More Like this

1. Trellis tree-based analysis reveals stromal regulation of patient-derived organoid drug responses

   https://doi.org/10.1016/j.cell.2023.11.005  

   Ramos_Zapatero, Maria; Tong, Alexander; Opzoomer, James W; O’Sullivan, Rhianna; Cardoso_Rodriguez, Ferran; Sufi, Jahangir; Vlckova, Petra; Nattress, Callum; Qin, Xiao; Claus, Jeroen; et al (December 2023, Cell)

   Patient-derived organoids (PDOs) can model personalized therapy responses; however, current screening technologies cannot reveal drug response mechanisms or how tumor microenvironment cells alter therapeutic performance. To address this, we developed a highly multiplexed mass cytometry platform to measure post- translational modification (PTM) signaling, DNA damage, cell-cycle activity, and apoptosis in >2,500 colorectal cancer (CRC) PDOs and cancer-associated fibroblasts (CAFs) in response to clinical therapies at single-cell resolution. To compare patient- and microenvironment-specific drug responses in thousands of single-cell da- tasets, we developed ‘‘Trellis’’—a highly scalable, tree-based treatment effect analysis method. Trellis single- cell screening revealed that on-target cell-cycle blockage and DNA-damage drug effects are common, even in chemorefractory PDOs. However, drug-induced apoptosis is rarer, patient-specific, and aligns with cancer cell PTM signaling. We find that CAFs can regulate PDO plasticity—shifting proliferative colonic stem cells (proCSCs) to slow-cycling revival colonic stem cells (revCSCs) to protect cancer cells from chemotherapy. 

   more » « less
2. Laser-Induced Nuclear Damage Signaling and Communication in Astrocyte Networks Through Parp-Dependent Calcium Oscillations

   https://doi.org/10.3389/fphy.2021.598930  

   Wakida, Nicole M.; Ha, Ryan D.; Kim, Edward K.; Kong, Xiangduo; Yokomori, Kyoko; Berns, Michael W. (April 2021, Frontiers in Physics)

   null (Ed.)

   Astrocytes are known to respond to various perturbations with oscillations of calcium, including to cellular injury. Less is known about astrocytes’ ability to detect DNA/nuclear damage. This study looks at changes in calcium signaling in response to laser-induced nuclear damage using a NIR Ti:Sapphire laser. Primary astrocytes derived from genetically engineered mice expressing G6Campf genetically encoded calcium indicator were imaged in response to laser induced injury. Combining laser nanosurgery with calcium imaging of primary astrocytes allow for spatial and temporal observation of the astrocyte network in response to nuclear damage. Nuclear damage resulted in a significant increase in calcium peak frequency, in nuclear damaged cells and astrocytes directly attached to it. The increase in calcium event frequency observed in response to damage and the transfer to neighboring cells was not observed in cytoplasm damaged cells. Targeted astrocytes and attached neighboring cells treated with Poly (ADP-ribose) polymerase inhibitor have a significantly lower peak frequency following laser damage to the nucleus. These results indicate the increase in calcium peak frequency following nuclear damage is poly (ADP-ribose) polymerase dependent. 

   more » « less
3. Global Transcriptome Analysis of Rice Seedlings in Response to Extracellular ATP

   https://doi.org/10.1016/j.rsci.2025.03.002  

   Lim, Chaemyeong; Lee, Sae Hyun; Lee, Haeun; Park, So-Yon; Kang, Kiyoon; Yoon, Hyeryung; Yang, Tae-Jin; Stacey, Gary; Paek, Nam-Chon; Cho, Sung-Hwan (May 2025, Rice Science)

   Herbivorous insects and pathogens cause severe damage to rice tissues, affecting yield and grain quality. Damaged cells trigger downstream defense responses through various signals. Extracellular ATP (eATP), a signaling molecule released during mechanical cell damage, is considered a constitutive damage-associated molecular pattern (DAMP), which is crucial for initiating plant defense responses. Thus, understanding how rice plants cope with DAMPs such as eATP is essential. Here, we found that exogenous ATP affected rice growth and development, cell wall composition, chloroplast development, and cell death. Subsequent global transcriptome analysis revealed that several pathways were involved in the eATP response, including genes related to cell surface receptors, cell wall organization, chlorophyll biosynthesis, heat and temperature stimulation, epigenetic regulation, and reactive oxygen species metabolism. Cell surface receptors, including members of the lectin receptor-like kinases (LecRKs), were found to participate in the eATP response. We further investigated ATP-induced genes in T-DNA activation mutants of OsLecRKs, demonstrating their involvement in eATP signaling in rice. This study confirms a DAMP-mediated transcriptional response in plants and provides novel candidates for advancing resistant rice breeding against insect herbivores and pathogens. 

   more » « less
4. A non-canonical, interferon-independent signaling activity of cGAMP triggers DNA damage response signaling

   https://doi.org/10.1038/s41467-021-26240-9  

   Banerjee, Daipayan; Langberg, Kurt; Abbas, Salar; Odermatt, Eric; Yerramothu, Praveen; Volaric, Martin; Reidenbach, Matthew A.; Krentz, Kathy J.; Rubinstein, C. Dustin; Brautigan, David L.; et al (December 2021, Nature Communications)

   null (Ed.)

   Abstract Cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), produced by cyclic GMP-AMP synthase (cGAS), stimulates the production of type I interferons (IFN). Here we show that cGAMP activates DNA damage response (DDR) signaling independently of its canonical IFN pathways. Loss of cGAS dampens DDR signaling induced by genotoxic insults. Mechanistically, cGAS activates DDR in a STING-TBK1-dependent manner, wherein TBK1 stimulates the autophosphorylation of the DDR kinase ATM, with the consequent activation of the CHK2-p53-p21 signal transduction pathway and the induction of G1 cell cycle arrest. Despite its stimulatory activity on ATM, cGAMP suppresses homology-directed repair (HDR) through the inhibition of polyADP-ribosylation (PARylation), in which cGAMP reduces cellular levels of NAD + ; meanwhile, restoring NAD + levels abrogates cGAMP-mediated suppression of PARylation and HDR. Finally, we show that cGAMP also activates DDR signaling in invertebrate species lacking IFN ( Crassostrea virginica and Nematostella vectensis ), suggesting that the genome surveillance mechanism of cGAS predates metazoan interferon-based immunity. 

   more » « less
5. pLMSNOSite: an ensemble-based approach for predicting protein S-nitrosylation sites by integrating supervised word embedding and embedding from pre-trained protein language model

   Pawel, Pratyush; Suresh, Pokharel; Hiroto, Saigo; Dukka, KC (February 2023, BMC bioinformatics)

   Protein S-nitrosylation (SNO) plays a key role in transferring nitric oxide-mediated signals in both animals and plants and has emerged as an important mechanism for regulating protein functions and cell signaling of all main classes of protein. It is involved in several biological processes including immune response, protein stability, transcription regulation, post translational regulation, DNA damage repair, redox regulation, and is an emerging paradigm of redox signaling for protection against oxidative stress. The development of robust computational tools to predict protein SNO sites would contribute to further interpretation of the pathological and physiological mechanisms of SNO. 

   more » « less