Biology as a Construct: Universals, Historicity, and the Postmodern Critique.

The integration of postmodern thinking in the sciences, especially in biology, has been subject to harsh criticism. Contrary to Enlightenment ideals of objectivity and neutrality in the scientific method, the postmodern stance holds that truth is relative, not universal, and therefore progress is ambiguous. The effect of postmodern thought has ramifications that extend from the distrust of preexisting scientific conclusions to questions about the impact of progress in society.

Nontraditional models as research tools: the road not taken.

Historical reasons resulted in the almost exclusive use of a few species, most prominently Mus musculus, as the mainstream models in biomedical research. This selection was not based on Mus's distinctive relevance to human disease but rather to the pre-existing availability of resources and tools for the species that were used as models, which has enabled their adoption for research in health sciences. Unless the utilization and range of nontraditional research models expand considerably, progress in biomedical research will remain restricted within the trajectory that has been set by the existing models and their ability to provide clinically relevant information.

Pair bonding and disruption impact lung transcriptome in monogamous Peromyscus californicus.

Social interactions affect physiological and pathological processes, yet their direct impact in peripheral tissues remains elusive. Recently we showed that disruption of pair bonds in monogamous Peromyscus californicus promotes lung tumorigenesis, pointing to a direct effect of bonding status in the periphery (Naderi et al., 2021).

Universal DNA methylation age across mammalian tissues.

Aging, often considered a result of random cellular damage, can be accurately estimated using DNA methylation profiles, the foundation of pan-tissue epigenetic clocks. Here, we demonstrate the development of universal pan-mammalian clocks, using 11,754 methylation arrays from our Mammalian Methylation Consortium, which encompass 59 tissue types across 185 mammalian species. These predictive models estimate mammalian tissue age with high accuracy (r > 0.

DNA methylation networks underlying mammalian traits.

Using DNA methylation profiles ( = 15,456) from 348 mammalian species, we constructed phyloepigenetic trees that bear marked similarities to traditional phylogenetic ones. Using unsupervised clustering across all samples, we identified 55 distinct cytosine modules, of which 30 are related to traits such as maximum life span, adult weight, age, sex, and human mortality risk. Maximum life span is associated with methylation levels in subclass homeobox genes and developmental processes and is potentially regulated by pluripotency transcription factors.

The SARS-CoV-2 spike protein induces long-term transcriptional perturbations of mitochondrial metabolic genes, causes cardiac fibrosis, and reduces myocardial contractile in obese mice.

Background: As the pandemic evolves, post-acute sequelae of CoV-2 (PASC) including cardiovascular manifestations have emerged as a new health threat. This study aims to study whether the Spike protein plus obesity can exacerbate PASC-related cardiomyopathy.

Methods: A Spike protein-pseudotyped (Spp) virus with the proper surface tropism of SARS-CoV-2 was developed for viral entry assay in vitro and administration into high fat diet (HFD)-fed mice.

RASSF1 is identified by transcriptome coordination analysis as a target of ATF4.

Evaluation of gene co-regulation is a powerful approach for revealing regulatory associations between genes and predicting biological function, especially in genetically diverse samples. Here, we applied this strategy to identify transcripts that are co-regulated with unfolded protein response (UPR) genes in cultured fibroblasts from outbred deer mice. Our analyses showed that the transcriptome associated with RASSF1, a tumor suppressor involved in cell cycle regulation and not previously linked to UPR, is highly correlated with the transcriptome of several UPR-related genes, such as BiP/GRP78, DNAJB9, GRP94, ATF4, DNAJC3, and CHOP/DDIT3.

The SARS-CoV-2 Spike protein induces long-term transcriptional perturbations of mitochondrial metabolic genes, causes cardiac fibrosis, and reduces myocardial contractile in obese mice.

Background: As the pandemic evolves, post-acute sequelae of CoV-2 (PACS) including cardiovascular manifestations have emerged as a new health threat. This study aims to study whether the Spike protein plus obesity can exacerbate PACS-related cardiomyopathy.

Methods: A Spike protein-pseudotyped (Spp) virus with the proper surface tropism of SARS-CoV-2 was developed for viral entry assay and administration into high fat diet (HFD)-fed mice.

Genetic Analysis of the Stereotypic Phenotype in Peromyscus maniculatus (deer mice).

Peromyscus maniculatus, including the laboratory stock BW, have been used as a model organism for autism spectrum disorder and obsessive-compulsive disorder because of the high occurrence of stereotypy. Several studies have identified neurological and environmental components of the phenotype; however, the heritability of the phenotype has not been examined. This study characterizes the incidence and heritability of vertical jumping stereotypy (VS) and backflipping (BF) behavior in the BW stock of the Peromyscus Genetic Stock Center, which are indicative of autism spectrum disorders.

Beneficial effects of CCL8 inhibition at lipopolysaccharide-induced lung injury.

CCL8 (MCP-2) is a chemoattractive cytokine associated with various immune-related pathologies. Recent studies show that CCL8 is significantly stimulated during acute respiratory distress syndrome in severely ill patients with COVID-19, making the inhibition of CCL8 activity a promising treatment. Lipopolysaccharide (LPS)-induced lung injury was evaluated in mice using a neutralizing antibody (1G3E5) against human CCL8.

SARS-CoV-2 infects multiple species of North American deer mice and causes clinical disease in the California mouse.

Unlabelled: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the virus that causes coronavirus disease-19 (COVID-19), emerged in late 2019 in Wuhan, China and its rapid global spread has resulted in millions of deaths. An important public health consideration is the potential for SARS-CoV-2 to establish endemicity in a secondary animal reservoir outside of Asia or acquire adaptations that result in new variants with the ability to evade the immune response and reinfect the human population. Previous work has shown that North American deer mice ( ) are susceptible and can transmit SARS-CoV-2 to naïve conspecifics, indicating its potential to serve as a wildlife reservoir for SARS-CoV-2 in North America.

The Spike Protein of SARS-CoV-2 Impairs Lipid Metabolism and Increases Susceptibility to Lipotoxicity: Implication for a Role of Nrf2.

Coronavirus disease 2019 (COVID-19) patients show lipid metabolic alterations, but the mechanism remains unknown. In this study, we aimed to investigate whether the Spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) impairs lipid metabolism in host cells. We generated a Spike cell line in HEK293 using the pcDNA vector carrying the Spike gene expression cassette.

Methylation studies in Peromyscus: aging, altitude adaptation, and monogamy.

DNA methylation-based biomarkers of aging have been developed for humans and many other mammals and could be used to assess how stress factors impact aging. Deer mice (Peromyscus) are long-living rodents that have emerged as an informative model to study aging, adaptation to extreme environments, and monogamous behavior. In the present study, we have undertaken an exhaustive, genome-wide analysis of DNA methylation in Peromyscus, spanning different species, stocks, sexes, tissues, and age cohorts.

Propensity to endoplasmic reticulum stress in deer mouse fibroblasts predicts skin inflammation and body weight gain.

The unfolded protein response (UPR) is involved in the pathogenesis of metabolic disorders, yet whether variations in the UPR among individuals influence the propensity for metabolic disease remains unexplored. Using outbred deer mice as a model, we show that the intensity of UPR in fibroblasts isolated early in life predicts the extent of body weight gain after high-fat diet (HFD) administration. Contrary to those with intense UPR, animals with moderate UPR in fibroblasts and therefore displaying compromised stress resolution did not gain body weight but developed inflammation, especially in the skin, after HFD administration.

Genomic variation in captive deer mouse (Peromyscus maniculatus) populations.

Background: Deer mice (genus Peromyscus) are the most common rodents in North America. Despite the availability of reference genomes for some species, a comprehensive database of polymorphisms, especially in those maintained as living stocks and distributed to academic investigators, is missing. In the present study we surveyed two populations of P.

Transcriptomic coordination at hepatic steatosis indicates robust immune cell engagement prior to inflammation.

Background: Deregulation in lipid metabolism leads to the onset of hepatic steatosis while at subsequent stages of disease development, the induction of inflammation, marks the transition of steatosis to non-alcoholic steatohepatitis. While differential gene expression unveils individual genes that are deregulated at different stages of disease development, how the whole transcriptome is deregulated in steatosis remains unclear.

Methods: Using outbred deer mice fed with high fat as a model, we assessed the correlation of each transcript with every other transcript in the transcriptome.

Persistent effects of pair bonding in lung cancer cell growth in monogamous .

Epidemiological evidence suggests that social interactions and especially bonding between couples influence tumorigenesis, yet whether this is due to lifestyle changes, homogamy (likelihood of individuals to marry people of similar health), or directly associated with host-induced effects in tumors remains debatable. In the present study, we explored if tumorigenesis is associated with the bonding experience in monogamous rodents at which disruption of pair bonds is linked to anxiety and stress. Comparison of lung cancer cell spheroids that formed in the presence of sera from bonded and bond-disrupted deer mice showed that in monogamous and , but not in polygamous , the disruption of pair bonds altered the size and morphology of spheroids in a manner that is consistent with the acquisition of increased oncogenic potential.

Resilience, plasticity and robustness in gene expression during aging in the brain of outbred deer mice.

Background: Genes that belong to the same network are frequently co-expressed, but collectively, how the coordination of the whole transcriptome is perturbed during aging remains unclear. To explore this, we calculated the correlation of each gene in the transcriptome with every other, in the brain of young and older outbred deer mice (P. leucopus and P.

An Infection-Tolerant Mammalian Reservoir for Several Zoonotic Agents Broadly Counters the Inflammatory Effects of Endotoxin.

Animals that are competent reservoirs of zoonotic pathogens commonly suffer little morbidity from the infections. To investigate mechanisms of this tolerance of infection, we used single-dose lipopolysaccharide (LPS) as an experimental model of inflammation and compared the responses of two rodents: , the white-footed deermouse and reservoir for the agents of Lyme disease and other zoonoses, and the house mouse Four hours after injection with LPS or saline, blood, spleen, and liver samples were collected and subjected to transcriptome sequencing (RNA-seq), metabolomics, and specific reverse transcriptase quantitative PCR (RT-qPCR). Differential expression analysis was at the gene, pathway, and network levels.

Coordination in the unfolded protein response during aging in outbred deer mice.

Endoplasmic reticulum (ER) stress has been linked to various metabolic pathologies, neurodegeneration and aging. Although various mechanistic aspects of the resulting unfolded protein response (UPR) have been elucidated, its regulation in genetically diverse populations remains elusive. In the present study we evaluated the expression of chaperones BiP/GRP78, GRP94 and calnexin (CANX) in the lungs, liver and brain of 7 months old and 2-3 years old outbred deer mice P.

Evaluating endoplasmic reticulum stress and unfolded protein response through the lens of ecology and evolution.

Considerable progress has been made in understanding the physiological basis for variation in the life-history patterns of animals, particularly with regard to the roles of oxidative stress and hormonal regulation. However, an underappreciated and understudied area that could play a role in mediating inter- and intraspecific variation of life history is endoplasmic reticulum (ER) stress, and the resulting unfolded protein response (UPR ). ER stress response and the UPR maintain proteostasis in cells by reducing the intracellular load of secretory proteins and enhancing protein folding capacity or initiating apoptosis in cells that cannot recover.