New therapies to treat multi-drug-resistant (MDR) pathogens are needed. Santos-Júnior et al. discover new antimicrobials by leveraging the history of warfare within microbial communities. This study ...in Cell highlights the immense power of combining large biological databases with emerging computational methods, creating a key resource (AMPSphere) to be used for treating superbugs.
New therapies to treat multi-drug-resistant pathogens are needed. Santos-Júnior et al. discover new antimicrobials by leveraging the history of warfare within microbial communities. This study in Cell highlights the immense power of combining large biological databases with emerging computational methods, creating a key resource (AMPSphere) to be used for treating superbugs.
Proteins display the capacity for adaptation to new functions, a property critical for evolvability. But what structural principles underlie the capacity for adaptation? Here, we show that adaptation ...to a physiologically distinct class of ligand specificity in a PSD95, DLG1, ZO-1 (PDZ) domain preferentially occurs through class-bridging intermediate mutations located distant from the ligand-binding site. These mutations provide a functional link between ligand classes and demonstrate the principle of “conditional neutrality” in mediating evolutionary adaptation. Structures show that class-bridging mutations work allosterically to open up conformational plasticity at the active site, permitting novel functions while retaining existing function. More generally, the class-bridging phenotype arises from mutations in an evolutionarily conserved network of coevolving amino acids in the PDZ family (the sector) that connects the active site to distant surface sites. These findings introduce the concept that allostery in proteins could have its origins not in protein function but in the capacity to adapt.
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•Adaptation in a PDZ domain involves intermediate mutations that bridge ligand classes•A simple model shows that class-bridging mutations are evolutionarily preferred•Class-bridging mutations act allosterically•The origin of allostery in proteins could be in the capacity to adapt
Mutations that are neutral but that potentiate functional protein adaptation by a subsequent mutation result in enhanced conformational plasticity at the distal “business end” of the protein. The data suggest a model in which the origin of allostery lies in the capacity for adaptation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
This study of the effect of a microbiota-directed supplement on the growth of young children with moderate acute malnutrition included tests of association between changes in growth and changes in ...the plasma proteome and fecal microbiota.
Understanding the mother-breastmilk-infant "triad" Bode, Lars; Raman, Arjun S; Murch, Simon H ...
Science (American Association for the Advancement of Science),
03/2020, Volume:
367, Issue:
6482
Journal Article
Peer reviewed
Breastmilk research holds important opportunities to improve maternal-child health
Breastfeeding and breastmilk exert remarkable influence on infant survival and health (
1
,
2
), including reduced ...risk from infections and promoting various aspects of postnatal development. The many maternal benefits include protection from breast and ovarian cancer and cardiometabolic disorders. Although the mechanisms underlying some of these benefits have been elucidated, the origins of others that have been reported, such as influence on adult IQ and later protection against obesity and diabetes, remain more obscure. Hence, timely investments in research designed to clarify the operations and biological effects of the mother-breastmilk-infant “triad,” and their translation into public health, are needed.
Changing food preferences brought about by westernization that have deleterious health effects
-combined with myriad forces that are contributing to increased food insecurity-are catalysing efforts ...to identify more nutritious and affordable foods
. Consumption of dietary fibre can help to prevent cardiovascular disease, type 2 diabetes and obesity
. A substantial number of reports have explored the effects of dietary fibre on the gut microbial community
. However, the microbiome is complex, dynamic and exhibits considerable intra- and interpersonal variation in its composition and functions. The large number of potential interactions between the components of the microbiome makes it challenging to define the mechanisms by which food ingredients affect community properties. Here we address the question of how foods containing different fibre preparations can be designed to alter functions associated with specific components of the microbiome. Because a marked increase in snack consumption is associated with westernization, we formulated snack prototypes using plant fibres from different sustainable sources that targeted distinct features of the gut microbiomes of individuals with obesity when transplanted into gnotobiotic mice. We used these snacks to supplement controlled diets that were consumed by adult individuals with obesity or who were overweight. Fibre-specific changes in their microbiomes were linked to changes in their plasma proteomes indicative of an altered physiological state.
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GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
Characterizing the organization of the human gut microbiota is a formidable challenge given the number of possible interactions between its components. Using a statistical approach initially applied ...to financial markets, we measured temporally conserved covariance among bacterial taxa in the microbiota of healthy members of a Bangladeshi birth cohort sampled from 1 to 60 months of age. The results revealed an "ecogroup" of 15 covarying bacterial taxa that provide a concise description of microbiota development in healthy children from this and other low-income countries, and a means for monitoring community repair in undernourished children treated with therapeutic foods. Features of ecogroup population dynamics were recapitulated in gnotobiotic piglets as they transitioned from exclusive milk feeding to a fully weaned state consuming a representative Bangladeshi diet.
Cellular behaviors emerge from layers of molecular interactions: proteins interact to form complexes, pathways, and phenotypes. We show that hierarchical networks of protein interactions can be ...defined from the statistical pattern of proteome variation measured across thousands of diverse bacteria and that these networks reflect the emergence of complex bacterial phenotypes. Our results are validated through gene-set enrichment analysis and comparison to existing experimentally derived databases. We demonstrate the biological utility of our approach by creating a model of motility in
Pseudomonas aeruginosa
and using it to identify a protein that affects pilus-mediated motility. Our method, SCALES (Spectral Correlation Analysis of Layered Evolutionary Signals), may be useful for interrogating genotype-phenotype relationships in bacteria.
Human gut microbiota development has been associated with healthy growth but understanding the determinants of community assembly and composition is a formidable challenge. We cultured bacteria from ...serially collected fecal samples from a healthy infant; 34 sequenced strains containing 103,102 genes were divided into two consortia representing earlier and later stages in community assembly during the first six postnatal months. The two consortia were introduced alone (singly), or sequentially in different order, or simultaneously into young germ-free mice fed human infant formula. The pattern of fitness of bacterial strains observed across the different colonization conditions indicated that later-phase strains substantially outcompete earlier-phase strains, although four early-phase members persist. Persistence was not determined by order of introduction, suggesting that priority effects are not prominent in this model. To characterize succession in the context of the metabolic potential of consortiummembers, we performed in silico reconstructions of metabolic pathways involved in carbohydrate utilization and amino acid and B-vitamin biosynthesis, then quantified the fitness (abundance) of strains in serially collected fecal samples and their transcriptional responses to different histories of colonization. Applying feature-reduction methods disclosed a set of metabolic pathways whose presence and/or expression correlates with strain fitness and that enable early-stage colonizers to survive during introduction of later colonizers. The approach described can be used to test the magnitude of the contribution of identified metabolic pathways to fitness in different community contexts, study various ecological processes thought to govern community assembly, and facilitate development of microbiotadirected therapeutics.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Microbial consortia exhibit complex functional properties in contexts ranging from soils to bioreactors to human hosts. Understanding how community composition determines function is a major goal of ...microbial ecology. Here we address this challenge using the concept of community-function landscapes-analogues to fitness landscapes-that capture how changes in community composition alter collective function. Using datasets that represent a broad set of community functions, from production/degradation of specific compounds to biomass generation, we show that statistically inferred landscapes quantitatively predict community functions from knowledge of species presence or absence. Crucially, community-function landscapes allow prediction without explicit knowledge of abundance dynamics or interactions between species and can be accurately trained using measurements from a small subset of all possible community compositions. The success of our approach arises from the fact that empirical community-function landscapes appear to be not rugged, meaning that they largely lack high-order epistatic contributions that would be difficult to fit with limited data. Finally, we show that this observation holds across a wide class of ecological models, suggesting community-function landscapes can be efficiently inferred across a broad range of ecological regimes. Our results open the door to the rational design of consortia without detailed knowledge of abundance dynamics or interactions.
Abstract Heterogeneity of therapeutic response amongst cancer patients has a profound impact on cancer-related mortality. It has been widely hypothesized that diversity in clinical outcomes is driven ...by variability in tumor biology at scales ranging from inter-patient to inter-cellular. Indeed, the advent of technologies describing the tumor microenvironment (TME) at cellular resolution has demonstrated that TME organization is heterogeneous with respect to intra-tumor spatial location, body tumor location (primary vs metastatic), patient, and tumor type. However, the organizing principles that govern TME heterogeneity remain unclear. Without such organizing principles, it remains an arduous task to link descriptions of tumor biology heterogeneity to clinical outcomes in a mechanistically explainable manner. Through the application of network statistical inference models to spatial transcriptomic data, we have identified that nested spatial units (NSUs) are a core organizing principle of the TME. We find that NSUs are widely conserved across 96 patient biopsies of 14 distinct tumor types and 3 body locations (primary, abdominal metastases, brain metastases). Moreover, NSUs represent a transferrable organizing blueprint that allows for the spatial location of individual spots (5-50 cells) in a tumor biopsy to be predicted by the NSUs of a secondary, unrelated biopsy (Pearson correlation of spot-spot distance: 0.04 - 0.71, median 0.25). By using NSUs as the organizing unit of comparison, we identify variation in gene expression, biological pathways, and multicellular structures occurring across tumors in a distance-dependent manner. In summary, NSUs provide a foundation for the comparative analysis of tumor spatial biology and a path by which spatial biology can be mechanistically linked to patient outcomes. Citation Format: Vivek Behera, Hannah Giba, Benjamin A. Doran, Justin P. Kline, Arjun S. Raman. Identifying nested spatial units as a conserved organizing principle of the spatial tumor microenvironment abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6226.
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