Selected Grantee Publications
Biological Activities of a New Crotamine-like Peptide from Crotalus oreganus helleri on C2C12 and CHO Cell Lines, and Ultrastructural Changes on Motor Endplate and Striated Muscle
Salazar et al., Toxicon. 2020.
https://pubmed.ncbi.nlm.nih.gov/33065200/
Crotamine and crotamine-like peptides are non-enzymatic polypeptides found in high concentration in the Crotalus genus venom. Helleramine was isolated and purified from the venom of the rattlesnake, Crotalus oreganus helleri. Purified helleramine increased intracellular Ca2+ in Chinese Hamster Ovary (CHO) cell line, inhibited cell viability of C2C12 (immortalized skeletal myoblast) and promoted early apoptosis and cell death. Skeletal muscle harvested from mice 24 hours after helleramine injection showed contracted myofibrils and profound vacuolization, with loss of plasmatic and basal membrane integrity. The effects of helleramine provide evidence of myotoxic activities of crotamine-like peptides and their possible role in crotalid envenoming. Supported by ORIP (P40OD010960).
Imbalance of Regulatory and Cytotoxic SARS-CoV-2-Reactive CD4+ T Cells in COVID-19
Meckiff et al., Cell. 2020.
https://pubmed.ncbi.nlm.nih.gov/33096020/
It is not clear why COVID-19 is deadly in some people and mild in others. To understand the underlying mechanism, investigators studied the contribution of CD4+ T cells in immune responses to SARS-CoV-2 infection. They analyzed single-cell transcriptomic data of >100,000 viral antigen-reactive CD4+ T cells from 40 COVID-19 patients. In hospitalized patients compared to non-hospitalized patients, they found increased proportions of cytotoxic follicular helper cells (TFH) and cytotoxic T helper (TH) cells responding to SARS-CoV-2 and reduced proportion of SARS-CoV-2-reactive regulatory T cells (TREG). Importantly, in hospitalized COVID-19 patients, a strong cytotoxic TFH response was observed early in the illness, which correlated negatively with antibody levels to SARS-CoV-2 spike protein. Polyfunctional TH1 and TH17 cell subsets were underrepresented in the repertoire of SARS-CoV-2-reactive CD4+ T cells compared to influenza-reactive CD4+ T cells. Together, these analyses provided insights into the gene expression patterns of SARS-CoV-2-reactive CD4+ T cells in distinct disease severities. Supported by ORIP (S10RR027366, S10OD025052), NIAID, NHLBI, and NIGMS.
Infant Isoflurane Exposure Affects Social Behaviours, but Does Not Impair Specific Cognitive Domains in Juvenile Non-Human Primates
Neudecker et al., British Journal of Anaesthesia. 2020.
https://www.sciencedirect.com/science/article/pii/S0007091220308503
Researchers investigated the impact of extended (5 hours) isoflurane anesthetic exposure (1-3 exposures) of rhesus macaque (RM) infants of both sexes on cognitive testing and behavioral assessments. Cognitive function did not differ among groups; however, compared to controls, RMs exposed three times during infancy exhibited less close social behavior. One isoflurane exposure resulted in increased anxiety-related behaviors and more inhibition towards novel objects. These findings are consistent with behavioral alterations observed in social settings of human clinical studies. Supported by ORIP (P51OD011092).
A Frog with Three Sex Chromosomes that Co-Mingle Together in Nature: Xenopus tropicalis Has a Degenerate W and a Y that Evolved from a Z Chromosome
Furman et al., PLOS Genetics. 2020.
https://pubmed.ncbi.nlm.nih.gov/33166278/
Genetic systems governing sexual differentiation vary among species. Furman et al. investigated a frog with three sex chromosomes, the Western clawed frog, Xenopus tropicalis. They demonstrate that natural populations from the western and eastern edges of Ghana have a young Y chromosome, and that a male-determining factor on this Y chromosome is in a similar genomic location as a previously known female-determining factor on the W chromosome. Their findings are consistent with theoretical expectations associated with recombination suppression on sex chromosomes and demonstrate that several characteristics of old and established sex chromosomes can arise well before they become cytogenetically distinguished. Supported by ORIP (P40OD010997) and NICHD.
Lipocalin-2 Is an Anorexigenic Signal in Primates
Petropoulou et al., eLife. 2020.
https://doi.org/10.7554/eLife.58949
The hormone lipocalin-2 (LCN2) suppresses food intake in mice. Researchers demonstrated that LCN2 increases after a meal and reduces hunger in people with normal weight or overweight, but not in obese individuals. The researchers also showed that LCN2 crosses the blood-brain barrier and binds to the hypothalamus in vervet monkeys. LCN2 was found to bind to the hypothalamus in human, baboon, and rhesus macaque brain sections. When injected into vervets, LCN2 suppressed food intake and lowered body weight without toxic effects in short-term experiments. These findings lay the groundwork to investigate whether LCN2 might be a useful treatment for obesity. Supported by ORIP (P40OD010965), NCATS, NIDDK, NIA, and NHLBI.
Estrogen Acts Through Estrogen Receptor 2b to Regulate Hepatobiliary Fate During Vertebrate Development
Chaturantabut et al., Hepatology. 2020.
https://aasldpubs.onlinelibrary.wiley.com/doi/full/10.1002/hep.31184
During liver development, bipotent progenitor cells differentiate into hepatocytes and biliary epithelial cells to ensure a functional liver. The developmental cues controlling the differentiation of committed progenitors into these cell types are not completely understood. These authors report an essential role for estrogenic regulation in vertebrate liver development to affect hepatobiliary fate decisions. The studies identify17β-estradiol (E2), nuclear estrogen receptor 2b (esr2b), and downstream bone morphogenetic protein (BMP) activity as important regulators of hepatobiliary fate decisions during vertebrate liver development. These results have significant implications for liver development in infants exposed to abnormal estrogen levels or estrogenic compounds during pregnancy. Supported by ORIP (R24OD017870) and NIDDK.
Fructose Stimulated De Novo Lipogenesis Is Promoted by Inflammation
Jelena et al., Nature Metabolism. 2020.
https://pubmed.ncbi.nlm.nih.gov/32839596
Non-alcoholic fatty liver disease (NAFD) affects 30% of adult Americans. While NAFD starts as simple steatosis with little liver damage, its severe manifestation as non-alcoholic steatohepatitis (NASH) is a leading cause of liver failure, cirrhosis, and cancer. Fructose consumption is proposed to increase the risk of hepatosteatosis and NASH. Excessive intake of fructose causes barrier deterioration and low-grade endotoxemia. Using a mouse model, the study examined the mechanism of how fructose triggers these alterations and their roles in hepatosteatosis and NASH pathogenesis. The results demonstrated that microbiota-derived Toll-like receptor (TLR) agonists promote hepatosteatosis without affecting fructose-1-phosphate (F1P) and cytosolic acetyl-CoA. Activation of mucosal-regenerative gp130 signaling, administration of the YAP-induced matricellular protein CCN1 or expression of the antimicrobial peptide Reg3b (beta) counteract fructose-induced barrier deterioration, which depends on endoplasmic-reticulum stress and subsequent endotoxemia. Endotoxin engages TLR4 to trigger TNF production by liver macrophages, thereby inducing lipogenic enzymes that convert F1P and acetyl-CoA to fatty acid in both mouse and human hepatocytes. The finding may be of relevance to several common liver diseases and metabolic disorders. Supported by ORIP (S10OD020025), NCI, NIEHS, NIDDK, NIAID, and NIAAA.
Antiretroviral Therapy Does Not Reduce Tuberculosis Reactivation in a Tuberculosis-HIV Coinfection Model
Ganatra et al., Journal of Clinical Investigation. 2020.
https://www.jci.org/articles/view/136502
Despite treatment of HIV with antiretroviral therapy (ART), the risk of tuberculosis (TB) reactivation is higher in HIV-infected than HIV-uninfected persons. Researchers used Mycobacterium tuberculosis/SIV-coinfected rhesus macaques to model the impact of ART on TB reactivation due to HIV-induced immunosuppression. ART significantly reduced viral loads and increased CD4+ T-cell counts in blood, spleen, and bronchoalveolar lavage samples, but it did not reduce the risk of SIV-induced TB reactivation during the early phase of treatment. This study offers a translational model for the investigation of TB/SIV coinfection and the evaluation of treatment regimens to prevent TB reactivation in HIV-infected individuals. Supported by ORIP (P51OD011133, P51OD011132) and NIAID.
Intra-Strain Genetic Variation of Platyfish (Xiphophorus maculatus) Strains Determines Tumorigenic Trajectory
Lu et al., Frontiers in Genetics . 2020.
https://www.frontiersin.org/articles/10.3389/fgene.2020.562594/full
Xiphophorus interspecies hybrids represent a valuable model system to study heritable tumorigenesis. Although the ancestors of the two X. maculatus parental lines, Jp163 A and Jp163 B, were siblings produced by the same mother, backcross interspecies hybrid progeny between X. hellerii and X. maculatus Jp163 A develop spontaneous melanoma initiating at the dorsal fin due to a regulator encoded by the X. maculatus genome; the backcross hybrid progeny with X. hellerii or X. couchianus and Jp163 B exhibit melanoma on their flanks. Comparative genomic analyses revealed genetic differences are associated with pathways highlighting fundamental cellular functions. Disruption of these baselines may give rise to spontaneous or inducible tumorigenesis. Supported by ORIP (R24OD011120), NCI, and NIGMS.
Induction and Characterization of Pancreatic Cancer in a Transgenic Pig Model
Boas et al., PLOS One. 2020.
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0239391
Preclinical testing of new therapies for pancreatic cancer has been challenging due to lack of a suitable large animal model. Pigs, however, have similar physiology and immune response to humans. Boas et al report the development of a porcine model for pancreatic cancer. H&E and immunohistochemical stains revealed undifferentiated carcinomas, like those of human pancreatobiliary systems. In several pigs, angiographies revealed that the artery supplying the pancreatic tumor could be catheterized using a 2.4 F microcatheter. In summary, pancreatic cancer can be induced in a transgenic pig, and intra-arterial procedures using catheters designed for human interventions were feasible in this model. Supported by ORIP (U42OD011140) and NCI.