Stanford Advisors

All Publications

  • Optimized Replacement T4 and T4+T3 Dosing in Male and Female Hypothyroid Patients With Different BMIs Using a Personalized Mechanistic Model of Thyroid Hormone Regulation Dynamics FRONTIERS IN ENDOCRINOLOGY Cruz-Loya, M., Chu, B. B., Jonklaas, J., Schneider, D. F., DiStefano, J. 2022; 13: 888429


    A personalized simulation tool, p-THYROSIM, was developed (1) to better optimize replacement LT4 and LT4+LT3 dosing for hypothyroid patients, based on individual hormone levels, BMIs, and gender; and (2) to better understand how gender and BMI impact thyroid dynamical regulation over time in these patients.p-THYROSIM was developed by (1) modifying and refining THYROSIM, an established physiologically based mechanistic model of the system regulating serum T3, T4, and TSH level dynamics; (2) incorporating sex and BMI of individual patients into the model; and (3) quantifying it with 3 experimental datasets and validating it with a fourth containing data from distinct male and female patients across a wide range of BMIs. For validation, we compared our optimized predictions with previously published results on optimized LT4 monotherapies. We also optimized combination T3+T4 dosing and computed unmeasured residual thyroid function (RTF) across a wide range of BMIs from male and female patient data.Compared with 3 other dosing methods, the accuracy of p-THYROSIM optimized dosages for LT4 monotherapy was better overall (53% vs. 44%, 43%, and 38%) and for extreme BMI patients (63% vs. ~51% low BMI, 48% vs. ~36% and 22% for high BMI). Optimal dosing for combination LT4+LT3 therapy and unmeasured RTFs was predictively computed with p-THYROSIM for male and female patients in low, normal, and high BMI ranges, yielding daily T3 doses of 5 to 7.5 μg of LT3 combined with 62.5-100 μg of LT4 for women or 75-125 μg of LT4 for men. Also, graphs of steady-state serum T3, T4, and TSH concentrations vs. RTF (range 0%-50%) for untreated patients showed that neither BMI nor gender had any effect on RTF predictions for our patient cohort data. Notably, the graphs provide a means for estimating unmeasurable RTFs for individual patients from their hormone measurements before treatment.p-THYROSIM can provide accurate monotherapies for male and female hypothyroid patients, personalized with their BMIs. Where combination therapy is warranted, our results predict that not much LT3 is needed in addition to LT4 to restore euthyroid levels, suggesting opportunities for further research exploring combination therapy with lower T3 doses and slow-releasing T3 formulations.

    View details for DOI 10.3389/fendo.2022.888429

    View details for Web of Science ID 000834032700001

    View details for PubMedID 35909562

    View details for PubMedCentralID PMC9330449

  • Antibiotics Shift the Temperature Response Curve of Escherichia coli Growth MSYSTEMS Cruz-Loya, M., Tekin, E., Kang, T., Cardona, N., Lozano-Huntelman, N., Rodriguez-Verdugo, A., Savage, V. M., Yeh, P. J. 2021; 6 (4): e0022821


    Temperature variation-through time and across climatic gradients-affects individuals, populations, and communities. Yet how the thermal response of biological systems is altered by environmental stressors is poorly understood. Here, we quantify two key features-optimal temperature and temperature breadth-to investigate how temperature responses vary in the presence of antibiotics. We use high-throughput screening to measure growth of Escherichia coli under single and pairwise combinations of 12 antibiotics across seven temperatures that range from 22°C to 46°C. We find that antibiotic stress often results in considerable changes in the optimal temperature for growth and a narrower temperature breadth. The direction of the optimal temperature shifts can be explained by the similarities between antibiotic-induced and temperature-induced damage to the physiology of the bacterium. We also find that the effects of pairs of stressors in the temperature response can often be explained by just one antibiotic out of the pair. Our study has implications for a general understanding of how ecological systems adapt and evolve to environmental changes. IMPORTANCE The growth of living organisms varies with temperature. This dependence is described by a temperature response curve that is described by an optimal temperature where growth is maximized and a temperature range (termed breadth) across which the organism can grow. Because an organism's temperature response evolves or acclimates to its environment, it is often assumed to change over only evolutionary or developmental timescales. Counter to this, we show here that antibiotics can quickly (over hours) change the optimal growth temperature and temperature breadth for the bacterium Escherichia coli. Moreover, our results suggest a shared-damage hypothesis: when an antibiotic damages similar cellular components as hot (or cold) temperatures do, this shared damage will combine and compound to more greatly reduce growth when that antibiotic is administered at hot (or cold) temperatures. This hypothesis could potentially also explain how temperature responses are modified by stressors other than antibiotics.

    View details for DOI 10.1128/mSystems.00228-21

    View details for Web of Science ID 000709920600013

    View details for PubMedID 34282938

    View details for PubMedCentralID PMC8422994

  • Hidden suppressive interactions are common in higher-order drug combinations ISCIENCE Lozano-Huntelman, N., Zhou, A., Tekin, E., Cruz-Loya, M., Ostman, B., Boyd, S., Savage, V. M., Yeh, P. 2021; 24 (4): 102355


    The rapid increase of multi-drug resistant bacteria has led to a greater emphasis on multi-drug combination treatments. However, some combinations can be suppressive-that is, bacteria grow faster in some drug combinations than when treated with a single drug. Typically, when studying interactions, the overall effect of the combination is only compared with the single-drug effects. However, doing so could miss "hidden" cases of suppression, which occur when the highest order is suppressive compared with a lower-order combination but not to a single drug. We examined an extensive dataset of 5-drug combinations and all lower-order-single, 2-, 3-, and 4-drug-combinations. We found that a majority of all combinations-54%-contain hidden suppression. Examining hidden interactions is critical to understanding the architecture of higher-order interactions and can substantially affect our understanding and predictions of the evolution of antibiotic resistance under multi-drug treatments.

    View details for DOI 10.1016/j.isci.2021.102355

    View details for Web of Science ID 000642261700099

    View details for PubMedID 33870144

    View details for PubMedCentralID PMC8044428

  • Using a newly introduced framework to measure ecological stressor interactions ECOLOGY LETTERS Tekin, E., Diamant, E. S., Cruz-Loya, M., Enriquez, V., Singh, N., Savage, V. M., Yeh, P. J. 2020; 23 (9): 1391-1403


    Understanding how stressors combine to affect population abundances and trajectories is a fundamental ecological problem with increasingly important implications worldwide. Generalisations about interactions among stressors are challenging due to different categorisation methods and how stressors vary across species and systems. Here, we propose using a newly introduced framework to analyse data from the last 25 years on ecological stressor interactions, for example combined effects of temperature, salinity and nutrients on population survival and growth. We contrast our results with the most commonly used existing method - analysis of variance (ANOVA) - and show that ANOVA assumptions are often violated and have inherent limitations for detecting interactions. Moreover, we argue that rescaling - examining relative rather than absolute responses - is critical for ensuring that any interaction measure is independent of the strength of single-stressor effects. In contrast, non-rescaled measures - like ANOVA - find fewer interactions when single-stressor effects are weak. After re-examining 840 two-stressor combinations, we conclude that antagonism and additivity are the most frequent interaction types, in strong contrast to previous reports that synergy dominates yet supportive of more recent studies that find more antagonism. Consequently, measuring and re-assessing the frequency of stressor interaction types is imperative for a better understanding of how stressors affect populations.

    View details for DOI 10.1111/ele.13533

    View details for Web of Science ID 000545317000001

    View details for PubMedID 32627356

  • Compounding Effects of Climate Warming and Antibiotic Resistance ISCIENCE Rodriguez-Verdugo, A., Lozano-Huntelman, N., Cruz-Loya, M., Savage, V., Yeh, P. 2020; 23 (4): 101024


    Bacteria have evolved diverse mechanisms to survive environments with antibiotics. Temperature is both a key factor that affects the survival of bacteria in the presence of antibiotics and an environmental trait that is drastically increasing due to climate change. Therefore, it is timely and important to understand links between temperature changes and selection of antibiotic resistance. This review examines these links by synthesizing results from laboratories, hospitals, and environmental studies. First, we describe the transient physiological responses to temperature that alter cellular behavior and lead to antibiotic tolerance and persistence. Second, we focus on the link between thermal stress and the evolution and maintenance of antibiotic resistance mutations. Finally, we explore how local and global changes in temperature are associated with increases in antibiotic resistance and its spread. We suggest that a multidisciplinary, multiscale approach is critical to fully understand how temperature changes are contributing to the antibiotic crisis.

    View details for DOI 10.1016/j.isci.2020.101024

    View details for Web of Science ID 000528359400054

    View details for PubMedID 32299057

    View details for PubMedCentralID PMC7160571

  • Stressor interaction networks suggest antibiotic resistance co-opted from stress responses to temperature ISME JOURNAL Cruz-Loya, M., Kang, T., Lozano, N., Watanabe, R., Tekin, E., Damoiseaux, R., Savage, V. M., Yeh, P. J. 2019; 13 (1): 12-23


    Environmental factors like temperature, pressure, and pH partly shaped the evolution of life. As life progressed, new stressors (e.g., poisons and antibiotics) arose as part of an arms race among organisms. Here we ask if cells co-opted existing mechanisms to respond to new stressors, or whether new responses evolved de novo. We use a network-clustering approach based purely on phenotypic growth measurements and interactions among the effects of stressors on population growth. We apply this method to two types of stressors-temperature and antibiotics-to discover the extent to which their cellular responses overlap in Escherichia coli. Our clustering reveals that responses to low and high temperatures are clearly separated, and each is grouped with responses to antibiotics that have similar effects to cold or heat, respectively. As further support, we use a library of transcriptional fluorescent reporters to confirm heat-shock and cold-shock genes are induced by antibiotics. We also show strains evolved at high temperatures are more sensitive to antibiotics that mimic the effects of cold. Taken together, our results strongly suggest that temperature stress responses have been co-opted to deal with antibiotic stress.

    View details for DOI 10.1038/s41396-018-0241-7

    View details for Web of Science ID 000453576600002

    View details for PubMedID 30171253

    View details for PubMedCentralID PMC6298959

  • Prevalence and patterns of higher-order drug interactions in Escherichia coli NPJ SYSTEMS BIOLOGY AND APPLICATIONS Tekin, E., White, C., Kang, T., Singh, N., Cruz-Loya, M., Damoiseaux, R., Savage, V. M., Yeh, P. J. 2018; 4: 31


    Interactions and emergent processes are essential for research on complex systems involving many components. Most studies focus solely on pairwise interactions and ignore higher-order interactions among three or more components. To gain deeper insights into higher-order interactions and complex environments, we study antibiotic combinations applied to pathogenic Escherichia coli and obtain unprecedented amounts of detailed data (251 two-drug combinations, 1512 three-drug combinations, 5670 four-drug combinations, and 13608 five-drug combinations). Directly opposite to previous assumptions and reports, we find higher-order interactions increase in frequency with the number of drugs in the bacteria's environment. Specifically, as more drugs are added, we observe an elevated frequency of net synergy (effect greater than expected based on independent individual effects) and also increased instances of emergent antagonism (effect less than expected based on lower-order interaction effects). These findings have implications for the potential efficacy of drug combinations and are crucial for better navigating problems associated with the combinatorial complexity of multi-component systems.

    View details for DOI 10.1038/s41540-018-0069-9

    View details for Web of Science ID 000459658100001

    View details for PubMedID 30181902

    View details for PubMedCentralID PMC6119685