Naturally transmitted mouse viruses highlight the heterogeneity of virus transmission dynamics in the dirty mouse model.

Unlabelled: Specific-pathogen-free (SPF) mice are widely used in biomedical research to model human infections. However, these animals do not always accurately recapitulate human immune responses. This is due, in part, to their lack of infection history.

FGF21 reverses MASH through coordinated actions on the CNS and liver.

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), represent a growing public health burden with limited therapeutic options. Recent studies have revealed that fibroblast growth factor 21 (FGF21)-based analogs can significantly improve MASH, but the mechanisms for this effect are not well understood. Here, we demonstrate that the beneficial metabolic effects of FGF21 to reverse MASH are mediated through distinct mechanisms to independently lower hepatic triglyceride and cholesterol levels.

Sumoylated Etv1 establishes mouse mammary cancer stem cells that support tumorigenesis by non-stem cancer cells.

The small ubiquitin-like modifier (SUMO) pathway is required for maintenance of cancer stem cells/tumor-initiating cells (CSCs/TICs), which drive tumorigenesis when transplanted into immunocompromised mice. We found that inhibition of the SUMO pathway blocked Neu-mediated mammary oncogenesis and inhibited the function of CSCs/TICs without effects on normal mammary stem cells. Transcriptomic analysis implicated SUMO-conjugated Etv1 as being critical for oncogenesis.

Comparison of histochemical methods for the analysis of eosinophils and mast cells using a porcine model of eosinophilic esophagitis.

Introduction: Accurate identification of eosinophils in tissue sections is required for diagnosis of eosinophilic esophagitis in humans and the assessment of severity of disease in allergy models. The pig may be a good model for sensitization and allergy models due to anatomical, physiological, and immunological similarities to humans. However, comparative studies on histochemical detection of eosinophils in fixed porcine tissue are lacking.

A Preclinical Model to Assess Intestinal Barrier Integrity Using Canine Enteroids and Colonoids.

While two-dimensional (2D) cell cultures, such as Caco-2 and Madin-Darby canine kidney (MDCK) cells are widely used in a variety of biological models, these two-dimensional in vitro systems present inherent limitations in replicating the complexities of in vivo biology. Recent progress in three-dimensional organoid technology has the potential to address these limitations. In this study, the characteristics of conventional 2D cell culture systems were compared to those of canine intestinal organoids (enteroids, ENT, and colonoids, COL).

Transcriptional repressor Capicua is a gatekeeper of cell-intrinsic interferon responses.

Early detection of viral infection and rapid activation of host antiviral defenses through transcriptional upregulation of interferons (IFNs) and IFN-stimulated genes (ISGs) are critical for controlling infection. However, aberrant production of IFN in the absence of viral infection leads to auto-inflammation and can be detrimental to the host. Here, we show that the DNA-binding transcriptional repressor complex composed of Capicua (CIC) and Ataxin-1 like (ATXN1L) binds to an 8-nucleotide motif near IFN and ISG promoters and prevents erroneous expression of inflammatory genes under homeostasis in humans and mice.

Complement is primarily activated in the lung in a mouse model of severe COVID-19.

studies and observational human disease data suggest the complement system contributes to SARS-CoV-2 pathogenesis, although how complement dysregulation develops in severe COVID-19 is unknown. Here, using a mouse-adapted SARS-CoV-2 virus (SARS2-N501Y) and a mouse model of COVID-19, we identify significant serologic and pulmonary complement activation post-infection. We observed C3 activation in airway and alveolar epithelia, and pulmonary vascular endothelia.

Cells that survive acute SARS-CoV-2 infection contribute to inflammation and lung regeneration in mice.

Unlabelled: Post-acute sequelae of COVID-19 involves several organs, but its basis remains poorly understood. Some infected cells in mice survive the acute infection and persist for extended periods in the respiratory tract but not in other tissues. Here, we describe two experimental models of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection to assess the effect of viral virulence on previously infected cells.

CXCL12 ameliorates neutrophilia and disease severity in SARS-CoV-2 infection.

Neutrophils, particularly low-density neutrophils (LDNs), are believed to contribute to acute COVID-19 severity. Here, we showed that neutrophilia can be detected acutely and even months after SARS-CoV-2 infection in patients and mice, while neutrophil depletion reduced disease severity in mice. A key factor in neutrophilia and severe disease in infected mice was traced to the chemokine CXCL12 secreted by bone marrow cells and unexpectedly, endothelial cells.

IL-13 induces loss of CFTR in ionocytes and reduces airway epithelial fluid absorption.

The airway surface liquid (ASL) plays a crucial role in lung defense mechanisms, and its composition and volume are regulated by the airway epithelium. The cystic fibrosis transmembrane conductance regulator (CFTR) is abundantly expressed in a rare airway epithelial cell type called an ionocyte. Recently, we demonstrated that ionocytes can increase liquid absorption through apical CFTR and basolateral barttin/chloride channels, while airway secretory cells mediate liquid secretion through apical CFTR channels and basolateral NKCC1 transporters.

Development and Initial Characterization of Pigs with Mutations and Primary Ciliary Dyskinesia.

Mutations in more than 50 different genes cause primary ciliary dyskinesia (PCD) by disrupting the activity of motile cilia that facilitate mucociliary transport (MCT). Knowledge of PCD has come from studies identifying disease-causing mutations, characterizing structural cilia abnormalities, finding genotype-phenotype relationships, and studying the cell biology of cilia. Despite these important findings, we still lack effective treatments and people with PCD have significant pulmonary impairment.

Respiratory syncytial virus infection provides protection against severe acute respiratory syndrome coronavirus challenge.

Unlabelled: Respiratory infections are a major health burden worldwide. Respiratory syncytial virus (RSV) is among the leading causes of hospitalization in both young children and older adults. The onset of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic and the public health response had a profound impact on the normal seasonal outbreaks of other respiratory viruses.

Upregulation of fatty acid synthesis genes in the livers of adolescent female rats caused by inhalation exposure to PCB52 (2,2',5,5'-Tetrachlorobiphenyl).

Elevated airborne PCB levels in older schools are concerning due to their health impacts, including cancer, metabolic dysfunction-associated steatotic liver disease (MASLD), cardiovascular issues, neurodevelopmental diseases, and diabetes. During a four-week inhalation exposure to PCB52, an air pollutant commonly found in school environments, adolescent rats exhibited notable presence of PCB52 and its hydroxylated forms in their livers, alongside changes in gene expression. Female rats exhibited more pronounced changes in gene expression compared to males, particularly in fatty acid synthesis genes regulated by the transcription factor SREBP1.

IL-13 decreases susceptibility to airway epithelial SARS-CoV-2 infection but increases disease severity in vivo.

Treatments available to prevent progression of virus-induced lung diseases, including coronavirus disease 2019 (COVID-19) are of limited benefit once respiratory failure occurs. The efficacy of approved and emerging cytokine signaling-modulating antibodies is variable and is affected by disease course and patient-specific inflammation patterns. Therefore, understanding the role of inflammation on the viral infectious cycle is critical for effective use of cytokine-modulating agents.

NF1 miniswine model the cellular disruptions and behavioral presentations of NF1-associated cognitive and motor impairment.

Cognitive or motor impairment is common among individuals with neurofibromatosis type 1 (NF1), an autosomal dominant tumor-predisposition disorder. As many as 70% of children with NF1 report difficulties with spatial/working memory, attention, executive function, and fine motor movements. In contrast to the utilization of various Nf1 mouse models, here we employ an NF1 miniswine model to evaluate the mechanisms and characteristics of these presentations, taking advantage of a large animal species more like human anatomy and physiology.

A predominately pulmonary activation of complement in a mouse model of severe COVID-19.

Evidence from in vitro studies and observational human disease data suggest the complement system plays a significant role in SARS-CoV-2 pathogenesis, although how complement dysregulation develops in patients with severe COVID-19 is unknown. Here, using a mouse-adapted SARS-CoV-2 virus (SARS2-N501Y) and a mouse model of severe COVID-19, we identify significant serologic and pulmonary complement activation following infection. We observed C3 activation in airway and alveolar epithelia, and in pulmonary vascular endothelia.

Mutations in nonstructural proteins essential for pathogenicity in SARS-CoV-2-infected mice.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) has resulted in substantial morbidity and mortality. The basis of severe disease in humans is difficult to determine without the use of experimental animal models. Mice are resistant to infection with ancestral strains of SARS-CoV-2, although many variants that arose later in the pandemic were able to directly infect mice.

Arteriovenous metabolomics in pigs reveals CFTR regulation of metabolism in multiple organs.

Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause cystic fibrosis (CF), a multiorgan disease that is characterized by diverse metabolic defects. However, other than specific CFTR mutations, the factors that influence disease progression and severity remain poorly understood. Aberrant metabolite levels have been reported, but whether CFTR loss itself or secondary abnormalities (infection, inflammation, malnutrition, and various treatments) drive metabolic defects is uncertain.

Pancreatic enzymes digest obstructive meconium from cystic fibrosis pig intestines.

Introduction: Meconium ileus (MI) is a life-threatening obstruction of the intestines affecting ∼15% of newborns with cystic fibrosis (CF). Current medical treatments for MI often fail, requiring surgical intervention. MI typically occurs in newborns with pancreatic insufficiency from CF.

In utero and postnatal ivacaftor/lumacaftor therapy rescues multiorgan disease in CFTR-F508del ferrets.

Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, with F508del being the most prevalent mutation. The combination of CFTR modulators (potentiator and correctors) has provided benefit to CF patients carrying the F508del mutation; however, the safety and effectiveness of in utero combination modulator therapy remains unclear. We created a F508del ferret model to test whether ivacaftor/lumacaftor (VX-770/VX-809) therapy can rescue in utero and postnatal pathologies associated with CF.

Evidence of antigenic drift in the fusion machinery core of SARS-CoV-2 spike.

Antigenic drift of SARS-CoV-2 is typically defined by mutations in the N-terminal domain and receptor binding domain of spike protein. In contrast, whether antigenic drift occurs in the S2 domain remains largely elusive. Here, we perform a deep mutational scanning experiment to identify S2 mutations that affect binding of SARS-CoV-2 spike to three S2 apex public antibodies.