skip to main content
US FlagAn official website of the United States government
dot gov icon
Official websites use .gov
A .gov website belongs to an official government organization in the United States.
https lock icon
Secure .gov websites use HTTPS
A lock ( lock ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.


Title: Disease from opposing forces in regulatory control
Abstract Danger requires a strong rapid response. Speedy triggers are prone to false signals. False alarms can be costly, requiring strong negative regulators to oppose the initial triggers. Strongly opposed forces can easily be perturbed, leading to imbalance and disease. For example, immunity and fear response balance strong rapid triggers against widespread slow negative regulators. Diseases of immunity and behavior arise from imbalance. A different opposition of forces occurs in mammalian growth, which balances strong paternally expressed accelerators against maternally expressed suppressors. Diseases of overgrowth or undergrowth arise from imbalance. Other examples of opposing forces and disease include control of dopamine expression and male versus female favored traits.  more » « less
Award ID(s):
1939423
PAR ID:
10470145
Author(s) / Creator(s):
Publisher / Repository:
Oxford University Press
Date Published:
Journal Name:
Evolution, Medicine, and Public Health
Volume:
11
Issue:
1
ISSN:
2050-6201
Format(s):
Medium: X Size: p. 348-352
Size(s):
p. 348-352
Sponsoring Org:
National Science Foundation
More Like this
  1. Abstract Neopterin, a product of activated white blood cells, is a marker of nonspecific inflammation that can capture variation in immune investment or disease-related immune activity and can be collected noninvasively in urine. Mounting studies in wildlife point to lifetime patterns in neopterin related to immune development, aging, and certain diseases, but rarely are studies able to assess whether neopterin can capture multiple concurrent dimensions of health and disease in a single system. We assessed the relationship between urinary neopterin stored on filter paper and multiple metrics of health and disease in wild geladas (Theropithecus gelada), primates endemic to the Ethiopian highlands. We tested whether neopterin captures age-related variation in inflammation arising from developing immunity in infancy and chronic inflammation in old age, inflammation related to intramuscular tapeworm infection, helminth-induced anti-inflammatory immunomodulation, and perturbations in the gastrointestinal microbiome. We found that neopterin had a U-shaped relationship with age, no association with larval tapeworm infection, a negative relationship with metrics related to gastrointestinal helminth infection, and a negative relationship with microbial diversity. Together with growing research on neopterin and specific diseases, our results demonstrate that urinary neopterin can be a powerful tool for assessing multiple dimensions of health and disease in wildlife. 
    more » « less
  2. Abstract Macrophages perform critical functions for homeostasis and immune defense in tissues throughout the body. These innate immune cells are capable of recognizing and clearing dead cells and pathogens, and orchestrating inflammatory and healing processes that occur in response to injury. In addition, macrophages are involved in the progression of many inflammatory diseases including cardiovascular disease, fibrosis, and cancer. Although it has long been known that macrophages respond dynamically to biochemical signals in their microenvironment, the role of biophysical cues has only recently emerged. Furthermore, many diseases that involve macrophages are also characterized by changes to the tissue biophysical environment. This review will discuss current knowledge about the effects of biophysical cues including matrix stiffness, material topography, and applied mechanical forces, on macrophage behavior. We will also describe the role of molecules that are known to be important for mechanotransduction, including adhesion molecules, ion channels, as well as nuclear mediators such as transcription factors, scaffolding proteins, and epigenetic regulators. Together, this review will illustrate a developing role of biophysical cues in macrophage biology, and also speculate upon molecular targets that may potentially be exploited therapeutically to treat disease. 
    more » « less
  3. Schneider, David S. (Ed.)
    The immune system continually battles against pathogen-induced pressures, which often leads to the evolutionary expansion of immune gene families in a species-specific manner. For example, thepalsgene family expanded to 39 members in theCaenorhabditis elegansgenome, in comparison to a single mammalianpalsortholog. Our previous studies have revealed that two members of this family,pals-22andpals-25, act as antagonistic paralogs to control the Intracellular Pathogen Response (IPR). The IPR is a protective transcriptional response, which is activated upon infection by two molecularly distinct natural intracellular pathogens ofC.elegans–the Orsay virus and the fungusNematocida parisiifrom the microsporidia phylum. In this study, we identify a previously uncharacterized member of thepalsfamily,pals-17, as a newly described negative regulator of the IPR.pals-17mutants show constitutive upregulation of IPR gene expression, increased immunity against intracellular pathogens, as well as impaired development and reproduction. We also find that two other previously uncharacterizedpalsgenes,pals-20andpals-16, are positive regulators of the IPR, acting downstream ofpals-17. These positive regulators reverse the effects caused by the loss ofpals-17on IPR gene expression, immunity, and development. We show that the negative IPR regulator protein PALS-17 and the positive IPR regulator protein PALS-20 colocalize inside and at the apical side of intestinal epithelial cells, which are the sites of infection for IPR-inducing pathogens. In summary, our study demonstrates that severalpalsgenes from the expandedpalsgene family act as ON/OFF switch modules to regulate a balance between organismal development and immunity against natural intracellular pathogens inC.elegans. 
    more » « less
  4. Alba, Mar (Ed.)
    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 aging. 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 coevolving 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 evolutionary processes of TCAI that were associated with rapid gene duplication in the early stages of vertebrates and subsequent sequence changes in TCAI-related genes. The analysis of vertebrate genomes provides evidence that a "big bang" of adaptive immune genes occurred 300-500 million years ago. These processes together suggest an early genetic construction of the vertebrate immune system and subsequent molecular adaptation to diverse antigens. 
    more » « less
  5. Abstract The hydrostatic equilibrium addresses the approximate balance between the positive force of the vertical pressure gradient and the negative gravity force and has been widely assumed for atmospheric applications. The hydrostatic imbalance of the mean atmospheric state for the acceleration of vertical motions in the vertical momentum balance is investigated using tower, the global positioning system radiosonde, and Doppler lidar and radar observations throughout the diurnally varying atmospheric boundary layer (ABL) under clear-sky conditions. Because of the negligibly small mean vertical velocity, the acceleration of vertical motions is dominated by vertical variations of vertical turbulent velocity variances. The imbalance is found to be mainly due to the vertical turbulent transport of changing air density as a result of thermal expansion/contraction in response to air temperature changes following surface temperature changes. In contrast, any pressure change associated with air temperature changes is small, and the positive vertical pressure-gradient force is strongly influenced by its background value. The vertical variation of the turbulent velocity variance from its vertical increase in the lower convective boundary layer (CBL) to its vertical decrease in the upper CBL is observed to be associated with the sign change of the imbalance from positive to negative due to the vertical decrease of the positive vertical pressure-gradient force and the relative increase of the negative gravity force as a result of the decreasing upward transport of the low-density air. The imbalance is reduced significantly at night but does not steadily approach zero. Understanding the development of hydrostatic imbalance has important implications for understanding large-scale atmosphere, especially for cloud development. Significance StatementIt is well known that the hydrostatic imbalance between the positive pressure-gradient force due to the vertical decrease of atmospheric pressure and the negative gravity forces in the vertical momentum balance equation has important impacts on the vertical acceleration of atmospheric vertical motions. Vertical motions for mass, momentum, and energy transfers contribute significantly to changing atmospheric dynamics and thermodynamics. This study investigates the often-assumed hydrostatic equilibrium and investigate how the hydrostatic imbalance is developed using field observations in the atmospheric boundary layer under clear-sky conditions. The results reveal that hydrostatic imbalance can develop from the large-eddy turbulent transfer of changing air density in response to the surface diabatic heating/cooling. The overwhelming turbulence in response to large-scale thermal forcing and mechanical work of the vast Earth surface contributes to the hydrostatic imbalance on large spatial and temporal scales in numerical weather forecast and climate models. 
    more » « less