Fundamental trade-offs between information flow in single cells and cellular populations

Signal transduction networks allow eukaryotic cells to make decisions based on information about intracellular state and the environment. Biochemical noise significantly diminishes the fidelity of signaling: networks examined to date seem to transmit less than 1 bit of information. It is unclear how networks that control critical cell-fate decisions (e.g., cell division and apoptosis) can function with such low levels of information transfer. Here, we use theory, experiments, and numerical analysis to demonstrate an inherent trade-off between the information transferred in individual cells and the information available to control population-level responses. Noise in receptor-mediated apoptosis reduces information transfer to approximately 1 bit at the single-cell level but allows 3–4 bits of information to be transmitted at the population level. For processes such as eukaryotic chemotaxis, in which single cells are the functional unit, we find high levels of information transmission at a single-cell level. Thus, low levels of information transfer are unlikely to represent a physical limit. Instead, we propose that signaling networks exploit noise at the single-cell level to increase population-level information transfer, allowing extracellular ligands, whose levels are also subject to noise, to incrementally regulate phenotypic changes. This is particularly critical for discrete changes in fate (e.g., life vs. death) for which the key variable is the fraction of cells engaged. Our findings provide a framework for rationalizing the high levels of noise in metazoan signaling networks and have implications for the development of drugs that target these networks in the treatment of cancer and other diseases

The combined effects of reactant kinetics and enzyme stability explain the temperature dependence of metabolic rates

A mechanistic understanding of the response of metabolic rate to temperature is essential for understanding thermal ecology and metabolic adaptation. Although the Arrhenius equation has been used to describe the effects of temperature on reaction rates and metabolic traits, it does not adequately describe two aspects of the thermal performance curve (TPC) for metabolic rate—that metabolic rate is a unimodal function of temperature often with maximal values in the biologically relevant temperature range and that activation energies are temperature dependent. We show that the temperature dependence of metabolic rate in ectotherms is well described by an enzyme-assisted Arrhenius (EAAR) model that accounts for the temperature-dependent contribution of enzymes to decreasing the activation energy required for reactions to occur. The model is mechanistically derived using the thermodynamic rules that govern protein stability. We contrast our model with other unimodal functions that also can be used to describe the temperature dependence of metabolic rate to show how the EAAR model provides an important advance over previous work. We fit the EAAR model to metabolic rate data for a variety of taxa to demonstrate the model’s utility in describing metabolic rate TPCs while revealing significant differences in thermodynamic properties across species and acclimation temperatures. Our model advances our ability to understand the metabolic and ecological consequences of increases in the mean and variance of temperature associated with global climate change. In addition, the model suggests avenues by which organisms can acclimate and adapt to changing thermal environments. Furthermore, the parameters in the EAAR model generate links between organismal level performance and underlying molecular processes that can be tested for in future work

The Monitoring the Future Project After Four Decades: Design and Procedures

http://deepblue.lib.umich.edu/bitstream/2027.42/170919/1/mtf-occ82.pdfSEL

Multi-Polygenic Analysis of Nicotine Dependence in Individuals of European Ancestry

Introduction: Heritability estimates of nicotine dependence (ND) range from 40% to 70%, but discovery GWAS of ND are underpowered and have limited predictive utility. In this work, we leverage genetically correlated traits and diseases to increase the accuracy of polygenic risk prediction. Methods: We employed a multi-trait model using summary statistic-based best linear unbiased predictors (SBLUP) of genetic correlates of DSM-IV diagnosis of ND in 6394 individuals of European Ancestry (prevalence = 45.3%, %female = 46.8%, mu(age) = 40.08 [s.d. = 10.43]) and 3061 individuals from a nationally-representative sample with Fagerstrom Test for Nicotine Dependence symptom count (FTND; 51.32% female, mean age = 28.9 [s.d. = 1.70]). Polygenic predictors were derived from GWASs known to be phenotypically and genetically correlated with ND (i.e., Cigarettes per Day [CPD], the Alcohol Use Disorders Identification Test [AUDIT-Consumption and AUDIT-Problems], Neuroticism, Depression, Schizophrenia, Educational Attainment, Body Mass Index [BMI], and Self-Perceived Risk-Taking); including Height as a negative control. Analyses controlled for age, gender, study site, and the first 10 ancestral principal components. Results: The multi-trait model accounted for 3.6% of the total trait variance in DSM-IV ND. Educational Attainment (beta = -0.125; 95% CI: [-0.149,-0.101]), CPD (0.071 [0.047,0.095]), and Self-Perceived Risk-Taking (0.051 [0.026,0.075]) were the most robust predictors. PGS effects on FTND were limited. Conclusions: Risk for ND is not only polygenic, but also pleiotropic. Polygenic effects on ND that are accessible by these traits are limited in size and act additively to explain risk.Peer reviewe

Monitoring the Future Panel Study annual report: National data on substance use among adults ages 19 to 60, 1976-2021.

http://deepblue.lib.umich.edu/bitstream/2027.42/175555/1/mtfpanelreport2022.pdfSEL

Multi-omic and multi-species meta-analyses of nicotine consumption.

Cross-species translational approaches to human genomic analyses are lacking. The present study uses an integrative framework to investigate how genes associated with nicotine use in model organisms contribute to the genetic architecture of human tobacco consumption. First, we created a model organism geneset by collecting results from five animal models of nicotine exposure (RNA expression changes in brain) and then tested the relevance of these genes and flanking genetic variation using genetic data from human cigarettes per day (UK BioBank N = 123,844; all European Ancestry). We tested three hypotheses: (1) DNA variation in, or around, the \u27model organism geneset\u27 will contribute to the heritability to human tobacco consumption, (2) that the model organism genes will be enriched for genes associated with human tobacco consumption, and (3) that a polygenic score based off our model organism geneset will predict tobacco consumption in the AddHealth sample (N = 1667; all European Ancestry). Our results suggested that: (1) model organism genes accounted for ~5-36% of the observed SNP-heritability in human tobacco consumption (enrichment: 1.60-31.45), (2) model organism genes, but not negative control genes, were enriched for the gene-based associations (MAGMA, H-MAGMA, SMultiXcan) for human cigarettes per day, and (3) polygenic scores based on our model organism geneset predicted cigarettes per day in an independent sample. Altogether, these findings highlight the advantages of using multiple species evidence to isolate genetic factors to better understand the etiological complexity of tobacco and other nicotine consumption

Caregiver Behavior Change for Child Survival and Development in Low- and Middle-Income Countries: An Examination of the Evidence

In June of 2012, representatives from more than 80 countries promulgated a Child Survival Call to Action, which called for reducing child mortality to 20 or fewer child deaths per 1,000 live births in every country by 2035. To address the problem of ending preventable child deaths, the U.S. Agency for International Development and the United Nations Children’s Fund convened, on June 3–4, 2013, an Evidence Summit on Enhancing Child Survival and Development in Lower- and Middle-Income Countries by Achieving Population-Level Behavior Change. Six evidence review teams were established on different topics related to child survival and healthy development to identify the relevant evidence-based interventions and to prepare reports. This article was developed by the evidence review team responsible for identifying the research literature on caregiver change for child survival and development. This article is organized into childhood developmental periods and cross-cutting issues that affect child survival and healthy early development across all these periods. On the basis of this review, the authors present evidence-based recommendations for programs focused on caregivers to increase child survival and promote healthy development. Last, promising directions for future research to change caregivers’ behaviors are given

Safety and efficacy of a testosterone patch for the treatment of hypoactive sexual desire disorder in surgically menopausal women: a randomized, placebo-controlled trial.

Background: Oophorectomy reduces serum testosterone levels. We studied the efficacy and safety of transdermal testosterone in treating hypoactive sexual desire disorder in surgically menopausal women

Religion's Role in Promoting Health and Reducing Risk Among American Youth

Although past research has long documented religion's salutary impact on adult health-related behaviors and outcomes, relatively little research has examined the relationship between religion and adolescent health. This study uses large, nationally representative samples of high school seniors to examine the relationship between religion and behavioral predictors of adolescent morbidity and mortality. Relative to their peers, religious youth are less likely to engage in behaviors that compromise their health (e.g., carrying weapons, getting into fights, drinking and driving) and are more likely to behave in ways that enhance their health (e.g., proper nutrition, exercise, and rest). Multivariate analyses suggest that these relationships persist even after controlling for demographic factors, and trend analyses reveal that they have existed over time. Particularly important is the finding that religious seniors have been relatively unaffected by past and recent increases in marijuana use.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66995/2/10.1177_109019819802500604.pd

Frontal circulation and submesoscale variability during the formation of a Southern Ocean mesoscale eddy

AbstractObservations made in the Scotia Sea during the May 2015 Surface Mixed Layer Evolution at Submesoscales (SMILES) research cruise captured submesoscale, O(1-10 km), variability along the periphery of a mesoscale O(10-100 km) meander precisely as it separated from the Antarctic Circumpolar Current (ACC) and formed a cyclonic eddy ~ 120 km in diameter. The meander developed in the Scotia Sea, an eddy-rich region east of the Drake Passage where the Subantarctic and Polar fronts converge and modifications of Subantarctic mode water (SAMW) occur. In situ measurements reveal a rich submesoscale structure of temperature and salinity and a loss of frontal integrity along the newly-formed southern sector of the eddy. A mathematical framework is developed to estimate vertical velocity from co-located drifter and horizontal water velocity time series, under certain simplifying assumptions appropriate for the current data set. Upwelling (downwelling) rates of O(100 m day-1) are found in the northern (southern) eddy sector. Favorable conditions for submesoscale instabilities are found in the mixed layer, particularly at the beginning of the survey in the vicinity of density fronts. Shallower mixed layer depths and increased stratification are observed later in the survey on the inner edge of the front. Evolution in T-S space indicates modification of water mass properties in the upper 200 m over 2 days. Modifications along �θ 27 - 27.2 kg m�3 have climate-related implications for mode and intermediate water transformation in the Scotia Sea on finer spatiotemporal scales than observed previously