Environmental risk factors include heavy metal or pesticide residue pollution, insect or harmful microbial infestation, and rancidity. Here, the diverse components in oil and various oil-producing processes are discussed, including plant species, oil yield, and composition complexity, environmental factors that degrade oil quality. Additionally, we propose a whole-industrial-chain monitoring system instead of current single-link-monitoring approach by monitoring and tracking the quality and safety of EPOs during the entire process of plant cultivation, raw materials harvest, oil process, and EPOs storage. This will provide guidance for monitoring the quality and safety of EPOs, which were challenged by the deteriorating environment.

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Edible Plant Oil: Global Status, Health Issues, and Perspectives.

Rhizoctonia solani is a nectrotrophic fungal pathogen that causes billions of dollars of damage to agriculture worldwide and infects a broad host range including wheat, rice, potato and legumes. In this study we identify wheat genes that are differentially expressed in response to the R. solani isolate, AG8, using microarray technology. A significant number of wheat genes identified in this screen were involved in reactive oxygen species (ROS) production and redox regulation. Levels of ROS species were increased in wheat root tissue following R. solani infection as determined by Nitro Blue Tetrazolium (NBT), 3,3'-diaminobenzidine (DAB) and titanium sulphate measurements. Pathogen/ROS related genes from R. solani were also tested for expression patterns upon wheat infection. TmpL, a R. solani gene homologous to a gene associated with ROS regulation in Alternaria brassicicola, and OAH, a R. solani gene homologous to oxaloacetate acetylhydrolase which has been shown to produce oxalic acid in Sclerotinia sclerotiorum, were highly induced in R. solani when infecting wheat. We speculate that the interplay between the wheat and R. solani ROS generating proteins may be important for determining the outcome of the wheat/R. solani interaction.

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Reactive Oxygen Species Play a Role in the Infection of the Necrotrophic Fungi, Rhizoctonia solani in Wheat.

M. phaseolina, a global devastating necrotrophic fungal pathogen causes charcoal rot disease in more than 500 host plants. With the aim of understanding the plant-necrotrophic pathogen interaction associated with charcoal rot disease of jute, biochemical approach was attempted to study cellular nitric oxide production under diseased condition. This is the first report on M. phaseolina infection in Corchorus capsularis (jute) plants which resulted in elevated nitric oxide, reactive nitrogen species and S nitrosothiols production in infected tissues. Time dependent nitric oxide production was also assessed with 4-Amino-5-Methylamino-2′,7′-Difluorofluorescein Diacetate using single leaf experiment both in presence of M. phaseolina and xylanases obtained from fungal secretome. Cellular redox status and redox active enzymes were also assessed during plant fungal interaction. Interestingly, M. phaseolina was found to produce nitric oxide which was detected in vitro inside the mycelium and in the surrounding medium. Addition of mammalian nitric oxide synthase inhibitor could block the nitric oxide production in M. phaseolina. Bioinformatics analysis revealed nitric oxide synthase like sequence with conserved amino acid sequences in M. phaseolina genome sequence. In conclusion, the production of nitric oxide and reactive nitrogen species may have important physiological significance in necrotrophic host pathogen interaction.

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Nitric oxide production by necrotrophic pathogen Macrophomina phaseolina and the host plant in charcoal rot disease of jute: complexity of the interplay between necrotroph-host plant interactions.

The extracellular role of DNA damage repair protein APE1 in regulation of IL-6 expression

Regulation of cell cycle and stress responses under nitrosative stress in Schizosaccharomyces pombe.

Fluorouracil (5-FU) remains a first-line chemotherapeutic agent for colorectal cancer. However, a subset of colorectal cancer patients who have defective mismatch-repair (dMMR) pathway show resistance to 5-FU. Here, we demonstrate that the efficacy of 5-FU in dMMR colorectal cancer cells is largely dependent on the DNA base excision repair (BER) pathway. Downregulation of APE1, a key enzyme in the BER pathway, decreases IC50 of 5-FU in dMMR colorectal cancer cells by 10-fold. Furthermore, we discover that the facilitates chromatin transcription (FACT) complex facilitates 5-FU repair in DNA via promoting the recruitment and acetylation of APE1 (AcAPE1) to damage sites in chromatin. Downregulation of FACT affects 5-FU damage repair in DNA and sensitizes dMMR colorectal cancer cells to 5-FU. Targeting the FACT complex with curaxins, a class of small molecules, significantly improves the 5-FU efficacy in dMMR colorectal cancer in vitro (∼50-fold decrease in IC50) and in vivo xenograft models. We show that primary tumor tissues of colorectal cancer patients have higher FACT and AcAPE1 levels compared with adjacent nontumor tissues. Additionally, there is a strong clinical correlation of FACT and AcAPE1 levels with colorectal cancer patients' response to chemotherapy. Together, our study demonstrates that targeting FACT with curaxins is a promising strategy to overcome 5-FU resistance in dMMR colorectal cancer patients.

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Targeting Histone Chaperone FACT Complex Overcomes 5-Fluorouracil Resistance in Colon Cancer

Myoglobin (Mb) maturation involves heme incorporation as a final step. We investigated a role for heat shock protein (hsp) 90 in Mb maturation in C2C12 skeletal muscle myoblasts and cell lines. We found the following: 1) Hsp90 directly interacts preferentially with heme-free Mb both in purified form and in cells. 2) Hsp90 drives heme insertion into apoprotein-Mb in an ATP-dependent process. 3) During differentiation of C2C12 myoblasts into myotubes, the apo-Mb-hsp90 complex associates with 5 cell cochaperons, Hsp70, activator of hsp90 ATPase protein 1 (Aha1), alanyl-tRNA synthetase domain containing 1 (Aarsd1), cell division cycle 37 (Cdc37), and stress induced phosphoprotein 1 (STIP1) in a pattern that is consistent with their enabling Mb maturation. 4) Mb heme insertion was significantly increased in cells that had a functional soluble guanylyl cyclase (sGC)-cGMP signaling pathway and was diminished upon small interfering RNA knockdown of sGCβ1 or upon overexpression of a phosphodiesterase to prevent cGMP buildup. Together, our findings suggest that hsp90 works in concert with cochaperons (Hsp70, Aha1, Aarsd1, STIP1, and Cdc37) and an active sGC-cGMP signaling pathway to promote heme insertion into immature apo-Mb, and thus generate functional Mb during muscle myotube formation. This fills gaps in our understanding and suggests new ways to potentially control these processes.-Ghosh, A., Dai, Y., Biswas, P., Stuehr, D. J. Myoglobin maturation is driven by the hsp90 chaperone machinery and by soluble guanylyl cyclase.

Pranjal Biswas

Papers

Nitric oxide production by necrotrophic pathogen Macrophomina phaseolina and the host plant in charcoal rot disease of jute: complexity of the interplay between necrotroph-host plant interactions.

The extracellular role of DNA damage repair protein APE1 in regulation of IL-6 expression

Regulation of cell cycle and stress responses under nitrosative stress in Schizosaccharomyces pombe.

Targeting Histone Chaperone FACT Complex Overcomes 5-Fluorouracil Resistance in Colon Cancer

Myoglobin maturation is driven by the hsp90 chaperone machinery and by soluble guanylyl cyclase.