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Confronting false discoveries in single-cell differential expression

Mark Andrew Anderson, Quentin Barraud, Grégoire Courtine, Matthieu Pierre Gautier, Rémi Bernard René Hudelle, Thomas Haynes Hutson, Nicholas David James, Claudia Kathe, Gioele La Manno, Michael Alexander Skinnider, Jordan Squair

Differential expression analysis of single-cell transcriptomics allows scientists to dissect cell-type-specific responses to biological perturbations. Here, the authors show that many commonly used methods are biased and can produce false discoveries. Differential expression analysis in single-cell transcriptomics enables the dissection of cell-type-specific responses to perturbations such as disease, trauma, or experimental manipulations. While many statistical methods are available to identify differentially expressed genes, the principles that distinguish these methods and their performance remain unclear. Here, we show that the relative performance of these methods is contingent on their ability to account for variation between biological replicates. Methods that ignore this inevitable variation are biased and prone to false discoveries. Indeed, the most widely used methods can discover hundreds of differentially expressed genes in the absence of biological differences. To exemplify these principles, we exposed true and false discoveries of differentially expressed genes in the injured mouse spinal cord.

NATURE PORTFOLIO2021

Structured nanoscale metallic glass fibres with extreme aspect ratios

Grégoire Courtine, Reinis Ignatans, Nicholas David James, Güven Kurtuldu, Stéphanie Lacour, Dang Tùng Nguyen, Yunpeng Qu, Inès Richard, Giuseppe Schiavone, Fabien Sorin, Jordan Squair, Vasiliki Tileli, Wei Yan

Micro- and nanoscale metallic glasses offer exciting opportunities for both fundamental research and applications in healthcare, micro-engineering, optics and electronics. The scientific and technological challenges associated with the fabrication and utilization of nanoscale metallic glasses, however, remain unresolved. Here, we present a simple and scalable approach for the fabrication of metallic glass fibres with nanoscale architectures based on their thermal co-drawing within a polymer matrix with matched rheological properties. Our method yields well-ordered and uniform metallic glasses with controllable feature sizes down to a few tens of nanometres, and aspect ratios greater than 10(10). We combine fluid dynamics and advanced in situ transmission electron microscopy analysis to elucidate the interplay between fluid instability and crystallization kinetics that determines the achievable feature sizes. Our approach yields complex fibre architectures that, combined with other functional materials, enable new advanced all-in-fibre devices. We demonstrate in particular an implantable metallic glass-based fibre probe tested in vivo for a stable brain-machine interface that paves the way towards innovative high-performance and multifunctional neuro-probes. Metallic glasses possess intriguing functional properties, but controlled fabrication with nanoscale feature sizes remains challenging. Thermal co-drawing within a viscosity-matched polymer matrix enables the fabrication of uniform metallic glass fibres with feature sizes down to a few tens of nanometres, arbitrary transverse geometries and aspect ratios greater than 10(10).

NATURE PUBLISHING GROUP2020

ErbB receptor signaling directly controls oligodendrocyte progenitor cell transformation and spontaneous remyelination after spinal cord injury

Nicholas David James

We recently discovered a novel role for neuregulin-1 (Nrg1) signaling in mediating spontaneous regenerative processes and functional repair after spinal cord injury (SCI). We revealed that Nrg1 is the molecular signal responsible for spontaneous functional remyelination of dorsal column axons by peripheral nervous system (PNS)-like Schwann cells after SCI. Here, we investigate whether Nrg1/ErbB signaling controls the unusual transformation of centrally derived progenitor cells into these functional myelinating Schwann cells after SCI using a fate-mapping/lineage tracing approach. Specific ablation of Nrg1-ErbB receptors in central platelet-derived growth factor receptor alpha (PDGFR)-derived lineage cells (using PDGFRCreERT2/Tomato-red reporter mice crossed with ErbB3fl/fl/ErbB4fl/fl mice) led to a dramatic reduction in P0-positive remyelination in the dorsal columns following spinal contusion injury. Central myelination, assessed by Olig2 and proteolipid protein expression, was unchanged. Loss of ErbB signaling in PDGFR lineage cells also significantly impacted the degree of spontaneous locomotor recovery after SCI, particularly in tests dependent on proprioception. These data have important implications, namely (a) cells from the PDGFR-expressing progenitor lineage (which are presumably oligodendrocyte progenitor cells, OPCs) can differentiate into remyelinating PNS-like Schwann cells after traumatic SCI, (b) this process is controlled by ErbB tyrosine kinase signaling, and (c) this endogenous repair mechanism has significant consequences for functional recovery after SCI. Thus, ErbB tyrosine kinase receptor signaling directly controls the transformation of OPCs from the PDGFR-expressing lineage into PNS-like functional remyelinating Schwann cells after SCI.

2019