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Macroecological relationships that describe various statistical associations between species' abundances, their spatial, and temporal variability are among the most general laws in ecology and biology. One of the most commonly observed relationships is a power-law scaling between means and variances of temporal species abundances, known in ecology as Taylor's law. Taylor's law has been observed across many ecosystems, from diverse plant and animal ecosystems to complex microbial communities. While many mathematical models have been proposed to explain the potential origins of Taylor's law, what determines its scaling exponents across species and ecosystems is not understood. Here, we use temporal trajectories of human and baboon gut microbiota to analyze the relationship between functional properties of individual bacterial species and microbial communities with the scaling of species-specific and community-level Taylor's law. The species Taylor law characterizes - for each individual species - the relationship between the species' temporal abundance means and temporal abundance variances across host organisms. On the other hand, community-level Taylor's law characterizes - in each host organism - the scaling across multiple species between their temporal abundance means and temporal abundance variances. For community Taylor's law, we find that the power law scaling is strongly associated with the microbiota abundance of certain nutrient-degrading enzymes in the gut. Notably, our results demonstrate that the availability of enzymes metabolizing starch glycogen significantly increases Taylor's law scaling. We also find that species Taylor's law depends on the individual species' functional properties. Specifically, we observe lower Taylor's law scaling for species with larger metabolic networks, for species that are able to grow on a larger number of carbon sources, and for species with particular metabolic functions, such as glutamine and folate metabolism. Overall, our study reveals that Taylor's law scaling is strongly associated with the functional capabilities of bacterial communities and individual microbial species' biosynthetic properties, which are likely related to their ecological roles in the gut microbiota.

Understanding the main determinants of protein evolution is a fundamental challenge in biology. Despite many decades of active research, the molecular and cellular mechanisms underlying the substantial variability of evolutionary rates across cellular proteins are not currently well understood. It also remains unclear how protein molecular function is optimized in the context of multicellular species and why many proteins, such as enzymes, are only moderately efficient on average. Our analysis of genomics and functional datasets reveals in multiple organisms a strong inverse relationship between the optimality of protein molecular function and the rate of protein evolution. Furthermore, we find that highly expressed proteins tend to be substantially more functionally optimized. These results suggest that cellular expression costs lead to more pronounced functional optimization of abundant proteins and that the purifying selection to maintain high levels of functional optimality significantly slows protein evolution. We observe that in multicellular species both the rate of protein evolution and the degree of protein functional efficiency are primarily affected by expression in several distinct cell types and tissues, specifically, in developed neurons with upregulated synaptic processes in animals and in young and fast-growing tissues in plants. Overall, our analysis reveals how various constraints from the molecular, cellular, and species' levels of biological organization jointly affect the rate of protein evolution and the level of protein functional adaptation., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Molecular Biology and Evolution.)

Metastases arise from subsets of cancer cells that disseminate from the primary tumour 1,2 . The ability of cancer cells to thrive in a new tissue site is influenced by genetic and epigenetic changes that are important for disease initiation and progression, but these factors alone do not predict if and where cancers metastasize 3,4 . Specific cancer types metastasize to consistent subsets of tissues, suggesting that primary tumour-associated factors influence where cancers can grow. We find primary and metastatic pancreatic tumours have metabolic similarities and that the tumour-initiating capacity and proliferation of both primary-derived and metastasis-derived cells is favoured in the primary site relative to the metastatic site. Moreover, propagating cells as tumours in the lung or the liver does not enhance their relative ability to form large tumours in those sites, change their preference to grow in the primary site, nor stably alter aspects of their metabolism relative to primary tumours. Primary liver and lung cancer cells also exhibit a preference to grow in their primary site relative to metastatic sites. These data suggest cancer tissue of origin influences both primary and metastatic tumour metabolism and may impact where cancer cells can metastasize., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Cholesterol biosynthesis is a highly regulated, oxygen-dependent pathway, vital for cell membrane integrity and growth. In fungi, the dependency on oxygen for sterol production has resulted in a shared transcriptional response, resembling prolyl hydroxylation of Hypoxia Inducible Factors (HIFs) in metazoans. Whether an analogous metazoan pathway exists is unknown. Here, we identify Sterol Regulatory Element Binding Protein 2 (SREBP2), the key transcription factor driving sterol production in mammals, as an oxygen-sensitive regulator of cholesterol synthesis. SREBP2 degradation in hypoxia overrides the normal sterol-sensing response, and is HIF independent. We identify MARCHF6, through its NADPH-mediated activation in hypoxia, as the main ubiquitin ligase controlling SREBP2 stability. Hypoxia-mediated degradation of SREBP2 protects cells from statin-induced cell death by forcing cells to rely on exogenous cholesterol uptake, explaining why many solid organ tumours become auxotrophic for cholesterol. Our findings therefore uncover an oxygen-sensitive pathway for governing cholesterol synthesis through regulated SREBP2-dependent protein degradation., (© 2023. Springer Nature Limited.)

Production of oxidized biomass, which requires regeneration of the cofactor NAD + , can be a proliferation bottleneck that is influenced by environmental conditions. However, a comprehensive quantitative understanding of metabolic processes that may be affected by NAD + deficiency is currently missing. Here, we show that de novo lipid biosynthesis can impose a substantial NAD + consumption cost in proliferating cancer cells. When electron acceptors are limited, environmental lipids become crucial for proliferation because NAD + is required to generate precursors for fatty acid biosynthesis. We find that both oxidative and even net reductive pathways for lipogenic citrate synthesis are gated by reactions that depend on NAD + availability. We also show that access to acetate can relieve lipid auxotrophy by bypassing the NAD + consuming reactions. Gene expression analysis demonstrates that lipid biosynthesis strongly anti-correlates with expression of hypoxia markers across tumor types. Overall, our results define a requirement for oxidative metabolism to support biosynthetic reactions and provide a mechanistic explanation for cancer cell dependence on lipid uptake in electron acceptor-limited conditions, such as hypoxia., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)