Biology subjects

Francis, D. M.

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

5 recordsLinked to original sources

bioRxiv2022

Tumor microenvironments impair T cell receptor affinity and function

CD8+ T cells underpin effective anti-tumor immune responses in melanoma; however, their functions are attenuated due to various immunosuppressive factors in the tumor microenvironment (TME), resulting in disease progression. T cell function is elicited by the T cell receptor (TCR), which recognizes antigen peptide-major histocompatibility complex (pMHC) expressed on tumor cells via direct physical contact, i.e., two-dimensional (2D) interaction. TCR-pMHC 2D affinity plays a central role in antigen recognition and discrimination, and is sensitive to both the conditions of the T cell and the microenvironment in which it resides. Herein, we demonstrate that CD8+ T cells residing in TME have lower 2D TCR-pMHC bimolecular affinity and TCR-pMHC-CD8 trimolecular avidity, pull fewer TCR-pMHC bonds by endogenous forces, flux lower level of intracellular calcium in response to antigen stimulation, exhibit impaired in vivo activation, and show diminished anti-tumor effector function. These detrimental effects are localized in the tumor and tumor draining lymph node (TdLN), and affect both antigen-inexperienced and antigen-experienced CD8+ T cells irrespective of their TCR specificities. These findings implicate impaired antigen recognition as a mechanism of T cell dysfunction in the TME.

immunology↗

bioRxiv2022

Short term tomato consumption alters the pig gut microbiome towards a more favorable profile

Diets rich in fruits and vegetables have been shown to exert positive effects on the gut microbiome. However, little is known about the specific effect of individual fruits or vegetables on gut microbe profiles. This study aims to elucidate the effects of tomato consumption on the gut microbiome, as tomatoes account for 22% of vegetable consumption in Western diets, and their consumption has been associated with positive health outcomes. Using piglets as a physiologically relevant model of human metabolism, 20 animals were assigned either to a control or tomato powder supplemented diet (both macronutrient matched and isocaloric) for 14 days. The microbiome was sampled rectally at three time points: day 0 (baseline), day 7 (midpoint), and at day 14 (end of study). DNA was sequenced using shotgun metagenomics, and reads were annotated using MG-RAST. There were no differences in body weight or feed intake between our two treatment groups. There was a microbial shift which included a higher ratio of Bacteroidota to Bacillota (formerly known as Bacteroidetes and Firmicutes, respectively) and higher alpha-diversity in tomato-fed animals, indicating a shift to a more desirable phenotype. Analyses at both the phyla and genera levels showed global microbiome profile changes (PERMANOVA P [≤] 0.05) over time, but not with tomato consumption. These data suggest that short-term tomato consumption can beneficially influence the gut microbial profile, warranting further investigation in humans. IMPORTANCEThe composition of the microorganisms in the gut is a contributor to overall health, prompting the development of strategies to alter the microbiome composition. Studies have investigated the role of the diet on the microbiome, as it is a major modifiable risk factor contributing to health; however, little is known about the causal effects of consumption of specific foods on the gut microbiota. A more complete understanding of how individual foods impact the microbiome will enable more evidence-based dietary recommendations for long-term health. Tomatoes are of interest as the most consumed non-starchy vegetable and a common source of nutrients and phytochemicals across the world. This study aimed to elucidate the effect of short-term tomato consumption on the microbiome, using piglets as a physiologically relevant model to humans. We found that tomato consumption can positively affect the gut microbial profile, which warrants further investigation in humans.

microbiology↗

bioRxiv2021

Solanum galapagense-derived purple tomato fruit color is conferred by novel alleles of the Anthocyanin fruit and atroviolacium loci

One hypothesis for the origin of endemic species of tomato on the Galapagos islands postulates a hybridization of Solanum pimpinellifolium and S. habrochaites. S. galapagense accession LA1141 has purple fruit pigmentation which has previously been described in green-fruited wild tomatoes such as S. habrochaites. Characterization of LA1141 derived purple pigmentation provides a test of the hybridization hypothesis. Purple pigmentation was recovered in progenies derived from LA1141 and the anthocyanins malvidin 3(coumaroyl)rutinoside-5-glucoside, petunidin 3-(coumaroyl) rutinoside-5-glucoside, and petunidin 3-(caffeoyl)rutinoside-5-glucoside were abundant. Fruit color was evaluated in an introgression population and three quantitative trait loci (QTLs) were mapped and validated in subsequent populations. The loci atroviolacium on chromosome 7, Anthocyanin fruit on chromosome 10, and uniform ripening also on chromosome 10, underly these QTLs. Sequence analysis suggested that the LA1141 alleles of Aft and atv are unique relative to those previously described from S. chilense accession LA0458 and S. cheesmaniae accession LA0434, respectively. Phylogenetic analysis of the LA1141 Aft genomic sequence did not support a green-fruited origin and the locus clustered with members of the red-fruited tomato clade. The LA1141 allele of Aft is not the result of an ancient introgression and underlies a gain of anthocyanin pigmentation in the red-fruited clade. HighlightAnthocyanin fruit and atroviolacium confer purple pigmentation in Solanum galapagense LA1141 confirming a mechanism described for green-fruited tomatoes. LA1141 alleles cluster with red-fruited homologs suggesting an independent gain of pigmentation.

plant biology↗

bioRxiv2021

Directing an mRNA-LNP vaccine toward lymph nodes improves humoral and cellular immunity against SARS-CoV-2

The exploration and identification of safe and effective vaccines for the SARS-CoV-2 pandemic has captured the worlds attention and remains an ongoing issue in order to protect against emerging variants of concern (VoCs) while generating long lasting immunity. Here, we report the synthesis of a novel messenger ribonucleic acid (mRNA) encoding the spike protein in a lipid nanoparticle formulation (LNP) (STI-7264) that generates robust humoral and cellular immunity following immunization of C57Bl6 mice. In efforts to continually improve immunity, a lymphatic drug delivery device (MuVaxx) was engineered and tested to modulate immune cells at the injection site (epidermis and dermis) and draining lymph node (LN) to elicit adaptive immunity. Using MuVaxx, immune responses were elicited and maintained at a 10-fold dose reduction compared to traditional intramuscular (IM) administration as measured by anti-spike antibodies, cytokine producing CD8 T cells, and neutralizing antibodies against the Washington (Wild Type, WT) and South African (beta) variants. Remarkably, a 4-fold elevated T cell response was observed in MuVaxx administered vaccination as compared to that of IM administered vaccination. Thus, these data support further investigation into STI-7264 and lymphatic mediated delivery using MuVaxx for SARS-CoV-2 and VoCs vaccines.

immunology↗

bioRxiv2021

Biosynthesis of Steroidal Alkaloids Are Coordinately Regulated and Differ Among Tomatoes in the Red-Fruited Clade

1.1O_LIWe quantitatively profiled and genotyped two tomato populations representing diversity in the red-fruited clade to address the lack of knowledge regarding the chemical diversity, concentration, and genetic architecture controlling tomato steroidal alkaloids. C_LIO_LIWe grew 107 genetically diverse fresh market, processing, land-race, and wild tomatoes in multiple environments. Nine steroidal alkaloids were quantified using ultra-high performance liquid chromatography tandem mass spectrometry. The diversity panel and a biparental population segregating for high alpha-tomatine, were genotyped to identify and validate quantitative trait loci (QTL) associated with steroidal alkaloids. C_LIO_LILand-races and wild material exhibited higher alkaloid concentrations and more chemical diversity. Average total content of steroidal alkaloids, often dominated by lycoperoside F/G/esculeoside A, ranged from 1.9 to 23.3 mg/100 g fresh weight across accessions. Land-race and wild cherry accessions distinctly clustered based on elevated early or late steroidal alkaloid concentrations. Significant correlations were observed among early and late steroidal alkaloids in a species-dependent manner. A QTL controlling multiple, early steroidal alkaloid pathway intermediates on chromosome 3 was identified by genome wide association (GWAS) and validated in a backcross population. C_LIO_LITomato steroidal alkaloids are diverse in the red-fruited tomato clade and their biosynthesis is regulated in a coordinated manner. C_LI

plant biology↗