RNA exosomopathies, a growing family of diseases, are linked to missense mutations in genes encoding structural subunits of the evolutionarily conserved, 10-subunit exoribonuclease complex, the RNA ...exosome. This complex consists of a three-subunit cap, a six-subunit, barrel-shaped core, and a catalytic base subunit. While a number of mutations in RNA exosome genes cause pontocerebellar hypoplasia, mutations in the cap subunit gene
cause an apparently distinct clinical presentation that has been defined as a novel syndrome SHRF (
hort stature,
earing loss,
etinitis pigmentosa, and distinctive
acies). We generated the first in vivo model of the SHRF pathogenic amino acid substitutions using budding yeast by modeling pathogenic
missense mutations (p.Gly30Val and p.Gly198Asp) in the orthologous
gene
The resulting
mutant cells show defects in cell growth and RNA exosome function. Consistent with altered RNA exosome function, we detect significant transcriptomic changes in both coding and noncoding RNAs in
cells that model
p.Gly198Asp, suggesting defects in nuclear surveillance. Biochemical and genetic analyses suggest that the Rrp4 G226D variant subunit shows impaired interactions with key RNA exosome cofactors that modulate the function of the complex. These results provide the first in vivo evidence that pathogenic missense mutations present in
impair the function of the RNA exosome. This study also sets the stage to compare exosomopathy models to understand how defects in RNA exosome function underlie distinct pathologies.
Somatic missense mutations in histone genes turn these essential proteins into oncohistones, which can drive oncogenesis. Understanding how missense mutations alter histone function is challenging in ...mammals as mutations occur in a single histone gene. For example, described oncohistone mutations predominantly occur in the histone H3.3 gene, despite the human genome encoding fifteen H3 genes. To understand how oncogenic histone missense mutations alter histone function, we leveraged the budding yeast model, which contains only two H3 genes, to explore the functional consequences of oncohistones H3K36M, H3G34W, H3G34L, H3G34R, and H3G34V. Analysis of cells that express each of these variants as the sole copy of H3 reveals that H3K36 mutants show different drug sensitivities compared to H3G34 mutants. This finding suggests that changes to proximal amino acids in the H3 N-terminal tail alter distinct biological pathways. We exploited the caffeine sensitive growth of H3K36 mutant cells to perform a high copy suppressor screen. This screen identified genes linked to histone function and transcriptional regulation, including Esa1, a histone H4/H2A acetyltransferase; Tos4, a forkhead-associated domain-containing gene expression regulator; Pho92, an N6-methyladenosine RNA binding protein and Sgv1/Bur1, a cyclin-dependent kinase. We show that the Esa1 lysine acetyltransferase activity is critical for suppression of the caffeine sensitive growth of H3K36R mutant cells while the previously characterized binding interactions of Tos4 and Pho92 are not required for suppression. This screen identifies pathways that could be altered by oncohistone mutations and highlights the value of yeast genetics to identify pathways altered by such mutations.
•Mouthfeel contributes significantly to food perception and is an important driver of food liking.•A hierarchically structured mouthfeel terminology unique to medical nutrition products was developed ...– emphasizing the need for consistency, customization and categorization.•Ultimately the mouthfeel wheel was developed as a communication tool to support product improvement and selection of medical nutrition products by health care professionals.
Product texture and mouthfeel contribute significantly to product appreciation. For medical nutrition products (MNP) the textural properties also contribute to both swallowing efficiency and safety, therefore impacting the nutrition and fluid intake of individuals in need of adapted textures (e.g. dysphagia, poor dental status). The need for an international terminology in a medical context has been expressed through several initiatives. The main reason was the inconsistency in mouthfeel terminology usage per country and care provider. A consistent terminology is important when selecting and preparing a safe and acceptable MNP. Current terminology is not specific to MNP, making it challenging to develop optimal MNP and communicating about them. The objective of the current study was to develop a hierarchically structured mouthfeel terminology suited to MNP. This terminology was developed with expert sensory panelists describing the mouthfeel terminology of 32 products, resulting in 9 umbrella terms and 51 individual attributes. To categorize the terminology appropriately and to make it accessible to a wide range of users, Taxonomic Free Sorting (TFS) was used to develop a hierarchical structure which is represented as a wheel. This structured terminology should assist sensory expert panels, Health Care Professionals (HCP), carers, individuals in need of adapted textures, chefs, food technologists and sensory scientists in their interpretation and use of terminology related to mouthfeel of MNP. Ultimately the mouthfeel wheel was developed as a communication tool to support product improvement and selection of MNP by HCP, with an optimized mouthfeel for individuals in need of adapted textures.
Paropsis charybdis (Coleoptera: Chrysomelidae) has been a major pest of Eucalyptus spp. since invading New Zealand from Australia over 100 years ago. Here, we report on the phenology, egg parasitism ...and defoliation levels of P. charybdis at two Eucalyptus nitens plantations in the central North Island of New Zealand and assess the establishment prospects and potential impact of a new biological control agent, the larval parasitoid Eadya daenerys. Field monitoring found that 90–100% of first generation P. charybdis eggs emerged, showing that the existing egg parasitoids Enoggera nassaui (Hymenoptera: Braconidae) and Neopolycystus insectifurax (Hymenoptera: Pteromalidae) are ineffective at controlling this generation. Further field monitoring revealed effective control of second generation eggs by E. nassaui and N. insectifurax despite the presence of Baeoanusia albifunicle (Hymenoptera: Encyrtidae), a hyperparasitoid of E. nassaui. Phenology data show that first generation P. charybdis larvae will likely be synchronous with the adult emergence of E. daenerys (Hymenoptera: Braconidae) the new larval endoparasitoid proposed to be introduced from Australia. Climate matching predicts E. daenerys could establish in all areas of New Zealand where P. charybdisimpacted Eucalyptus spp. plantations are grown. The addition of a larval endoparasitoid could significantly contribute to the suppression of P. charybdis by decreasing first generation larval survival.
Mendelian disease genomic research has undergone a massive transformation over the past decade. With increasing availability of exome and genome sequencing, the role of Mendelian research has ...expanded beyond data collection, sequencing, and analysis to worldwide data sharing and collaboration.
Over the past 10 years, the National Institutes of Health-supported Centers for Mendelian Genomics (CMGs) have played a major role in this research and clinical evolution.
We highlight the cumulative gene discoveries facilitated by the program, biomedical research leveraged by the approach, and the larger impact on the research community. Beyond generating a list of gene-phenotype relationships and participating in widespread data sharing, the CMGs have created resources, tools, and training for the larger community to foster understanding of genes and genome variation. The CMGs have participated in a wide range of data sharing activities, including deposition of all eligible CMG data into the Analysis, Visualization, and Informatics Lab-space (AnVIL), sharing candidate genes through the Matchmaker Exchange and the CMG website, and sharing variants in Genotypes to Mendelian Phenotypes (Geno2MP) and VariantMatcher.
The work is far from complete; strengthening communication between research and clinical realms, continued development and sharing of knowledge and tools, and improving access to richly characterized data sets are all required to diagnose the remaining molecularly undiagnosed patients.
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