Biology subjects

Hutchinson, R.

Publications and source records attributed to Hutchinson, R..

4 recordsLinked to original sources

bioRxiv2026

Metallothionein loss in cancer cells contributes to increased mutations through defective DNA repair and metabolic imbalance

Understanding which genes are involved in mutagenesis is essential for developing cancer prevention and treatment strategies; establishing protectors of the genome has revolutionized cancer biology. Here, we describe metallothionein (MT) proteins as previously uncharacterized protectors against mutagenesis. MT is a heavy metal binding protein essential for zinc homeostasis and protection against heavy metal cytotoxicity. Because zinc binds approximately 10-15% of the proteome and is critical for processes such as DNA repair and mitochondrial health, MT loss is expected to disrupt these processes. We hypothesized that MT loss induces genomic instability by impairing DNA repair and mitochondrial function. In this study, the consequences of MT deficiency in high-grade serous ovarian cancer (HGSC) were investigated by knockdown of the most highly expressed MT, MT2A. Loss of MT2A resulted in the impaired DNA repair pathway base excision repair (BER), leading to increased mutagenesis. MT2A deficiency produced mitochondrial dysfunction, characterized by a decrease in mitochondrial membrane potential, glycolysis, oxidative phosphorylation, amino acids, and an imbalance of nucleobases. Together, these defects reflect cellular states associated with increased cancer aggressiveness. These findings identify MT as a fundamental hub maintaining genomic and metabolic integrity. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=84 SRC="FIGDIR/small/736843v2_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@1af4adeorg.highwire.dtl.DTLVardef@15c588forg.highwire.dtl.DTLVardef@1ba5181org.highwire.dtl.DTLVardef@13d150b_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2024

Human coronavirus 229E infection inactivates pyroptosis executioner gasdermin D but ultimately leads to lytic cell death partly mediated by gasdermin E

Human coronavirus 229E (HCoV-229E) is associated with upper respiratory tract infections and causes local respiratory symptoms. It has been reported that HCoV-229E can cause cell death in a variety of cells in vitro. However, the molecular pathways that lead to virus-induced cell death remain poorly characterized. Here, we show that the main protease (Mpro) of HCoV-229E can cleave the pyroptosis executioner gasdermin D (GSDMD) within its active N-terminal domain at two different sites (Q29 and Q193) to generate fragments unable to cause pyroptosis. Despite GSDMD cleavage by HCoV-229E Mpro, we show that HCoV-229E infection leads to lytic cell death. We further demonstrate that virus-induced lytic cell death is partially dependent on the activation of caspases-3 and -8. Interestingly, inhibition of caspases does not only reduce lytic cell death upon infection, but also sustains the release of virus particles over time, which suggests that caspase-mediated cell death is a mechanism to limit virus replication and spread. Finally, we show that pyroptosis is partially dependent on another gasdermin family member, gasdermin E (GSDME). During HCoV-229E infection, GSDME is cleaved to yield its N-terminal pore-forming domain (p30). Accordingly, GSDME knockout cells show a significant decrease in lytic cell death upon virus, whereas this is not the case for GSDMD knockout cells, which aligns with the observation that GSDMD is also inactivated by caspase-3 during infection. These results suggest that GSDMD is inactivated during HCoV-229E infection, and point to GSDME as an important player in the execution of virus-induced cell death. ImportanceRecently, it has been shown that the Mpros of coronaviruses possess accessory functions other than their main role in the proteolytic processing of the viral polyproteins. Although the SARS-CoV-2 outbreak has fuelled the discovery of host cellular substrates of SARS-CoV-2 Mpro, less is known about the interplay of less pathogenic human coronavirus Mpros with host proteins. We demonstrate that HCoV-229E Mpro cleaves GSDMD at two sites within its pore-forming domain, which disrupts GSDMD-mediated pyroptosis. These results point to a new strategy for HCoV-229E to escape the host antiviral response. Additionally, we show that GSDME contributes to virus-induced lytic cell death upon activation by caspase-3, shedding light on a previously undescribed cell death mechanism occurring in HCoV-229E infected cells.

microbiology↗

bioRxiv2020

Duck, duck, goose: Benchmark bird surveys help quantify counting errors and bias in a citizen-science database

The growth of biodiversity data sets generated by citizen scientists continues to accelerate. The availability of such data has greatly expanded the scale of questions researchers can address. Yet, error, bias, and noise continue to be serious concerns for analysts, particularly when data being contributed to these giant online data sets are difficult to verify. Counts of birds contributed to eBird, the worlds largest biodiversity online database, present a potentially useful resource for tracking trends over time and space in species abundances. We quantified counting errors in a sample of 1406 eBird checklists by comparing numbers contributed by birders (N=246) who visited a popular birding location in Oregon, USA, with numbers generated by a professional ornithologist engaged in a long-term study creating benchmark (reference) measurements of daily waterbird counts. We focused on waterbirds, which are easily visible at this site. We evaluated potential predictors of count differences, including characteristics of contributed checklists, of each species, and of time of day and year. Count differences were biased toward undercounts, with more than 75% of counts being below the daily benchmark value. When only checklists that actually reported a species known to be present were included, median count errors were -29.1% (range: 0 to -42.8 %; N=20 species). Model sets revealed an important influence of each species reference count, which varied seasonally as waterbird numbers fluctuated, and of percent of species known to be present each day that were included on each checklist. That is, checklists indicating a more thorough survey of the species richness at the site also had, on average, lower counting errors. However, even on checklists with the most thorough species lists, counts were biased low and exceptionally variable in their accuracy. To improve utility of such bird count data, we suggest three strategies to pursue in the future. One is to assess additional options for analytically determining how to select checklists that have the highest probability of including less biased count data, as well as exploring options for correcting bias during the analysis stage. Another is to add options for users to provide additional information that helps analysts choose checklists, such as an option for users to tag checklists where they focused on obtaining accurate counts. We also recommend exploration of opportunities to effectively calibrate citizen-science bird count data by establishing a formalized network of marquis sites where dedicated observers regularly contribute carefully collected benchmark data.

ecology↗

bioRxiv2019

Perinatal Inflammation Influences but Does Not Arrest Rapid Immune Development in Preterm Babies

Infection and infection-related complications are important causes of death and morbidity following preterm birth. Despite this, there is limited understanding of the development of the immune system in those born prematurely and how it is influenced by perinatal factors. To investigate this, we prospectively and longitudinally followed a cohort of babies born before 32 weeks of gestation. We demonstrated that preterm babies, including those born extremely prematurely, were capable of rapidly acquiring adult levels of immune functionality; that immune maturation appeared to occur independently of the developing microbiome, which was highly heterogeneous across different infants; and that the biggest drivers of change in the trajectory of perinatal immune development was exposure to infection in utero or post-natally. Conspicuously, a unifying factor among infants who developed infection despite their growing immune potentials was an inability to mount adequate T cell CXCL8 responses. Because this defect was present at birth, it may predict those babies likely to have poor clinical outcomes.

immunology↗