Biology subjects

Martin, S. A.

Publications and source records attributed to Martin, S. A..

4 recordsLinked to original sources

bioRxiv2022

Single cell transcriptomics of Atlantic salmon (Salmo salar L.) liver reveals cellular heterogeneity and immunological responses to challenge by Aeromonas salmonicida

The liver is a multitasking organ with essential functions for vertebrate health spanning metabolism and immunity. In contrast to mammals, our understanding of liver cellular heterogeneity and its role in regulating immunological status remains poorly defined in fishes. Addressing this knowledge gap, we generated a transcriptomic atlas of 47,432 nuclei isolated from the liver of Atlantic salmon (Salmo salar L.) contrasting control fish with those challenged with a pathogenic strain of Aeromonas salmonicida, a problematic bacterial pathogen in global aquaculture. We identified the major liver cell types and their sub-populations, revealing poor conservation of many hepatic cell marker genes utilized in mammals, while identifying novel heterogeneity within the hepatocyte, lymphoid, and myeloid lineages. This included polyploid hepatocytes, multiple T cell populations including {gamma}{delta} T cells, and candidate populations of monocytes/macrophages/dendritic cells. A dominant hepatocyte population radically remodeled its transcriptome following infection to activate the acute phase response and other defense functions, while repressing routine functions such as metabolism. These defense-specialized hepatocytes showed strong activation of genes controlling protein synthesis and secretion, presumably to support the release of acute phase proteins into circulation. The infection response further involved up-regulation of numerous genes in an immune-cell specific manner, reflecting functions in pathogen recognition and killing, antigen presentation, phagocytosis, regulation of inflammation, B cell differentiation and T cell activation. Overall, this study greatly enhances our understanding of the multifaceted role played by liver cells in immune defense and metabolic remodeling following infection and provides many novel cell-specific marker genes to empower future studies of this organ in fishes.

immunology↗

bioRxiv2022

Transcriptomic response to ISAV infection in the gills, head kidney and spleen of resistant and susceptible Atlantic salmon

BackgroundInfectious Salmonid Anaemia virus (ISAV) is an orthomyxovirus responsible of large losses in Atlantic salmon (Salmo salar) aquaculture. Current available treatments and vaccines are not fully effective, and therefore selective breeding to produce ISAV-resistant strains of Atlantic salmon (Salmo salar) is a high priority for the industry. Genomic selection and potentially genome editing can be applied to enhance the disease resistance of aquaculture stocks, and both approaches can benefit from increased knowledge on the genomic mechanisms of resistance to ISAV. To improve our understanding of the mechanisms underlying resistance to ISAV in Atlantic salmon we performed a transcriptomic study in ISAV-infected salmon with contrasting levels of resistance to this virus. ResultsThree different tissues (gills, head kidney and spleen) were collected on 12 resistant and 12 susceptible fish at three timepoints (pre-challenge, 7 and 14 days post infection) and RNA sequenced. The transcriptomes of Infected and non-infected fish and of resistant and susceptible fish were compared at each timepoint. The results show that the responses to ISAV are organ-specific; an important response to the infection was observed in the head kidney, with up-regulation of immune processes such as interferon and NLR pathways, while in gills and spleen the response was more moderate. In addition to immune related genes our results suggest that other processes such as ubiquitination or ribosomal processing are important during early infection to ISAV. Moreover, the comparison between resistant and susceptible have also highlighted some interesting genes related to ubiquitination, intracellular transport or the inflammasome. ConclusionsAtlantic salmon infection by ISAV revealed an organ-specific response, implying differential function during the infection. An early immune response was observed in the head kidney, while gills and spleen showed modest responses in comparison. Comparison between resistance and susceptible samples have highlighted genes of interest for further studies, for instance those related to ubiquitination or the inflammasome.

genomics↗

bioRxiv2021

Targeted therapy for LIMD1-deficient non-small cell lung cancer subtypes.

An early event in lung oncogenesis is loss of the tumour suppressor gene LIMD1 (LIM domains containing 1); this encodes a scaffold protein, which suppresses tumourigenesis via a number of different mechanisms. Approximately 45% of non-small cell lung cancers (NSCLC) are deficient in LIMD11, yet this subtype of NSCLC has been overlooked in preclinical and clinical investigations. Defining therapeutic targets in these LIMD1 loss-of-function patients is difficult due to a lack of druggable targets, thus alternative approaches are required. To this end, we performed the first drug repurposing screen to identify compounds that confer synthetic lethality with LIMD1 loss in NSCLC cells. PF-477736 was shown to selectively target LIMD1 deficient cells in vitro through inhibition of multiple kinases, inducing cell death via apoptosis. Furthermore, PF-477736 was effective in treating LIMD1-/- tumors in subcutaneous xenograft models, with no significant effect in LIMD1+/+ cells. We have identified a novel drug tool with significant preclinical characterization that serves as an excellent candidate to explore and define LIMD1-deficient cancers as a new therapeutic subgroup of critical unmet need. Significance StatementHere we provide the first proof-of-concept data validating the scope for development of a targeted therapy against the non-small cell lung cancers (NSCLC) subtypes deficient in expression of the LIMD1 tumor suppressor gene. Approximately 45% of NSCLC are deficient in LIMD11 representing at least 1.2 million lung cancer patients worldwide; yet this subtype has been ignored in preclinical and clinical investigations with no targeted therapies available. This seminal study applied synthetic lethality drug screening to target the loss/reduction of LIMD1 in lung cancer and normal cell lines, identifying and validating the multi-kinase inhibitor PF-477736 as a selectively cytotoxic compound towards LIMD1 deficient cells. This study provides rationale for further investigation into targeting LIMD1 loss in lung cancer, thereby addressing a critical unmet need for therapeutic approached to targeting LIMD1-deficent cancer subtypes.

cancer biology↗

bioRxiv2020

Loss of coiled-coil protein Cep55 impairs abscission processes and results in p53-dependent apoptosis in developing cortex

To produce a brain of normal size and structure, embryonic neural stem cell (NSCs) must tightly regulate their cell divisions. Cerebral cortex NSCs undergo a polarized form of cytokinesis whose regulation is poorly understood. Cytokinetic abscission severs the daughter cells and is mediated by the midbody at the apical membrane. Here we elucidate the role of the coiled-coil midbody protein Cep55 in NSC abscission and brain development. A knockout of Cep55 in mice causes microcephaly with reduced NSCs and neurons, but relatively normal body size. Fixed and live analyses show NSCs lacking Cep55 have decreased but not eliminated ESCRT recruitment, and have abnormal abscission and higher rates of failure. P53-mediated apoptosis is greatly increased in the brain, but not other tissues, and p53 knockout partly rescues brain size. Thus, loss of Cep55 causes abscission defects and failures in multiple cell types, but the secondary p53 response and apoptosis is brain-specific.

developmental biology↗