Selected Grantee Publications
- 666 results found
Phenotypic Characterization of Subtype A and Recombinant AC Transmitted/Founder Viruses From a Rwandan HIV-1 Heterosexual Transmission Cohort
Yue et al., Viruses. 2024.
https://pubmed.ncbi.nlm.nih.gov/39599821
HIV-1 is classified into several phylogenetic groups and subgroups, and to be effective, a vaccine would require broad activity across diverse viral strains. The most widespread group, M, is subdivided into several subgroups (A–D, F–H, J, K, and L). In a previous study, these researchers analyzed cohorts of people with recent or acute HIV infection in Rwanda. Subtype A was the dominant subtype, but a significant number of infections were caused by recombinants of subtypes A and C. This study assessed the characteristics of 16 infectious molecular clones (IMCs) of subtype A or AC recombinant viruses. Viral replication scores varied among the IMCs, and amino acid substitutions in the viral Gag gene were linked to higher replication activity. The sensitivity of different clones to broadly neutralizing antibodies also was assessed. This panel of well-characterized viral IMCs will support studies required to develop an effective HIV-1 vaccine. Supported by ORIP (P51OD011132) and NIAID.
SHIV Remission in Macaques With Early Treatment Initiation and Ultra Long-Lasting Antiviral Activity
Daly et al., Nature Communications. 2024.
https://pubmed.ncbi.nlm.nih.gov/39632836
Antiretroviral therapy (ART) suppresses HIV and simian immunodeficiency virus (SIV) replication but cannot eliminate reservoirs of long-lived infected cells that enable rebound after discontinuation of ART. These researchers hypothesized that ART designed to have long-lasting activity and penetrate tissue reservoirs would be optimized against HIV or SIV remission. Macaques were treated with a four-drug regimen (i.e., oral emtricitabine/tenofovir alafenamide and long-acting cabotegravir/rilpivirine) designed to improve dosing of immune cells, with or without the immune-activating drug vesatolimod (VES), after the onset of SIV viremia. The animals were monitored for 1 year with treatment and 2 additional years following treatment discontinuation. Durable viral suppression was observed in all animals treated with the optimized ART regimen with or without VES. These results will inform novel HIV treatment regimens with long-lasting antiviral activity in humans. Supported by ORIP (P40OD028116).
Multimodal Analysis of Dysregulated Heme Metabolism, Hypoxic Signaling, and Stress Erythropoiesis in Down Syndrome
Donovan et al., Cell Reports. 2024.
https://pubmed.ncbi.nlm.nih.gov/39120971
Down syndrome (DS), a genetic condition caused by the presence of an extra copy of chromosome 21, is characterized by intellectual and developmental disability. Infants with DS often suffer from low oxygen saturation, and DS is associated with obstructive sleep apnea. Investigators assessed the role that hypoxia plays in driving health conditions that are comorbid with DS. A multiomic analysis showed that people with DS exhibit elevated heme metabolism and activated stress erythropoiesis, which are indicators of chronic hypoxia; these results were recapitulated in a mouse model for DS. This study identified hypoxia as a possible mechanism underlying several conditions that co-occur with DS, including congenital heart defects, seizure disorders, autoimmune disorders, several leukemias, and Alzheimer's disease. Supported by ORIP (R24OD035579), NCATS, NCI, and NIAID.
Mechanical Force of Uterine Occupation Enables Large Vesicle Extrusion From Proteostressed Maternal Neurons
Wang et al., eLife. 2024.
https://pubmed.ncbi.nlm.nih.gov/39255003
This study investigates how mechanical forces from uterine occupation influence large vesicle extrusion (exopher production) from proteostressed maternal neurons in Caenorhabditis elegans. Exophers, previously found to remove damaged cellular components, are poorly understood. Researchers demonstrate that mechanical stress significantly increases exopher release from touch receptor neurons (i.e., ALMR) during peak reproductive periods, coinciding with egg production. Genetic disruptions reducing reproductive activity suppress exopher extrusion, whereas interventions promoting egg retention enhance it. These findings reveal that reproductive and mechanical factors modulate neuronal stress responses, providing insight on how systemic physiological changes affect neuronal health and proteostasis, with broader implications for reproductive-neuronal interactions. Supported by ORIP (R24OD010943, P40OD010440), NIA, and NIGMS.
Stat3 Mediates Fyn Kinase-Driven Dopaminergic Neurodegeneration and Microglia Activation
Siddiqui et al., Disease Models & Mechanisms. 2024.
https://pubmed.ncbi.nlm.nih.gov/39641161
The FYN gene is a risk locus for Alzheimer’s disease and several other neurodegenerative disorders. FYN encodes Fyn kinase, and previous studies have shown that Fyn signaling in dopaminergic neurons and microglia plays a role during neurodegeneration. This study investigated Fyn signaling using zebrafish that express a constitutively active Fyn Y531F mutant in neural cells. Activated neural Fyn signaling in the mutant animals resulted in dopaminergic neuron loss and induced inflammatory cytokine expression when compared with controls. Transcriptomic and chemical inhibition analyses revealed that Fyn-driven changes were dependent on the Stat3 and NF-κB signaling pathways, which work synergistically to activate neuronal inflammation and degeneration. This study provides insight into the mechanisms underlying neurodegeneration, identifying Stat3 as a novel effector of Fyn signaling and a potential translational target. Supported by ORIP (R24OD020166).
Extracted Plasma Cell-Free DNA Concentrations Are Elevated in Colic Patients With Systemic Inflammation
Bayless et al., Veterinary Sciences. 2024.
https://pmc.ncbi.nlm.nih.gov/articles/PMC11435807
Researchers investigated cell-free DNA (cfDNA) as a potential biomarker to detect colic in humans. In horses, colic is a life-threatening gastrointestinal (GI) condition. Measurements of cfDNA released from damaged or dying cells in the blood of male and female horses with colic were compared across groups based on GI disease type, signs of inflammation, and survival status. Elevated cfDNA levels were prominent in horses with systemic inflammation, but did not significantly differ by GI disease type or survival. This study suggests that cfDNA may be linked to inflammatory responses in colic conditions. Supported by ORIP (T32OD011130).
A Comparative Review of Cytokines and Cytokine Targeting in Sepsis: From Humans to Horses
Hobbs et al., Cells. 2024.
https://pubmed.ncbi.nlm.nih.gov/39273060
Bacterial infections resulting in endotoxin or exotoxin exposure can lead to sepsis because of dysregulated host responses. Sepsis causes organ dysfunction that can lead to death if not treated immediately, yet no proven pharmacological treatments exist. Horses can serve as a comparative and translational model for sepsis in humans because both species share mechanisms of immune response, including severe neutropenia, cytokine storms, formation of neutrophil extracellular traps, and decreased perfusion. Research on sepsis has focused on the pathophysiological role of interleukin-6, interleukin-1β, tumor necrosis factor-α, and interleukin10. Research on novel sepsis therapies has focused on monoclonal antibodies, cytokine antagonists, and cytokine removal through extracorporeal hemoperfusion. Future sepsis research should focus on optimizing therapeutic strategies of cytokine modulation and analyzing the underlying mechanisms of cytokine dysregulation. Supported by ORIP (T32OD011130).
Proinflammatory Cytokines Suppress Stemness-Related Properties and Expression of Tight Junction in Canine Intestinal Organoids
Nakazawa et al., In Vitro Cellular & Developmental Biology—Animal. 2024.
https://pmc.ncbi.nlm.nih.gov/articles/PMC11419940
Cells in the gastrointestinal tract are exposed to numerous stressors that can promote excessive inflammation, including environmental chemicals and dietary substances. Researchers studied how canine intestinal epithelial cell (IEC)–derived organoids responded to exposure to one of three proinflammatory cytokines; interferon-γ (IFN-γ), tumor necrosis factor-α (TNFα), or interleukin-1β (IL1β). Exposure to IFN-γ resulted in downregulation of the stem cell marker Lgr5. Only IFN-γ exposure resulted in increased production of caspase 3 and caspase 8. Exposure to either IFN-γ or IL1β resulted in suppressed cell proliferation. The pro-inflammatory cytokines caused reduced tight junction protein expression and compromised membrane integrity. These findings are important to understanding IEC response to different inflammatory stimuli and to broadening knowledge of gut physiology. Supported by ORIP (K01OD030515, R21OD031903).
Establishment and Characterization of Three Human Ocular Adnexal Sebaceous Carcinoma Cell Lines
Lee et al., International Journal of Molecular Sciences. 2024.
https://pmc.ncbi.nlm.nih.gov/articles/PMC11432008
Researchers established three new cell lines to model ocular adnexal sebaceous carcinoma (SebCA) and test new therapies. SebCA is a highly problematic periorbital tumor requiring aggressive surgical treatment, and its pathobiology remains poorly understood. With consent from one male and two female patients, tumor tissue was cultured under conditional reprograming, and the cells were analyzed for growth, clonogenicity, apoptosis, and differentiation using methods including western blotting, short tandem repeat profiling, and next-generation sequencing. These newly developed cell lines provide valuable preclinical models for understanding and treating SebCA. Supported by ORIP (K01OD034451).
Transcriptomic Analysis of Skeletal Muscle Regeneration Across Mouse Lifespan Identifies Altered Stem Cell States
Walter et al., Nature Aging. 2024.
https://pubmed.ncbi.nlm.nih.gov/39578558
Age-related skeletal muscle regeneration dysfunction is poorly understood. Using single-cell transcriptomics and high-resolution spatial transcriptomics, researchers evaluated factors contributing to age-related decline in skeletal muscle regeneration after injury in young, old, and geriatric male and female mice (5, 20, and 26 months old). Eight immune cell types were identified and associated with age-related dynamics and distinct muscle stem cell states specific to old and geriatric tissue. The findings emphasize the role of extrinsic and intrinsic factors, including cellular senescence, in disrupting muscle repair. This study provides a spatial and molecular framework for understanding regenerative decline and cellular heterogeneity in aging skeletal muscle. Supported by ORIP (F30OD032097), NIA, NIAID, NIAMS, NICHD, and NIDA.