Proteostatic reactivation of the developmental transcription factor TBX3 drives BRAF/MAPK-mediated tumorigenesis.

MAPK pathway-driven tumorigenesis, often induced by BRAFV600E, relies on epithelial dedifferentiation. However, how lineage differentiation events are reprogrammed remains unexplored. Here, we demonstrate that proteostatic reactivation of developmental factor, TBX3, accounts for BRAF/MAPK-mediated dedifferentiation and tumorigenesis. During embryonic development, BRAF/MAPK upregulates USP15 to stabilize TBX3, which orchestrates organogenesis by restraining differentiation. The USP15-TBX3 axis is reactivated during tumorigenesis, and Usp15 knockout prohibits BRAFV600E-driven tumor development in a Tbx3-dependent manner. Deleting Tbx3 or Usp15 leads to tumor redifferentiation, which parallels their overdifferentiation tendency during development, exemplified by disrupted thyroid folliculogenesis and elevated differentiation factors such as Tpo, Nis, Tg. The clinical relevance is highlighted in that both USP15 and TBX3 highly correlates with BRAFV600E signature and poor tumor prognosis. Thus, USP15 stabilized TBX3 represents a critical proteostatic mechanism downstream of BRAF/MAPK-directed developmental homeostasis and pathological transformation, supporting that tumorigenesis largely relies on epithelial dedifferentiation achieved via embryonic regulatory program reinitiation.

Evolution of Grain Boundaries Promoted Hydrogen Production for Industrial-Grade Current Density.

The development of efficient and durable high-current-density hydrogen production electrocatalysts is crucial for the large-scale production of green hydrogen and the early realization of hydrogen economic blueprint. Herein, the evolution of grain boundaries through Cu-mediated NiMo bimetallic oxides (MCu-BNiMo), which leading to the high efficiency of electrocatalyst for hydrogen evolution process (HER) in industrial-grade current density, is successfully driven. The optimal MCu0.10-BNiMo demonstrates ultrahigh current density (>2 A cm-2) at a smaller overpotential in 1 m KOH (572 mV), than that of BNiMo, which does not have lattice strain. Experimental and theoretical calculations reveal that MCu0.10-BNiMo with optimal lattice strain generated more electrophilic Mo sites with partial oxidation owing to accelerated charge transfer from Cu to Mo, which lowers the energy barriers for H* adsorption. These synergistic effects lead to the enhanced HER performance of MCu0.10-BNiMo. More importantly, industrial application of MCu0.10-BNiMo operated in alkaline electrolytic cell is also determined, with its current density reached 0.5 A cm-2 at 2.12 V and 0.1 A cm-2 at 1.79 V, which is nearly five-fold that of the state-of-the-art HER electrocatalyst Pt/C. The strategy provides valuable insights for achieving industrial-scale hydrogen production through a highly efficient HER electrocatalyst.

The Improved DC Breakdown Strength Induced by Enhanced Interaction between SiO2 Nanoparticles and LLDPE Matrix.

Direct current (DC) power transmission systems have received great attention because it can easily integrate many types of renewable energies and have low energy loss in long-distance and large-capacity power transmission for electricity global sharing. Nanoparticles (NPs) have a positive effect on the insulation properties of polymers, but weak interaction between NPs and polymer matrix greatly decreases the effort of NPs on the enhancement of insulation properties, and thereby limits its engineering application. In this work, grafting strategy was used to link the modified NPs and polymer matrix to improve their interactions. Silica NPs (SiO2-NPs) were modified by 3-(methacrylyloxy) propyl-trimethoxysilane (MPS) to introduce highly active groups on the SiO2-NPs surface, followed by the pre-irradiated linear low-density polyethylene (LLDPE) being easily grafted onto the MPS modified SiO2-NPs (MPS-SiO2-NPs) in the melt blending process to obtain LLDPE-g-MPS-SiO2-NPs nanocomposites. Fourier-transform infrared (FT-IR) spectrum and X-ray photoelectron spectroscopy (XPS) confirm the successful incorporation of MPS into SiO2-NPs. Transmission electron microscopy (TEM) verifies that the modified SiO2-NPs exhibits more uniform distribution. The rheology result shows that the interaction between MPS-SiO2-NPs and LLDPE significantly improves. More importantly, the LLDPE-g-MPS-SiO2-NPs nanocomposites displays superior DC breakdown strength to that fabricated by conventional modification methods. When the addition of MPS-SiO2-NPs is 0.1 wt%, the highest DC breakdown strength values of 525 kV/mm and 372 kV/mm are obtained at 30 °C and 70 °C, respectively, and high DC breakdown strength can be well maintained in a wide loading range of NPs.

Targeting myeloid derived suppressor cells reverts immune suppression and sensitizes BRAF-mutant papillary thyroid cancer to MAPK inhibitors.

MAPK signaling inhibitor (MAPKi) therapies show limited efficacy for advanced thyroid cancers despite constitutive activation of the signaling correlates with disease recurrence and persistence. Understanding how BRAF pathway stimulates tumorigenesis could lead to new therapeutic targets. Here, through genetic and pathological approaches, we demonstrate that BRAFV600E promotes thyroid cancer development by increasing myeloid-derived suppressor cells (MDSCs) penetrance. This BRAFV600E-induced immune suppression involves re-activation of the developmental factor TBX3, which in turn up-regulates CXCR2 ligands in a TLR2-NFκB dependent manner, leading to MDSCs recruitment into the tumor microenvironment. CXCR2 inhibition or MDSCs repression improves MAPKi therapy effect. Clinically, high TBX3 expression correlates with BRAFV600E mutation and increased CXCR2 ligands, along with abundant MDSCs infiltration. Thus, our study uncovers a BRAFV600E-TBX3-CXCLs-MDSCs axis that guides patient stratification and could be targeted to improve the efficacy of MAPKi therapy in advanced thyroid cancer patients.

Drosophila Netrin-B controls mushroom body axon extension and regulates courtship-associated learning and memory of a Drosophila fragile X syndrome model.

Mushroom body (MB) is a prominent structure essential for olfactory learning and memory in the Drosophila brain. The development of the MB involves the appropriate guidance of axon lobes and sister axon branches. Appropriate guidance that accurately shapes MB development requires the integration of various guidance cues provided by a series of cell types, which guide axons to reach their final positions within the MB neuropils. Netrins are axonal guidance molecules that are conserved regulators of embryonic nerve cord patterning. However, whether they contribute to MB morphogenesis has not yet been evaluated. Here, we find that Netrin-B (NetB) is highly expressed in the MB lobes, regulating lobe length through genetic interactions with the receptors Frazzled and Uncoordinated-5 from 24 h after pupal formation onwards. We observe that overexpression of NetB causes severe ß lobe fusion in the MB, which is similar to the MB defects seen in the Drosophila model of fragile X syndrome (FXS). Our results further show that fragile-X mental retardation protein FMRP inhibits the translational activity of human ortholog Netrin-1 (NTN1). Knock-down of NetB significantly rescues the MB defects and ameliorates deficits in the learning and memory in FXS model Drosophila. These results indicate a critical role for NetB in MB lobe extension and identify NetB as a novel target of FMRP which contributes to learning and memory.

Mutations in the non-structural protein region contribute to intra-genotypic evolution of enterovirus 71.

BACKGROUND: Clinical manifestations of enterovirus 71 (EV71) range from herpangina, hand-foot-and-mouth disease (HFMD), to severe neurological complications. Unlike the situation of switching genotypes seen in EV71 outbreaks during 1998-2008 in Taiwan, genotype B5 was responsible for two large outbreaks in 2008 and 2012, respectively. In China, by contrast, EV71 often persists as a single genotype in the population and causes frequent outbreaks. To investigate genetic changes in viral evolution, complete EV71 genome sequences were used to analyze the intra-genotypic evolution pattern in Taiwan, China, and the Netherlands. RESULTS: Genotype B5 was predominant in Taiwan's 2008 outbreak and was re-emergent in 2012. EV71 strains from both outbreaks were phylogenetically segregated into two lineages containing fourteen non-synonymous substitutions predominantly in the non-structural protein coding region. In China, genotype C4 was first seen in 1998 and caused the latest large outbreak in 2008. Unlike shifting genotypes in Taiwan, genotype C4 persisted with progressive drift through time. A majority of non-synonymous mutations occurred in residues located in the non-structural coding region, showing annual increases. Interestingly, genotype B1/B2 in the Netherlands showed another stepwise evolution with dramatic EV71 activity increase in 1986. Phylogeny of the VP1 coding region in 1971-1986 exhibited similar lineage turnover with genotype C4 in China; however, phylogeny of the 3D-encoding region indicated separate lineage appearing after 1983, suggesting that the 3D-encoding region of genotype B2 was derived from an unidentified ancestor that contributed to intra-genotypic evolution in the Netherlands. CONCLUSIONS: Unlike VP1 coding sequences long used for phylogenetic study of enteroviruses due to expected host immune escape, our study emphasizes a dominant role of non-synonymous mutations in non-structural protein regions that contribute to (re-)emergent genotypes in continuous stepwise evolution. Dozens of amino acid substitutions, especially in non-structural proteins, were identified via genetic changes driven through intra-genotypic evolution worldwide. These identified substitutions appeared to increase viral fitness in the population, affording valuable insights not only for viral evolution but also for prevention, control, and vaccine against EV71 infection.