Mol Nutr Food Res. 2023 May 12:e2200601. doi: 10.1002/mnfr.202200601. Online ahead of print.

ABSTRACT

SCOPE: Red meat is a staple food of Western diets, but it can also induce IgE-mediated allergic reactions. Yet, apart from the heat-labile protein serum albumin and the carbohydrate α-Gal, the molecules involved in allergic reactions to red meat remain unknown.

METHODS AND RESULTS: IgE reactivity profiles of beef-sensitized individuals were analyzed by IgE-immunoblotting with protein extracts from raw and cooked beef. IgE-reactive proteins were identified by peptide mass fingerprinting. Bovine myosin light chains (MYLs) were produced recombinantly. IgE reactivity of the recombinant allergens was analyzed by ELISA and the molecules' fold evaluated by circular dichroism analysis. The stability of the proteins to gastrointestinal digestion was investigated in vitro. The transport of recombinant myosin light chain 1 (rMYL1) through the intestinal epithelium was evaluated by exposing a monolayer of Caco-2 cells to rMYL1. Two IgE-reactive proteins were identified as myosin light chain 1 (MYL1) and myosin light chain 3 (MYL3) in the cooked-beef extract and were designated Bos d 13 isoallergens. rMYL1 and rMYL3 represent folded, IgE reactive proteins and they both display remarkable thermal stability. rMYL1 showed higher resistance to gastrointestinal digestion than rMYL3 and was able to cross a monolayer of intestinal cells without disturbing the integrity of the tight junctions, suggesting the sensitizing capacity of MYL1.

CONCLUSION: MYLs were identified as novel heat-stable bovine meat allergens. This article is protected by copyright. All rights reserved.

PMID:37173826 | DOI:10.1002/mnfr.202200601

Nat Commun. 2023 May 12;14(1):2744. doi: 10.1038/s41467-023-38271-5.

ABSTRACT

With the continued promise of immunotherapy for treating cancer, understanding how host genetics contributes to the tumor immune microenvironment (TIME) is essential to tailoring cancer screening and treatment strategies. Here, we study 1084 eQTLs affecting the TIME found through analysis of The Cancer Genome Atlas and literature curation. These TIME eQTLs are enriched in areas of active transcription, and associate with gene expression in specific immune cell subsets, such as macrophages and dendritic cells. Polygenic score models built with TIME eQTLs reproducibly stratify cancer risk, survival and immune checkpoint blockade (ICB) response across independent cohorts. To assess whether an eQTL-informed approach could reveal potential cancer immunotherapy targets, we inhibit CTSS, a gene implicated by cancer risk and ICB response-associated polygenic models; CTSS inhibition results in slowed tumor growth and extended survival in vivo. These results validate the potential of integrating germline variation and TIME characteristics for uncovering potential targets for immunotherapy.

PMID:37173324 | DOI:10.1038/s41467-023-38271-5

FEMS Yeast Res. 2023 May 12:foad029. doi: 10.1093/femsyr/foad029. Online ahead of print.

ABSTRACT

Budding yeast uses the TORC1-Sch9p and cAMP-PKA signalling pathways to regulate adaptations to changing nutrient environments. Dynamic and single-cell measurements of the activity of these cascades will improve our understanding of cellular adaptation of yeast. Here, we employed the AKAR3-EV biosensor developed for mammalian cells to measure the cellular phosphorylation status determined by Sch9p and PKA activity in budding yeast. Using various mutant strains and inhibitors, we show that AKAR3-EV measures the Sch9p- and PKA-dependent phosphorylation status in intact yeast cells. At the single-cell level, we found that the phosphorylation responses are homogenous for glucose, sucrose and fructose, but heterogeneous for mannose. Cells that start to grow after a transition to mannose correspond to higher normalized FRET levels, in line with the involvement of Sch9p and PKA pathways to stimulate growth-related processes. The Sch9p and PKA pathways have a relatively high affinity for glucose (K0.5 of 0.24 mM) under glucose derepressed conditions. Lastly, steady-state FRET levels of AKAR3-EV seem to be independent of growth rates, suggesting that Sch9p- and PKA-dependent phosphorylation activities are transient responses to nutrient transitions. We believe that the AKAR3-EV sensor is an excellent addition to the biosensor arsenal for illuminating cellular adaptation in single yeast cells.

PMID:37173282 | DOI:10.1093/femsyr/foad029

Trends Endocrinol Metab. 2023 May 10:S1043-2760(23)00087-5. doi: 10.1016/j.tem.2023.04.001. Online ahead of print.

ABSTRACT

Effective pharmacological treatments to achieve significant and sustained weight loss in obese individuals remain limited. Here, we apply a 'reverse engineering' approach to cancer cachexia, an extreme form of dysregulated energy balance resulting in net catabolism. We discuss three phenotypic features of the disease, summarize the underlying molecular checkpoints, and explore their translation to obesity research. We then provide examples for established pharmaceuticals, which follow a reverse engineering logic, and propose additional targets that may be of relevance for future studies. Finally, we argue that approaching diseases from this perspective may prove useful as a generic strategy to fuel the development of innovative therapies.

PMID:37173233 | DOI:10.1016/j.tem.2023.04.001

Trends Genet. 2023 May 10:S0168-9525(23)00088-4. doi: 10.1016/j.tig.2023.04.002. Online ahead of print.

ABSTRACT

Phenotypic plasticity, the ability of an organism to display different phenotypes across environments, is widespread in nature. Plasticity aids survival in novel environments. Herein, we review studies from yeast that allow us to start uncovering the genetic architecture of phenotypic plasticity. Genetic variants and their interactions impact the phenotype in different environments, and distinct environments modulate the impact of genetic variants and their interactions on the phenotype. Because of this, certain hidden genetic variation is expressed in specific genetic and environmental backgrounds. A better understanding of the genetic mechanisms of phenotypic plasticity will help to determine short- and long-term responses to selection and how wide variation in disease manifestation occurs in human populations.

PMID:37173192 | DOI:10.1016/j.tig.2023.04.002

Am J Clin Nutr. 2023 Apr;117 Suppl 1:S61-S86. doi: 10.1016/j.ajcnut.2022.12.021.

ABSTRACT

Human milk contains all of the essential nutrients required by the infant within a complex matrix that enhances the bioavailability of many of those nutrients. In addition, human milk is a source of bioactive components, living cells and microbes that facilitate the transition to life outside the womb. Our ability to fully appreciate the importance of this matrix relies on the recognition of short- and long-term health benefits and, as highlighted in previous sections of this supplement, its ecology (i.e., interactions among the lactating parent and breastfed infant as well as within the context of the human milk matrix itself). Designing and interpreting studies to address this complexity depends on the availability of new tools and technologies that account for such complexity. Past efforts have often compared human milk to infant formula, which has provided some insight into the bioactivity of human milk, as a whole, or of individual milk components supplemented with formula. However, this experimental approach cannot capture the contributions of the individual components to the human milk ecology, the interaction between these components within the human milk matrix, or the significance of the matrix itself to enhance human milk bioactivity on outcomes of interest. This paper presents approaches to explore human milk as a biological system and the functional implications of that system and its components. Specifically, we discuss study design and data collection considerations and how emerging analytical technologies, bioinformatics, and systems biology approaches could be applied to advance our understanding of this critical aspect of human biology.

PMID:37173061 | DOI:10.1016/j.ajcnut.2022.12.021

Am J Clin Nutr. 2023 Apr;117 Suppl 1:S28-S42. doi: 10.1016/j.ajcnut.2022.11.027.

ABSTRACT

Human milk is universally recognized as the preferred food for infants during the first 6 mo of life because it provides not only essential and conditionally essential nutrients in necessary amounts but also other biologically active components that are instrumental in protecting, communicating important information to support, and promoting optimal development and growth in infants. Despite decades of research, however, the multifaceted impacts of human milk consumption on infant health are far from understood on a biological or physiological basis. Reasons for this lack of comprehensive knowledge of human milk functions are numerous, including the fact that milk components tend to be studied in isolation, although there is reason to believe that they interact. In addition, milk composition can vary greatly within an individual as well as within and among populations. The objective of this working group within the Breastmilk Ecology: Genesis of Infant Nutrition (BEGIN) Project was to provide an overview of human milk composition, factors impacting its variation, and how its components may function to coordinately nourish, protect, and communicate complex information to the recipient infant. Moreover, we discuss the ways whereby milk components might interact such that the benefits of an intact milk matrix are greater than the sum of its parts. We then apply several examples to illustrate how milk is better thought of as a biological system rather than a more simplistic "mixture" of independent components to synergistically support optimal infant health.

PMID:37173059 | DOI:10.1016/j.ajcnut.2022.11.027

Cell Chem Biol. 2023 May 10:S2451-9456(23)00118-6. doi: 10.1016/j.chembiol.2023.04.011. Online ahead of print.

ABSTRACT

Chemical genetic approaches have had a transformative impact on discovery of drug targets for malaria but have primarily been used for parasite targets. To identify human pathways required for intrahepatic development of parasite, we implemented multiplex cytological profiling of malaria infected hepatocytes treated with liver stage active compounds. Some compounds, including MMV1088447 and MMV1346624, exhibited profiles similar to cells treated with nuclear hormone receptor (NHR) agonist/antagonists. siRNAs targeting human NHRs, or their signaling partners identified eight genes that were critical for Plasmodium berghei infection. Knockdown of NR1D2, a host NHR, significantly impaired parasite growth by downregulation of host lipid metabolism. Importantly, treatment with MMV1088447 and MMV1346624 but not other antimalarials, phenocopied the lipid metabolism defect of NR1D2 knockdown. Our data underlines the use of high-content imaging for host-cellular pathway deconvolution, highlights host lipid metabolism as a drug-able human pathway and provides new chemical biology tools for studying host-parasite interactions.

PMID:37172592 | DOI:10.1016/j.chembiol.2023.04.011

Neuron. 2023 May 3:S0896-6273(23)00303-3. doi: 10.1016/j.neuron.2023.04.018. Online ahead of print.

ABSTRACT

Alzheimer's disease (AD) is a spatially dynamic pathology that implicates a growing volume of multiscale data spanning genetic, cellular, tissue, and organ levels of the organization. These data and bioinformatics analyses provide clear evidence for the interactions within and between these levels. The resulting heterarchy precludes a linear neuron-centric approach and necessitates that the numerous interactions are measured in a way that predicts their impact on the emergent dynamics of the disease. This level of complexity confounds intuition, and we propose a new methodology that uses non-linear dynamical systems modeling to augment intuition and that links with a community-wide participatory platform to co-create and test system-level hypotheses and interventions. In addition to enabling the integration of multiscale knowledge, key benefits include a more rapid innovation cycle and a rational process for prioritization of data campaigns. We argue that such an approach is essential to support the discovery of multilevel-coordinated polypharmaceutical interventions.

PMID:37172582 | DOI:10.1016/j.neuron.2023.04.018

Sci Immunol. 2023 May 12;8(83):eade5019. doi: 10.1126/sciimmunol.ade5019. Epub 2023 May 12.

ABSTRACT

Chemosensory epithelial tuft cells contribute to innate immunity at barrier surfaces, but their differentiation from epithelial progenitors is not well understood. Here, we exploited differences between inbred mouse strains to identify an epithelium-intrinsic mechanism that regulates tuft cell differentiation and tunes innate type 2 immunity in the small intestine. Balb/cJ (Balb) mice had fewer intestinal tuft cells than C57BL/6J (B6) mice and failed to respond to the tuft cell ligand succinate. Most of this differential succinate response was determined by the 50- to 67-Mb interval of chromosome 9 (Chr9), such that congenic Balb mice carrying the B6 Chr9 interval had elevated baseline numbers of tuft cells and responded to succinate. The Chr9 locus includes Pou2af2, which encodes the protein OCA-T1, a transcriptional cofactor essential for tuft cell development. Epithelial crypts expressed a previously unannotated short isoform of Pou2af2 predicted to use a distinct transcriptional start site and encode a nonfunctional protein. Low tuft cell numbers and the resulting lack of succinate response in Balb mice were explained by a preferential expression of the short isoform and could be rescued by expression of full-length Pou2af2. Physiologically, Pou2af2 isoform usage tuned innate type 2 immunity in the small intestine. Balb mice maintained responsiveness to helminth pathogens while ignoring commensal Tritrichomonas protists and reducing norovirus burdens.

PMID:37172102 | DOI:10.1126/sciimmunol.ade5019

Oncotarget. 2023 May 12;14:449. doi: 10.18632/oncotarget.28286.

NO ABSTRACT

PMID:37171383 | DOI:10.18632/oncotarget.28286

Genome Biol Evol. 2023 May 12:evad081. doi: 10.1093/gbe/evad081. Online ahead of print.

ABSTRACT

T cells are a type of white blood cell that play a critical role in the immune response against foreign pathogens through a process called T Cell Adaptive Immunity (TCAI). However, the evolution of the genes and nucleotide sequences involved in TCAI is not well understood. To investigate this, we performed comparative studies of gene annotations and genome assemblies of 28 vertebrate species and identified sets of human genes that are involved in TCAI, carcinogenesis, and ageing. We found that these gene sets share interaction pathways which may have contributed to the evolution of longevity in the vertebrate lineage leading to humans. Our human gene age dating analyses revealed that there was rapid origination of genes with TCAI-related functions prior to the Cretaceous eutherian radiation and these new genes mainly encode negative regulators. We identified no new TCAI-related genes after the divergence of placental mammals, but we did detect an extensive number of amino acid substitutions under strong positive selection in recently evolved human immunity genes suggesting they are co-evolving with adaptive immunity. More specifically, we observed that antigen processing and presentation and checkpoint genes are significantly enriched among new genes evolving under positive selection. These observations reveal an evolutionary process of T Cell Adaptive Immunity that were associated with rapid gene duplication in the early stages of vertebrates and subsequent sequence changes in TCAI-related genes. These processes together suggest an early genetic construction of the vertebrate immune system and subsequent molecular adaptation to diverse antigens.

PMID:37170918 | DOI:10.1093/gbe/evad081

J Exp Bot. 2023 May 12:erad177. doi: 10.1093/jxb/erad177. Online ahead of print.

ABSTRACT

Modern genetics and biochemistry have revolutionized our understanding of plant biology. However, biochemical genetics can be traced to the foundation of Mendelian genetics indeed one of the milestone discoveries of Mendels seven characteristics of pea plants could later be ascribed to be due to mutation in starch branching enzyme. Here we review both current and historical strategies for the elucidation of plant metabolic pathways and the genes which encode their component enzymes and regulators. We utilize this historical review to discuss a range of classical genetic phenomena including, epistasis, canalization and heterosis as viewed through the lens of contemporary high-throughput data obtained via the array of approaches currently adopted in multi-omics studies.

PMID:37170864 | DOI:10.1093/jxb/erad177

iScience. 2023 Apr 10;26(5):106596. doi: 10.1016/j.isci.2023.106596. eCollection 2023 May 19.

ABSTRACT

The intricate network of interactions between cells and molecules in the tumor microenvironment creates a heterogeneous ecosystem. The proximity of the cells and molecules to their activators and inhibitors is essential in the progression of tumors. Here, we develop a system of partial differential equations coupled with linear elasticity to investigate the effects of spatial interactions on the tumor microenvironment. We observe interesting cell and cytokine distribution patterns, which are heavily affected by macrophages. We also see that cytotoxic T cells get recruited and suppressed at the site of macrophages. Moreover, we observe that anti-tumor macrophages reorganize the patterns in favor of a more spatially restricted cancer and necrotic core. Furthermore, the adjoint-based sensitivity analysis indicates that the most sensitive model's parameters are directly related to macrophages. The results emphasize the widely acknowledged effect of macrophages in controlling cancer cells population and spatially arranging cells in the tumor microenvironment.

PMID:37168560 | PMC:PMC10165418 | DOI:10.1016/j.isci.2023.106596

iScience. 2023 Apr 7;26(5):106590. doi: 10.1016/j.isci.2023.106590. eCollection 2023 May 19.

ABSTRACT

To detect novel endometrial cancer risk variants, we leveraged information from endometrial cancer risk factors in a multi-trait GWAS analysis. We first assessed causal relationships between established and suspected endometrial cancer risk factors, and endometrial cancer using Mendelian randomization. Following multivariable analysis, five independent risk factors (waist circumference, testosterone levels, sex hormone binding globulin levels, age at menarche, and age at natural menopause) were included in a multi-trait Bayesian GWAS analysis. We identified three potentially novel loci that associate with endometrial cancer risk, one of which (7q22.1) replicated in an independent endometrial cancer GWAS dataset and was genome-wide significant in a meta-analysis. This locus may affect endometrial cancer risk through altered testosterone levels. Consistent with this, we observed colocalization between the signals for endometrial cancer risk and expression of CYP3A7, a gene involved in testosterone metabolism. Thus, our findings suggest opportunities for hormone therapy to prevent or treat endometrial cancer.

PMID:37168552 | PMC:PMC10165198 | DOI:10.1016/j.isci.2023.106590

Structure. 2023 Apr 28:S0969-2126(23)00130-2. doi: 10.1016/j.str.2023.04.007. Online ahead of print.

ABSTRACT

Ras is a central cellular hub protein controlling multiple cell fates. How Ras interacts with a variety of potential effector proteins is relatively unexplored, with only some key effectors characterized in great detail. Here, we have used homology modeling based on X-ray and AlphaFold2 templates to build structural models for 54 Ras-effector complexes. These models were used to estimate binding affinities using a supervised learning regressor. Furthermore, we systematically introduced Ras "branch-pruning" (or branchegetic) mutations to identify 200 interface mutations that affect the binding energy with at least one of the model structures. The impacts of these branchegetic mutants were integrated into a mathematical model to assess the potential for rewiring interactions at the Ras hub on a systems level. These findings have provided a quantitative understanding of Ras-effector interfaces and their impact on systems properties of a key cellular hub.

PMID:37167973 | DOI:10.1016/j.str.2023.04.007

BMC Zool. 2021 Sep 9;6(1):26. doi: 10.1186/s40850-021-00089-3.

ABSTRACT

BACKGROUND: Increasing temperatures and changes in precipitation patterns threaten the existence of many organisms. It is therefore informative to identify the functional traits that underlie differences in desiccation resistance to understand the response of different species to changes in water availability resulting from climate change. We used adult dung beetles as model species due to their importance to ecosystem services. We investigated: (i) the effect of physiological (water loss rate, water loss tolerance, body water content), morphological (body mass) and ecological (nesting behaviour) traits on desiccation resistance; (ii) the role of phylogenetic relatedness in the above associations; and, (iii) whether relatively large or small individuals within a species have similar desiccation resistance and whether these responses are consistent across species.

RESULTS: Desiccation resistance decreased with increasing water loss rate and increased with increasing water loss tolerance (i.e. proportion of initial water content lost at the time of death). A lack of consistent correlation between these traits due to phylogenetic relatedness suggests that the relationship is not determined by a shared evolutionary history. The advantage of a large body size in favouring desiccation resistance depended on the nesting behaviour of the dung beetles. In rollers (one species), large body sizes increased desiccation resistance, while in tunnelers and dwellers, desiccation resistance seemed not to be dependent on body mass. The phylogenetic correlation between desiccation resistance and nesting strategies was significant. Within each species, large individuals showed greater resistance to desiccation, and these responses were consistent across species.

CONCLUSIONS: Resistance to desiccation was explained mainly by the dung beetles' ability to reduce water loss rate (avoidance) and to tolerate water loss (tolerance). A reduction in water availability may impose a selection pressure on body size that varies based on nesting strategies, even though these responses may be phylogenetically constrained. Changes in water availability are more likely to affect dweller species, and hence the ecosystem services they provide.

PMID:37170349 | DOI:10.1186/s40850-021-00089-3

IMA Fungus. 2023 May 11;14(1):10. doi: 10.1186/s43008-023-00115-8.

ABSTRACT

Tree diseases constitute a significant threat to biodiversity worldwide. Pathogen discovery in natural habitats is of vital importance to understanding current and future threats and prioritising efforts towards developing disease management strategies. Ash dieback is a fungal disease of major conservational concern that is infecting common ash trees, Fraxinus excelsior, in Europe. The disease is caused by a non-native fungal pathogen, Hymenoscyphus fraxineus. Other dieback causing-species have not previously been identified in the genus Hymenoscyphus. Here, we discover the pathogenicity potential of two newly identified related species of Asian origin, H. koreanus and H. occultus, and one Europe-native related species, H. albidus. We sequence the genomes of all three Hymenoscyphus species and compare them to that of H. fraxineus. Phylogenetic analysis of core eukaryotic genes identified H. albidus and H. koreanus as sister species, whilst H. occultus diverged prior to these and H. fraxineus. All four Hymenoscyphus genomes are of comparable size (55-62 Mbp) and GC contents (42-44%) and encode for polymorphic secretomes. Surprisingly, 1133 predicted secreted proteins are shared between the ash dieback pathogen H. fraxineus and the three related Hymenoscyphus endophytes. Amongst shared secreted proteins are cell death-inducing effector candidates, such as necrosis, and ethylene-inducing peptide 1-like proteins, Nep1-like proteins, that are upregulated during in planta growth of all Hymenoscyphus species. Indeed, pathogenicity tests showed that all four related Hymenoscyphus species develop pathogenic growth on European ash stems, with native H. albidus being the least virulent. Our results identify the threat Hymenoscypohus species pose to the survival of European ash trees, and highlight the importance of promoting pathogen surveillance in environmental landscapes. Identifying new pathogens and including them in the screening for durable immunity of common ash trees is key to the long-term survival of ash in Europe.

PMID:37170345 | DOI:10.1186/s43008-023-00115-8

BMC Zool. 2021 Jul 29;6(1):22. doi: 10.1186/s40850-021-00085-7.

ABSTRACT

BACKGROUND: Prioritizing groupings of organisms or 'units' below the species level is a critical issue for conservation purposes. Several techniques encompassing different time-frames, from genetics to ecological markers, have been considered to evaluate existing biological diversity at a sufficient temporal resolution to define conservation units. Given that acoustic signals are expressions of phenotypic diversity, their analysis may provide crucial information on current differentiation patterns within species. Here, we tested whether differences previously delineated within dolphin species based on i) geographic isolation, ii) genetics regardless isolation, and iii) habitat, regardless isolation and genetics, can be detected through acoustic monitoring. Recordings collected from 104 acoustic encounters of Stenella coeruleoalba, Delphinus delphis and Tursiops truncatus in the Azores, Canary Islands, the Alboran Sea and the Western Mediterranean basin between 1996 and 2012 were analyzed. The acoustic structure of communication signals was evaluated by analyzing parameters of whistles in relation to the known genetic and habitat-driven population structure.

RESULTS: Recordings from the Atlantic and Mediterranean were accurately assigned to their respective basins of origin through Discriminant Function Analysis, with a minimum 83.8% and a maximum 93.8% classification rate. A parallel pattern between divergence in acoustic features and in the genetic and ecological traits within the basins was highlighted through Random Forest analysis. Although it is not yet possible to establish a causal link between each driver and acoustic differences between basins, we showed that signal variation reflects fine-scale diversity and may be used as a proxy for recognizing discrete units.

CONCLUSION: We recommend that acoustic analysis be included in assessments of delphinid population structure, together with genetics and ecological tracer analysis. This cost-efficient non-invasive method can be applied to uncover distinctiveness and local adaptation in other wide-ranging marine species.

PMID:37170140 | DOI:10.1186/s40850-021-00085-7

Nat Rev Genet. 2023 May 11. doi: 10.1038/s41576-023-00601-0. Online ahead of print.

ABSTRACT

Epithelial-mesenchymal plasticity (EMP) enables cells to interconvert between several states across the epithelial-mesenchymal landscape, thereby acquiring hybrid epithelial/mesenchymal phenotypic features. This plasticity is crucial for embryonic development and wound healing, but also underlies the acquisition of several malignant traits during cancer progression. Recent research using systems biology and single-cell profiling methods has provided novel insights into the main forces that shape EMP, which include the microenvironment, lineage specification and cell identity, and the genome. Additionally, key roles have emerged for hysteresis (cell memory) and cellular noise, which can drive stochastic transitions between cell states. Here, we review these forces and the distinct but interwoven layers of regulatory control that stabilize EMP states or facilitate epithelial-mesenchymal transitions (EMTs) and discuss the therapeutic potential of manipulating the EMP landscape.

PMID:37169858 | DOI:10.1038/s41576-023-00601-0