Biology subjects

Hammond, S.

Publications and source records attributed to Hammond, S..

4 recordsLinked to original sources

bioRxiv2023

Identification of intestinal mediators of Caenorhabditis elegans DBL-1/BMP immune signaling shaping gut microbiome composition

The composition of the gut microbiome is determined by a complex interplay of diet, host genetics, microbe-microbe competition, abiotic factors, and stochasticity. Previous studies have demonstrated the importance of host genetics in community assembly of the Caenorhabditis elegans gut microbiome and identified a pivotal role for DBL-1/BMP immune signaling in determining the abundance of gut Enterobacteriaceae, in particular of the genus Enterobacter. However, the effects of DBL-1 signaling on gut bacteria were found to depend on its activation in extra-intestinal tissues, suggesting that yet unidentified intestinal factors must mediate these effects. In the present study, we used RNA-seq gene expression analysis of wildtype, dbl-1 and sma-3 mutants, and dbl-1 over-expressors to identify genes regulated by DBL-1/BMP signaling that take part in interactions with gut commensals. Following confirmation of several putative targets by qRT-PCR, we carried out colonization experiments with respective mutants raised on monocultures as well as on defined bacterial communities. These experiments identified five intestinal DBL-1/BMP targets, predicted to be secreted, that showed increased Enterobacteriaceae abundance compared to wildtype. The extent of increases was for the most part lower than those seen in DBL-1 pathway mutants, suggesting that identified mediators are components of a DBL-1-regulated antibacterial cocktail, which may additively contribute to shaping of gut microbiome composition. IMPORTANCECompared to the roles of diet, environmental availability, or lifestyle in determining gut microbiome composition, that of genetic factors is the least understood and often underestimated. The identification of intestinal mediators acting downstream of DBL-1/BMP signaling to control enteric bacteria, describes a cocktail of effectors with distinct molecular functions, thus offering a glimpse into the genetic logic of microbiome control as well as a list of targets for future exploration of this logic.

microbiology↗

bioRxiv2022

Type I PRMT inhibitor MS023 promotes SMN2 exon 7 inclusion and synergizes with nusinersen to rescue the phenotype of SMA mice

Spinal muscular atrophy (SMA) is the leading genetic cause of infant mortality. The advent of approved treatments for this devastating condition has significantly changed SMA patients life expectancy and quality of life. Nevertheless, these are not without limitations, and research efforts are underway to develop new approaches to be used alone and in combination, to ensure improved and long-lasting benefits for SMA patients. Protein arginine methyltransferases (PRMT) are emerging as druggable epigenetic targets, with several small molecule PRMT inhibitors already in clinical trial stage. From a screen of highly potent and selective next generation epigenetic small molecules, we have identified MS023, a potent and selective type I PRMT inhibitor, able to promote SMN2 exon 7 inclusion and increase SMN protein levels in preclinical SMA model, by inhibiting the binding of splicing factor hnRNPA1 to SMN2 pre-mRNA. Treatment of SMA mice with MS023 results in amelioration of the disease phenotype, with strong synergistic amplification of the positive effect when delivered in combination with the SMN2-targeting antisense oligonucleotide nusinersen. Moreover, transcriptomic analysis revealed that MS023 treatment has very minimal off-target effects and that the added benefit of the combination therapy is mainly attributable to targeting neuroinflammation. Our study warrants further clinical investigation of PRMT inhibition both as a stand-alone and add-on therapy for SMA patients.

neuroscience↗

bioRxiv2022

NKG2A and HLA-E define a novel alternative immune checkpoint axis in bladder cancer

PD-1/PD-L1-blockade immunotherapies have limited efficacy in the treatment of muscle-invasive bladder cancer (MIBC) and metastatic urothelial carcinoma. Here, we show that KLRC1 (NKG2A) expression associates with improved survival and responsiveness to PD-L1 blockade immunotherapy in CD8Ahigh bladder tumors. The loss of antigen presentation is a common mechanism for tumor escape in bladder cancer. NKG2A+ CD8 T cells are able to circumvent HLA-ABC loss through TCR-independent cytotoxicity, which is partly mediated by DNAM-1. In bladder tumors, NKG2A is acquired on a subset of PD-1+ CD8 T cells, alongside stronger tissue-residency memory features, TCR-independent cytotoxicity and evidence of recent proliferation. HLA-E is low but variably expressed on bladder tumors. When expressed, NKG2A+ CD8 T cell anti-tumor responses to HLA-ABC-deficient tumors are inhibited and partly restored upon NKG2A blockade. Overall, our study identifies an alternative path for CD8 T cell exhaustion, that is mediated by NKG2A upregulation and TCR-independent cytotoxicity.

immunology↗

bioRxiv2017

Evolution Of Coprophagy And Nutrient Absorption In A Cave Salamander

The transition from carnivory to omnivory is poorly understood. The ability to feed at more than one trophic level theoretically increases an animals fitness in a novel environment. Because of the absence of light and photosynthesis, most subterranean ecosystems are characterized by very few trophic levels, such that food scarcity is a challenge in many subterranean habitats. One strategy against starvation is to expand diet breadth. Grotto salamanders (Eurycea spelaea) are known to ingest bat guano deliberately, challenging the general understanding that salamanders are strictly carnivorous. Here we tested the hypothesis that grotto salamanders have broadened their diet related to cave adaptation and found that, although coprophagous behavior is present, salamanders are unable to acquire sufficient nutrition from bat guano alone. Our results suggest that the coprophagic behavior has emerged prior to physiological or gut biome adaptations.

animal behavior and cognition↗