Articles in 2020

Natalia Tikhenko et al. investigate the genetic contribution of the wheat chromosome 1D to its development and evolution. They find a novel locus, DEFECTIVE ENDOSPERM-D1, on the long arm of 1D that is required for normal endosperm development as its absence leads to non-viable grains and altered grain shape.

Sonal Prasad et al. identify several mutations in the radixin (RDX) gene that are associated with early-life hearing loss. Using a guinea pig model, they propose that radixin helps convert sound into electrical signals in the mature inner ear.

Steven Chen et al. develop an automated, time-lapsed, high-content screen to quantify the responses of Schistosoma mansoni larvae to chemical insult. They apply their method to evaluate 45 static and kinetic response endpoints for seven drugs and screen 1323 approved drugs. Their work identifies anti-schistosomal compounds and underscores the value of quantifying motion in phenotypic drug discovery.

DeNies et al. identify a new mechanism of intracellular GPCR signalling. Using CXC chemokine receptor 4 (CXCR4) as a model, they show that upon stimulation with receptor agonists that not only plasma membrane-localized receptors, but also intracellular CXCR4 molecules are post-translationally modified and regulate transcription. This study suggests that a small pool of plasma membrane-localized GPCRs can activate internal receptor-dependent signaling, and that β-arrestin-1 mediates this activation.

Yao Yao et al. perform transcriptome-wide association analysis through integration of gene expression data and results of a previously-published genome-wide association study for neutrophil count. They find 34 independent genomic regions associated with expression changes and show that knockout of one candidate gene, TAF9, in CD34⁺ progenitor cells increases neutrophil maturation in vitro.

Oguchi et al. developed an in-house sequencing system to spatially decode DNA barcode molecules at single-molecule resolution. They obtain an average read length of 20 nucleotides with an error rate of less than 5% per nucleotide. Leveraging this system, they devised a molecular foot printing method that can be applied spatial proteomics as well as spatial transcriptomics.

Dumitru et al. probe the ligand-binding mechanism and activation of the human G protein-coupled C5a receptor (C5aR) and discover a cooperativity between the two orthosteric binding sites. Their findings, probing the dynamic aspects of receptor–ligand interaction, are valuable to develop a better understanding of GPCR activation and signalling.

Wu et al. demonstrate utility of a novel, ultrahigh ductility Mg alloy-based biodegradable stent in vitro and in vivo for use in congenital disorders like pediatric laryngotracheal stenosis. Tested in both bioreactor system and rabbit airway model, these stents display higher corrosion resistance and better in vivo degradation without affecting growth of rabbit airway.

Qianxing Mo et al. identify basal and luminal integrative subtypes of muscle-invasive bladder cancer (MIBC) using multi-omics data from The Cancer Genome Atlas. Using a gene panel for classification of MIBC derived from gene expression data, they find that the basal subtype is associated with worse survival in patients receiving no neoadjuvant chemotherapy (NAC), but better survival in patients receiving cisplatin-based NAC and further identify genes associated with response to PD-L1 blockade immunotherapy, suggesting potential clinical use of these genes’ expression signature.

Tapia-Alveal, Olsen and Worgall develop a novel strategy for patient-specific multiple myeloma diagnostics platform using DNA aptamers. The high affinity DNA aptamers enabled detection of minimal residual disease (MRD) when conventional MRD methods assessed complete remission and are adaptable to multiple diagnostic formats including point-of-care devices.

Nina Muñoz et al. present a novel thermal ablation technique, termed molecularly targeted photothermal ablation (MTPA) that generates hyperthermia specifically within tumor tissue in a clinically-relevant rat model of liver cancer. They further show that MTPA modulates the intratumoral immune profile toward stronger tumor immunogenicity while reducing the release of oncogenic cytokines relative to conventional ablation techniques.

Kennedy et al. report the pharmacological and in vivo profiling of two small molecule PAR2 inhibitors and an agonist. They conclude that while the small molecule agonist and one of the inhibitors bind to the orthosteric PAR2 binding site, the other inhibitor is a negative allosteric modulator, highlighting two distinct mechanisms of inhibition that could be targeted for future development of drugs that modulate PAR2.

Jinghua Yang et al. provide the de novo assemblies of the transcriptomes of wasabi, horseradish and mustard to examine the evolution of specialized glucosinolates. This study demonstrates convergent evolution of super-accumulation of sinigrin in these taxa and may allow for potential strategies to engineer metabolic pathways of bioactive compounds for human food sources or pharmaceutical purposes.

Yu et al. provide evidence that Ustilago maydis employs two structurally distinct telomere-binding proteins to perform complementary functions in telomere maintenance in this organism. While UmTay1 regulates primarily telomere replication and recombination, UmTrf2 is responsible for telomere protection.

Romel Somwar et al. find that cancer-causing NTRK gene fusions resistant to one form of inhibitor therapy can be resistant to other inhibitor types. Using molecular simulations, they show that some NTRK1 mutations resistant to the type I inhibitor larotrectinib are hypersensitive to the type II inhibitor altiratinib, potentially due to the introduction of a sulfur moiety in the kinase binding pocket.

Using single-cell RNA sequencing, Dong, Miao, Wang et al. profile the transcriptomes of 21,292 cells from biopsies of 6 castration-resistant prostate cancers. They find that all neuroendocrine tumor cells display a luminal-like epithelial phenotype, providing insights into the cellular states underlying neuroendocrine transdifferentiation in human prostate cancer.

Takayoshi Ishii et al. report that two functional centromere-specific histone H3 (CENH3) paralogs with different centromere occupancy among different tissue types present in diploid cowpea. They demonstrate that CENH3.1 of cowpea is essential for normal plant growth and reproduction, while CENH3.2 is a gene likely to be undergoing early pseudogenization.

Yuan et al. characterise metabolic profiles of human mesenchymal stem cells (hMSCs) during cell expansion in culture. They find that late passage hMSCs exhibit a NAD + /NADH redox cycle imbalance and that adding NAD + precursor nicotinamide restores mitochondrial fitness and cellular homeostasis in senescent hMSCs indicating a possible route to preserve hMSC homeostasis for therapeutic use.

Laflamme and Mekhail discuss emerging nuclear roles for LLPS in genome organization, gene expression and DNA repair, highlighting the emerging notion that biomolecular condensates regulate the sequential engagement of molecules in multistep biological processes.

In this Perspective, Axel Newton and Andrew Pask examine the role of the Runt-related transcription factor 2 (RUNX2) QA repeat during skeletal development and discuss how its emergence and expansion may have facilitated the evolution of morphological novelty in vertebrates.