Despite gains in survival, outcomes for patients with metastatic or recurrent rhabdomyosarcoma (RMS) remain dismal. In a collaboration between the National Cancer Institute, Children's Oncology Group, and Broad Institute, we performed whole-genome, whole-exome and transcriptome sequencing to characterize the landscape of somatic alterations in 147 tumor/normal pairs. Two genotypes are evident in RMS tumors; those characterized by the PAX3 or PAX7 fusion and those that lack these fusions but harbor mutations in key signaling pathways. The overall burden of somatic mutations in RMS is relatively low, especially in tumors that harbor a PAX3/7 gene fusion. In addition to previously reported mutations of NRAS, KRAS, HRAS, FGFR4, PIK3CA, CTNNB1, we found novel recurrent mutations in FBXW7, and BCOR providing potential new avenues for therapeutic intervention. Furthermore, alteration of the receptor tyrosine kinase/RAS/PIK3CA axis affects 93% of cases providing a framework for genomics directed therapies that might improve outcomes for RMS patients.
Undesired ice accumulation leads to severe economic issues and, in some cases, loss of lives. Although research on anti-icing has been carried out for decades, environmentally harmless, economical, and efficient strategies for anti-icing remain to be developed. Recent researches have provided new insights into the icing phenomenon and shed light on some promising bio-inspired anti-icing strategies. The present review critically categorizes and discusses recent developments. Effectively trapping air in surface textures of superhydrophobic surfaces weakens the interaction of the surfaces with liquid water, which enables timely removal of impacting and condensed water droplets before freezing occurs. When ice already forms, ice adhesion can be significantly reduced if liquid is trapped in surface textures as a lubricating layer. As such, ice could be shed off by an action of wind or its gravity. In addition, bio-inspired anti-icing strategies via trapping or introducing other media, such as phase change materials and antifreeze proteins, are discussed.
Human apolipoprotein E (apoE) is one of the major determinants in lipid transport, playing a critical role in atherosclerosis and other diseases. Binding to lipid and heparan sulfate proteoglycans (HSPG) induces apoE to adopt active conformations for binding to lowdensity lipoprotein receptor (LDLR) family. ApoE also interacts with beta amyloid peptide, manifests critical isoform-specific effects on Alzheimer's disease. Despite the importance of apoE in these major human diseases, the fundamental questions of how apoE adjusts its structure upon binding to regulate its diverse functions remain unsolved. We report the NMR structure of apoE3, displaying a unique topology of three structural domains. The C-terminal domain presents a large exposed hydrophobic surface that likely initiates interactions with lipids, HSPG, and beta amyloid peptides. The unique topology precisely regulates apoE tertiary structure to permit only one possible conformational adaptation upon binding and provides a double security in preventing lipid-free and partiallylipidated apoE from premature binding to apoE receptors during receptor biogenesis. This topology further ensures the optimal receptor-binding activity by the fully lipidated apoE during lipoprotein transport in circulation and in the brain. These findings provide a structural framework for understanding the structural basis of the diverse functions of this important protein in human diseases.H uman apoE is one of the major determinants in lipid transport throughout the body, playing a critical role in atherosclerosis and other metabolic diseases (1). Binding to lipid and heparan sulfate proteoglycans (HSPG) induces apoE to adopt active conformations for low-density lipoprotein receptor (LDLR) and LDLR-related protein (LRP)-binding (2). ApoE functions during lipid transport by binding to the LDLR family (2, 3), with the major LDLR-binding region spanning residues 130-160 (1). Three common isoforms of human apoE have been identified: ApoE3 has C112/R158, apoE4 has R112/R158, and apoE2 has C112/C158 (1). ApoE also interacts with amyloid peptide and manifests critical isoform-specific effects on several major human diseases (4-7). The most pronounced pathological effect attributes to the association of apoE4 with neurodegenerative diseases, including Alzheimer's disease (2). Clearly, apoE carries out diverse biological functions in several major human diseases by binding to different partners. However, fundamental questions of how apoE adjusts its structure upon binding to regulate its diverse functions remain unsolved. Because apoE isoforms only differ by one amino acid, the structural basis of this isoform-specific effect is another most challenging unanswered question for apoE to date.It was proposed that apoE contains two domains: an N-terminal (NT) domain (residues 1-191) and a C-terminal (CT) domain (residues 216-299), linked by a flexible hinge region (1). The NT domain is responsible for the LDLR-binding, yet, in isolation, binds weakly to lipids. The CT domain possesses th...
The Ewing sarcoma family of tumors (EFT) is a group of highly malignant small round blue cell tumors occurring in children and young adults. We report here the largest genomic survey to date of 101 EFT (65 tumors and 36 cell lines). Using a combination of whole genome sequencing and targeted sequencing approaches, we discover that EFT has a very low mutational burden (0.15 mutations/Mb) but frequent deleterious mutations in the cohesin complex subunit STAG2 (21.5% tumors, 44.4% cell lines), homozygous deletion of CDKN2A (13.8% and 50%) and mutations of TP53 (6.2% and 71.9%). We additionally note an increased prevalence of the BRCA2 K3326X polymorphism in EFT patient samples (7.3%) compared to population data (OR 7.1, p = 0.006). Using whole transcriptome sequencing, we find that 11% of tumors pathologically diagnosed as EFT lack a typical EWSR1 fusion oncogene and that these tumors do not have a characteristic Ewing sarcoma gene expression signature. We identify samples harboring novel fusion genes including FUS-NCATc2 and CIC-FOXO4 that may represent distinct small round blue cell tumor variants. In an independent EFT tissue microarray cohort, we show that STAG2 loss as detected by immunohistochemistry may be associated with more advanced disease (p = 0.15) and a modest decrease in overall survival (p = 0.10). These results significantly advance our understanding of the genomic and molecular underpinnings of Ewing sarcoma and provide a foundation towards further efforts to improve diagnosis, prognosis, and precision therapeutics testing.
The discovery of ultrahigh piezoelectricity in relaxor-ferroelectric solid solution single crystals is a breakthrough in ferroelectric materials. A key signature of relaxor-ferroelectric solid solutions is the existence of polar nanoregions, a nanoscale inhomogeneity, that coexist with normal ferroelectric domains. Despite two decades of extensive studies, the contribution of polar nanoregions to the underlying piezoelectric properties of relaxor ferroelectrics has yet to be established. Here we quantitatively characterize the contribution of polar nanoregions to the dielectric/piezoelectric responses of relaxor-ferroelectric crystals using a combination of cryogenic experiments and phase-field simulations. The contribution of polar nanoregions to the room-temperature dielectric and piezoelectric properties is in the range of 50–80%. A mesoscale mechanism is proposed to reveal the origin of the high piezoelectricity in relaxor ferroelectrics, where the polar nanoregions aligned in a ferroelectric matrix can facilitate polarization rotation. This mechanism emphasizes the critical role of local structure on the macroscopic properties of ferroelectric materials.
SummaryThe key regulator of salicylic acid (SA)-mediated resistance, NPR1, is functionally conserved in diverse plant species, including rice ( Oryza sativa L.). Investigation in depth is needed to provide an understanding of NPR1 -mediated resistance and a practical strategy for the improvement of disease resistance in the model crop rice. The rice genome contains five NPR1 -like genes. In our study, three rice homologous genes, OsNPR1 / NH1 , OsNPR2 / NH2 and OsNPR3 , were found to be induced by rice bacterial blight Xanthomonas oryzae pv.oryzae and rice blast Magnaporthe grisea , and the defence molecules benzothiadiazole, methyl jasmonate and ethylene. We confirmed that OsNPR1 is the rice orthologue by complementing the Arabidopsis npr1 mutant. Over-expression of OsNPR1 conferred disease resistance to bacterial blight, but also enhanced herbivore susceptibility in transgenic plants. The OsNPR1-green fluorescent protein (GFP) fusion protein was localized in the cytoplasm and moved into the nucleus after redox change. Mutations in its conserved cysteine residues led to the constitutive localization of OsNPR1(2CA)-GFP in the nucleus and also abolished herbivore hypersensitivity in transgenic rice. Different subcellular localizations of OsNPR1 antagonistically regulated SA-and jasmonic acid (JA)-responsive genes, but not SA and JA levels, indicating that OsNPR1 might mediate antagonistic cross-talk between the SA-and JA-dependent pathways in rice. This study demonstrates that rice has evolved an SA-mediated systemic acquired resistance similar to that in Arabidopsis, and also provides a practical approach for the improvement of disease resistance without the penalty of decreased herbivore resistance in rice.
Huntington's disease (HD) is caused by polyglutamine (polyQ) expansion in huntingtin (htt), a large (350 kDa) protein that localizes predominantly to the cytoplasm. Proteolytic cleavage of mutant htt yields polyQ-containing N-terminal fragments that are prone to misfolding and aggregation. Disease progression in HD transgenic models correlates with age-related accumulation of soluble and aggregated forms of N-terminal mutant htt fragments, suggesting that multiple forms of mutant htt are involved in the selective neurodegeneration in HD. Although mitochondrial dysfunction is implicated in the pathogenesis of HD, it remains unclear which forms of cytoplasmic mutant htt associate with mitochondria to affect their function. Here we demonstrate that specific N-terminal mutant htt fragments associate with mitochondria in Hdh(CAG)150 knock-in mouse brain and that this association increases with age. The interaction between soluble N-terminal mutant htt and mitochondria interferes with the in vitro association of microtubule-based transport proteins with mitochondria. Mutant htt reduces the distribution and transport rate of mitochondria in the processes of cultured neuronal cells. Reduced ATP level was also found in the synaptosomal fraction isolated from Hdh(CAG)150 knock-in mouse brain. These findings suggest that specific N-terminal mutant htt fragments, before the formation of aggregates, can impair mitochondrial function directly and that this interaction may be a novel target for therapeutic strategies in HD.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
334 Leonard St
Brooklyn, NY 11211
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.