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Single-Component Multilayered Self-Assembling Protein Nanoparticles Presenting Glycan-Trimmed Uncleaved Prefusion Optimized Envelope Trimers as HIV-1 Vaccine Candidates
Zhang, Nature Communications. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10082823/
Researchers are interested in engineering protein nanoparticles to mimic virus-like particles for an HIV-1 vaccine. In this study, researchers explored a strategy that combines HIV envelope glycoprotein (Env) stabilization, nanoparticle display, and glycan trimming. They designed a panel of constructs for biochemical, biophysical, and structural characterization. Using female mice, female rabbits, and rhesus macaques of both sexes, they demonstrated that glycan trimming increases the frequency of vaccine responders and steers antibody responses away from immunodominant glycan holes and glycan patches. This work offers a potential strategy for overcoming the challenges posed by the Env glycan shield in vaccine development. Supported by ORIP (P51OD011133, P51OD011104, U42OD010442) and NIAID.
Lipid Droplets and Peroxisomes Are Co-Regulated to Drive Lifespan Extension in Response to Mono-Unsaturated Fatty Acids
Papsdorf et al., Nature Cell Biology. 2023.
https://www.nature.com/articles/s41556-023-01136-6
Investigators studied the mechanism by which mono-unsaturated fatty acids (MUFAs) extend longevity. They found that MUFAs upregulated the number of lipid droplets in fat storage tissues of Caenorhabditis elegans, and increased lipid droplets are necessary for MUFA-induced longevity and predicted remaining lifespan. Lipidomics data revealed that MUFAs modify the ratio of membrane lipids and ether lipids, which leads to decreased lipid oxidation in middle-aged individuals. MUFAs also upregulate peroxisome number. A targeted screen revealed that induction of both lipid droplets and peroxisomes is optimal for longevity. This study opens new interventive avenues to delay aging. Supported by ORIP (S10OD025004, S10OD028536, P40OD010440), NIA, NCCIH, NIDDK, and NHGRI.
Global Frequency Analyses of Canine Progressive Rod-Cone Degeneration-Progressive Retinal Atrophy and Collie Eye Anomaly Using Commercial Genetic Testing Data
Clark et al., Genes (Basel). 2023.
https://pubmed.ncbi.nlm.nih.gov/38003037/
Hundreds of genetic variants associated with canine traits and disorders have been identified; however, the geographic distributions and changes in allele and genotype frequencies over prolonged, continuous periods of time are lacking. This study utilized a large set of genotypes from dogs tested for progressive rod-cone degeneration-progressive retinal atrophy (prcd‑PRA) and collie eye anomaly (CEA). Both diseases exhibited significant differences in genotype frequencies (p=2.7 × 10-152 for prcd-PRA and 0.023 for CEA) with opposing graphical trends. This study shows that genetic testing informed breeding decisions to produce fewer affected dogs. Supported by ORIP (K01OD027051).
A SACS Deletion Variant in Great Pyrenees Dogs Causes Autosomal Recessive Neuronal Degeneration
Ekenstedt et al., Human Genetics. 2023.
https://pubmed.ncbi.nlm.nih.gov/37758910/
ARSACS (autosomal recessive spastic ataxia of Charlevoix-Saguenay) is an early-onset, slowly progressive neurodegenerative disorder. To date, no naturally occurring large animal model has been reported for ARSACS. In this study, the authors describe a novel spontaneous genetic model for SACS-associated neuronal degeneration using Great Pyrenees dogs of both sexes. The canine models described in this study fit closely with the typical early‑onset ARSACS phenotype in humans, and molecular genetic studies demonstrated that these dogs exhibit a deleterious SACS mutation. The clinical and histopathological descriptions of this canine disorder contribute to the description of human ARSACS. Supported by ORIP (R01OD01027051).
Allelic Strengths of Encephalopathy-Associated UBA5 Variants Correlate Between In Vivo and In Vitro Assays
Pan et al., eLife. 2023.
https://pubmed.ncbi.nlm.nih.gov/37502976/
The UBA5 gene is associated with developmental and epileptic encephalopathy 44 (DEE44), an autosomal recessive disorder, in humans. The link between UBA5 variants and severity of DEE44, however, is not established. Investigators developed humanized fly models carrying a series of patient UBA5 variants. These flies showed differences in survival rates, developmental progress, life span, and neurological well-being. The severity of these defects correlated strongly with functional defects of UBA5 variants, allowing the classification of UBA5 loss-of-function variants into mild, intermediate, and severe allelic strengths in patients. This study provides resources for systematic investigation of the mechanistic link between UBA5 variants and DEE44 and for developing diagnostic approaches. Supported by ORIP (R24OD022005, R24OD031447, U54OD035865) and NCATS.
Increased Collective Migration Correlates With Germline Stem Cell Competition in a Basal Chordate
Fentress and De Tomaso et al., PLOS One. 2023.
https://pubmed.ncbi.nlm.nih.gov/37903140/
Cell competition is a process that compares the relative fitness of progenitor cells and results in healthier cells, contributing a higher proportion to the final tissue composition. Investigators are studying cell competition in a novel model organism, the colonial ascidian, Botryllus schlosseri. They demonstrated that winner germline stem cells show enhanced migratory ability to chemotactic cues ex vivo and that enhanced migration correlates with both expression of the Notch ligand, Jagged, and cluster size. The ability to study conserved aspects of cell migration makes Botryllus an excellent model for future studies on competition, chemotaxis, and collective cell migration. Supported by ORIP (R21OD030520) and NIGMS.
Body Stiffness Is a Mechanical Property That Facilitates Contact-Mediated Mate Recognition in Caenorhabditis elegans
Weng et al., Current Biology. 2023.
https://www.sciencedirect.com/science/article/abs/pii/S0960982223009272
Body stiffness is a mechanical property that facilitates contact-mediated mate recognition in Caenorhabditis elegans. Chemical cues have been extensively studied as sensory cures of mate recognition, whereas the role of mechanical cues is largely unknown. Investigators studied the link of the hypodermis and body stiffness with mate recognition and mating efficiency in the worm C. elegans. They found that worm males assess attractiveness of potential mates though contact-mediated cues determined by species, sex, and developmental stages of the hypodermis. Body stiffness maintained by a group of cuticular collagens is critical for mate recognition and mating efficiency. This study suggests the important role of mechanosensory cues in mate recognition and provides a platform for mechanistically studying social behavior. Supported by ORIP (R24OD023041, P40OD010440) and NINDS.
A Defect in Mitochondrial Fatty Acid Synthesis Impairs Iron Metabolism and Causes Elevated Ceramide Levels
Dutta et al., Nature Metabolism. 2023.
https://pubmed.ncbi.nlm.nih.gov/37653044/
Human mitochondrial enoyl coenzyme A reductase (Mecr), required for the last step of mitochondrial fatty acid synthesis (mtFAS), is linked to pediatric-onset neurodegeneration, but with unknown mechanisms. Researchers investigated phenotypes of mecr mutants in Drosophila and human-derived fibroblasts. They found that loss of function of Mecr in the whole body resulted in a defect in Fe-S cluster biogenesis and increased iron levels, leading to elevated ceramide levels and lethality in flies. Similar elevated ceramide levels and impaired iron homeostasis were observed human-derived fibroblasts with Mecr deficiency. Neuronal loss of Mecr led to progressive neurodegeneration in flies. This study pointed out a mechanistic link between mtFAS and neurodegeneration through Mecr. Supported by ORIP (R24OD022005, R24OD031447), NICHD, and NINDS.
Baseline Tumor Gene Expression Signatures Correlate With Chemoimmunotherapy Treatment Responsiveness in Canine B Cell Lymphoma
Dittrich et al., PLOS ONE. 2023.
https://pubmed.ncbi.nlm.nih.gov/37624862/
Pet dogs develop spontaneous diffuse large B cell lymphoma (DLBCL), and veterinary clinical trials have been employed to treat canine DLBCL and to inform clinical trials for their human companions. Investigators evaluated gene expression in lymph node aspirates from 18 trial dogs and defined good responders as those who relapsed after 90 days, and poor responders as those who relapsed prior to 90 days. They found increased CCND3 correlated with poor prognosis and increased CD36 correlated with good prognosis, as is observed in humans. These findings identify biomarkers that may help guide the choice of chemoimmunotherapy treatment in dogs. Supported by ORIP (K01OD028268) and NCI.
Canine Models of Charcot-Marie-Tooth: MTMR2, MPZ, and SH3TC2 Variants in Golden Retrievers With Congenital Hypomyelinating Polyneuropathy
Cook et al., Neuromuscular Disorders. 2023.
https://pubmed.ncbi.nlm.nih.gov/37400349/
Both demyelination and hypomyelination of the nervous system are associated with various clinical diseases. Using whole-genome sequencing, researchers determined the genetic underpinnings of congenital hypomyelinating polyneuropathy in canines of both sexes. These variants genetically describe the first peripheral nervous system–exclusive hypomyelinating polyneuropathies in dogs. By testing for these mutations, breeders can prevent the production of affected offspring. Supported by ORIP (K01OD027051, K01OD027058).