Biology subjects

Wallace, M. D.

Publications and source records attributed to Wallace, M. D..

3 recordsLinked to original sources

bioRxiv2021

Herbicidal activity of fluoroquinolone derivatives

Development of herbicides with novel modes of action are crucial for weed control and to hinder herbicide resistance. An attractive novel herbicidal target is plant DNA gyrase, which has been demonstrated to be effectively inhibited by the known antimicrobial ciprofloxacin. Despite this good herbicidal activity ciprofloxacin is not suitable as a herbicide due to its antimicrobial activity, therefore, a diverse library of analogues was analysed to gain insight into the aspects required for herbicidal activity. This analysis revealed significant structural modifications were tolerated and that the fluoride at C-6 and a cyclic amino group at C-7 were not crucial for herbicidal activity. The analysis also revealed that these modifications also affected the antibacterial activity with one compound demonstrating good herbicidal activity and weak antibacterial activity, against both Gram-positive and Gram-negative bacteria.

plant biology↗

bioRxiv2018

Female-biased embryonic death from genomic instability-induced inflammation

Genomic instability (GIN) can trigger cellular responses including checkpoint activation, senescence, and inflammation. Though extensively studied in cell culture and cancer paradigms, little is known about the impact of GIN during embryonic development, a period of rapid cellular proliferation. We report that GIN-causing mutations in the MCM2-7 DNA replicative helicase render female mouse embryos to be dramatically more susceptible than males to embryonic lethality. This bias was not attributable to X-inactivation defects, differential replication licensing, or X vs Y chromosome size, but rather \"maleness,\" since XX embryos could be rescued by transgene-mediated sex reversal or testosterone (T) administration. The ability of exogenous or endogenous T to protect embryos was related to its anti-inflammatory properties. The NSAID ibuprofen rescued female embryos containing mutations not only in MCM genes but also Fancm, which have elevated GIN from compromised replication fork repair. Additionally, deficiency for the anti-inflammatory IL10 receptor was synthetically lethal with the GIN-causing Mcm4Chaos3 helicase mutant. Our experiments indicate that embryonic and maternal GIN arising from DNA replication-associated DNA damage induces embryonic inflammation likely via the cGAS-STING response, preferentially killing female embryos while male embryos are protected by high levels of intrinsic T.

genetics↗

bioRxiv2018

Dexi disruption depletes gut microbial metabolites and accelerates autoimmune diabetes

Non-coding genetic variants in the CLEC16A gene on human chromosome 16p13.13 are associated with risk of autoimmune diseases, including type 1 diabetes and multiple sclerosis. In this region, we previously identified DEXI, a candidate causal gene of unknown function, which alters the risk of type 1 diabetes, where the T1D predisposing allele is associated with lower DEXI expression. Here, we demonstrate by CRISPR mutagenesis in vivo and deep phenotyping that disrupted Dexi expression accelerates diabetes in the non-obese diabetic (NOD) mouse, a spontaneous model of autoimmune pancreatic beta-cell destruction. Mutant mice have increased serum IgM and IgA concentrations compared to wild-type NOD mice, as well as changes in both the gut microbiome and molecular metabolites associated with microbial metabolism. These findings suggest that the mechanism by which DEXI alters diabetes risk involves the composition and function of the microbiome and its impact on host metabolites. Such metabolites, including short chain fatty acids such as butyrate, have been shown to alter the activity of the immune cells involved in beta-cell destruction and susceptibility of the beta cells to autoimmune attack.\n\nOne Sentence Summary: Disruption of the Dexi gene leads to accelerated diabetes in the non-obese diabetic (NOD) mouse, accompanied by changes in serum immunoglobulins, gut microbiome and microbial metabolites.

genetics↗