Miracle-dz/UniFAR-FTUs huggingface dataset:
Therapeutic targeting of FOS in mutant TERT cancers through removing TERT suppression of apoptosis via regulating survivin and TRAIL-R2

Significance Given that oncogenic hotspot mutations in the promoter of the gene for telomerase reverse transcriptase (TERT) are common, it has been attractive to develop therapeutic strategies targeting TERT in mutant TERT human cancers. No direct TERT inhibitor is currently available, however, hindering this pursuit. By targeting FOS in the FOS/GABPB/(mutant) TERT cascade using a FOS inhibitor to inhibit mutant TERT cancer cells and tumors through induction of apoptosis by relieving TERT suppression, this study identifies a therapeutic strategy of targeting the TERT cascade for cancers. This study also uncovers a molecular mechanism in which TERT controls apoptosis by specifically regulating two key players among many in the apoptotic cascade, answering a long-time question of how TERT suppresses apoptosis. The telomerase reverse transcriptase (TERT) has long been pursued as a direct therapeutic target in human cancer, which is currently hindered by the lack of effective specific inhibitors of TERT. The FOS/GABPB/(mutant) TERT cascade plays a critical role in the regulation of mutant TERT, in which FOS acts as a transcriptional factor for GABPB to up-regulate the expression of GABPB, which in turn activates mutant but not wild-type TERT promoter, driving TERT-promoted oncogenesis. In the present study, we demonstrated that inhibiting this cascade by targeting FOS using FOS inhibitor T-5224 suppressed mutant TERT cancer cells and tumors by inducing robust cell apoptosis; these did not occur in wild-type TERT cells and tumors. Mechanistically, among 35 apoptotic cascade-related proteins tested, the apoptosis induced in this process specifically involved the transcriptional activation of tumor necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAIL-R2) and inactivation of survivin, two key players in the apoptotic cascade, which normally initiate and suppress the apoptotic cascade, respectively. These findings with suppression of FOS were reproduced by direct knockdown of TERT and prevented by prior knockdown of TRAIL-R2. Further experiments demonstrated that TERT acted as a direct transcriptional factor of survivin, up-regulating its expression. Thus, this study identifies a therapeutic strategy for TERT promoter mutation-driven cancers by targeting FOS in the FOS/GABPB/(mutant) TERT cascade, circumventing the current challenge in pharmacologically directly targeting TERT itself. This study also uncovers a mechanism through which TERT controls cell apoptosis by transcriptionally regulating two key players in the apoptotic cascade.
Antigenic cartography reveals complexities of genetic determinants that lead to antigenic differences among pandemic GII.4 noroviruses

Significance The GII.4 genotype of human noroviruses accounts for the majority of gastroenteritis outbreaks worldwide. This predominance is characterized by the chronological emergence of new variants in response to immune pressure. We performed a comprehensive analysis on a large panel of GII.4 viruses to investigate the genetic determinants of antigenic diversification. Using immunoassays and neutralization data, we observed major changes to antigenic properties over the course of GII.4 evolution and increased intervariant cross-reactivity across contemporary viruses. Antigenic cartography and sequence analyses indicated a minimum number of coevolving amino acid changes on the structural protein necessary for the emergence of antigenically distinct variants. These insights could facilitate the monitoring and characterization of emerging GII.4 noroviruses and the development of cross-protective vaccines. Noroviruses are the predominant cause of acute gastroenteritis, with a single genotype (GII.4) responsible for the majority of infections. This prevalence is characterized by the periodic emergence of new variants that present substitutions at antigenic sites of the major structural protein (VP1), facilitating escape from herd immunity. Notably, the contribution of intravariant mutations to changes in antigenic properties is unknown. We performed a comprehensive antigenic analysis on a virus-like particle panel representing major chronological GII.4 variants to investigate diversification at the inter- and intravariant level. Immunoassays, neutralization data, and cartography analyses showed antigenic similarities between phylogenetically related variants, with major switches to antigenic properties observed over the evolution of GII.4 variants. Genetic analysis indicated that multiple coevolving amino acid changes—primarily at antigenic sites—are associated with the antigenic diversification of GII.4 variants. These data highlight complexities of the genetic determinants and provide a framework for the antigenic characterization of emerging GII.4 noroviruses.
Ancient noeggerathialean reveals the seed plant sister group diversified alongside the primary seed plant radiation

Significance There were two heterosporous lignophyte lineages of which only one, the seed plants, survived the Permian–Triassic mass extinction. Based on exceptionally complete fossil trees from a 300-My-old volcanic ash, the enigmatic Noeggerathiales are now recognized as belonging to the other lineage. They diversified alongside the primary seed plant radiation and constitute seed plants’ closest relatives. Noeggerathiales are reconstructed as members of a plexus of free-sporing woody plants called progymnosperms, extending their age range by 60 My. Following the origin of seed plants, progymnosperms were previously thought to have become gradually less abundant before dying out in Carboniferous. We show they diversified and evolved complex morphologies including cone-like structures from modified leaves before going extinct at the Permian–Triassic extinction. Noeggerathiales are enigmatic plants that existed during Carboniferous and Permian times, ∼323 to 252 Mya. Although their morphology, diversity, and distribution are well known, their systematic affinity remained enigmatic because their anatomy was unknown. Here, we report from a 298-My-old volcanic ash deposit, an in situ, complete, anatomically preserved noeggerathialean. The plant resolves the group’s affinity and places it in a key evolutionary position within the seed plant sister group. Paratingia wuhaia sp. nov. is a small tree producing gymnospermous wood with a crown of pinnate, compound megaphyllous leaves and fertile shoots each with Ω-shaped vascular bundles. The heterosporous (containing both microspores and megaspores), bisporangiate fertile shoots appear cylindrical and cone-like, but their bilateral vasculature demonstrates that they are complex, three-dimensional sporophylls, representing leaf homologs that are unique to Noeggerathiales. The combination of heterospory and gymnospermous wood confirms that Paratingia, and thus the Noeggerathiales, are progymnosperms. Progymnosperms constitute the seed plant stem group, and Paratingia extends their range 60 My, to the end of the Permian. Cladistic analysis resolves the position of the Noeggerathiales as the most derived members of a heterosporous progymnosperm clade that are the seed plant sister group, altering our understanding of the relationships within the seed plant stem lineage and the transition from pteridophytic spore-based reproduction to the seed. Permian Noeggerathiales show that the heterosporous progymnosperm sister group to seed plants diversified alongside the primary radiation of seed plants for ∼110 My, independently evolving sophisticated cone-like fertile organs from modified leaves.
A bird-like genome from a frog: Mechanisms of genome size reduction in the ornate burrowing frog, Platyplectrum ornatum

Significance The mechanisms by which genomes become smaller in lineages with large genomes, such as many frogs, are poorly understood. Here, we present the sequence of a very small genome from a frog—that of the ornate burrowing frog, Platyplectrum ornatum, whose genome is smaller than that of many birds, a group well known for small genomes. Our data show that this frog evolved molecular mechanisms to keep in check a major process characterizing large genomes: namely, proliferation of transposable elements. We also present basic data on gene expression and sex determination in this emerging model for genome miniaturization. The diversity of genome sizes across the tree of life is of key interest in evolutionary biology. Various correlates of variation in genome size, such as accumulation of transposable elements (TEs) or rate of DNA gain and loss, are well known, but the underlying molecular mechanisms driving or constraining genome size are poorly understood. Here, we study one of the smallest genomes among frogs characterized thus far, that of the ornate burrowing frog (Platyplectrum ornatum) from Australia, and compare it to other published frog and vertebrate genomes to examine the forces driving reduction in genome size. At ∼1.06 gigabases (Gb), the P. ornatum genome is like that of birds, revealing four major mechanisms underlying TE dynamics: reduced abundance of all major classes of TEs; increased net deletion bias in TEs; drastic reduction in intron lengths; and expansion via gene duplication of the repertoire of TE-suppressing Piwi genes, accompanied by increased expression of Piwi-interacting RNA (piRNA)-based TE-silencing pathway genes in germline cells. Transcriptomes from multiple tissues in both sexes corroborate these results and provide insight into sex-differentiation pathways in Platyplectrum. Genome skimming of two closely related frog species (Lechriodus fletcheri and Limnodynastes fletcheri) confirms a reduction in TEs as a major driver of genome reduction in Platyplectrum and supports a macroevolutionary scenario of small genome size in frogs driven by convergence in life history, especially rapid tadpole development and tadpole diet. The P. ornatum genome offers a model for future comparative studies on mechanisms of genome size reduction in amphibians and vertebrates generally.
Brassinosteroid signaling integrates multiple pathways to release apical dominance in tomato

Significance For almost a century, auxin had been well-known as the master regulator of apical dominance. Recently, however, sugars were shown to be the initial regulator of apical dominance, while strigolactones (SLs) and cytokinins (CKs) act downstream of auxin to control bud outgrowth. However, the interactions of the different pathways have remained outstanding questions. Here, we report that brassinosteroids (BRs) are essential for the release of apical dominance in tomato. CK signaling relays information from auxin, SL, and sugars to promote the production of BRs, which activate the BZR1 transcription factor to suppress the expression of BRANCHED1, an inhibitor of bud outgrowth. These findings demonstrate that hormonal and metabolic pathways impinge on a common BR signaling for controlling shoot branching. The control of apical dominance involves auxin, strigolactones (SLs), cytokinins (CKs), and sugars, but the mechanistic controls of this regulatory network are not fully understood. Here, we show that brassinosteroid (BR) promotes bud outgrowth in tomato through the direct transcriptional regulation of BRANCHED1 (BRC1) by the BR signaling component BRASSINAZOLE-RESISTANT1 (BZR1). Attenuated responses to the removal of the apical bud, the inhibition of auxin, SLs or gibberellin synthesis, or treatment with CK and sucrose, were observed in bud outgrowth and the levels of BRC1 transcripts in the BR-deficient or bzr1 mutants. Furthermore, the accumulation of BR and the dephosphorylated form of BZR1 were increased by apical bud removal, inhibition of auxin, and SLs synthesis or treatment with CK and sucrose. These responses were decreased in the DELLA-deficient mutant. In addition, CK accumulation was inhibited by auxin and SLs, and decreased in the DELLA-deficient mutant, but it was increased in response to sucrose treatment. CK promoted BR synthesis in axillary buds through the action of the type-B response regulator, RR10. Our results demonstrate that BR signaling integrates multiple pathways that control shoot branching. Local BR signaling in axillary buds is therefore a potential target for shaping plant architecture.
A specific RIP3+ subpopulation of microglia promotes retinopathy through a hypoxia-triggered necroptotic mechanism

Significance Retinopathy is the leading cause of blindness, and development of effective therapy is urgently needed. Here, we defined an unprecedented subgroup of microglia that is responsible for causing retinopathy under hypoxia. Mechanistic studies demonstrated the signaling pathway of hypoxia-induced necroptosis of retinal microglia, i.e., the hypoxia–RIP1–RIP3–MLKL signaling axis, triggered an explosive release of FGF2, which in its turn to induce retinal neovascularization. Simultaneous targeting of necroptosis–FGF2 pathway and VEGF produces synergistic effects for treating retinopathy. On the basis of our findings, we propose a concept of necroptotic microglia-induced retinal angiogenesis and highlight a combination therapy for effective treatment of retinopathy. Retinal neovascularization is a leading cause of severe visual loss in humans, and molecular mechanisms of microglial activation-driven angiogenesis remain unknown. Using single-cell RNA sequencing, we identified a subpopulation of microglia named sMG2, which highly expressed necroptosis-related genes Rip3 and Mlkl. Genetic and pharmacological loss of function demonstrated that hypoxia-induced microglial activation committed to necroptosis through the RIP1/RIP3-mediated pathway. Specific deletion of Rip3 gene in microglia markedly decreased retinal neovascularization. Furthermore, hypoxia induced explosive release of abundant FGF2 in microglia through RIP3-mediated necroptosis. Importantly, blocking signaling components of the microglia necropotosis–FGF2 axis largely ablated retinal angiogenesis and combination therapy with simultaneously blocking VEGF produced synergistic antiangiogenic effects. Together, our data demonstrate that targeting the microglia necroptosis axis is an antiangiogenesis therapy for retinal neovascular diseases.
Ultrafast nanometric imaging of energy flow within and between single carbon dots

Significance Carbon dots are promising fluorescent nanomaterials, but their fluorescence yield is fairly low when measured in the bulk. By observing single dots directly using femtosecond single-nanometer resolution imaging, we find that some carbon dots fluoresce exceedingly well and others not at all. We propose a simple mechanism, which suggests that near-perfect fluorescence yield is possible by improved separation or synthesis, as indeed quantum yields of carbon dots have been improving. Time- and space-resolved excited states at the individual nanoparticle level provide fundamental insights into heterogeneous energy, electron, and heat flow dynamics. Here, we optically excite carbon dots to image electron–phonon dynamics within single dots and nanoscale thermal transport between two dots. We use a scanning tunneling microscope tip as a detector of the optically excited state, via optical blocking of electron tunneling, to record movies of carrier dynamics in the 0.1–500-ps time range. The excited-state electron density migrates from the bulk to molecular-scale (∼1 nm2) surface defects, followed by heterogeneous relaxation of individual dots to either long-lived fluorescent states or back to the ground state. We also image the coupling of optical phonons in individual carbon dots with conduction electrons in gold as an ultrafast energy transfer mechanism between two nearby dots. Although individual dots are highly heterogeneous, their averaged dynamics is consistent with previous bulk optical spectroscopy and nanoscale heat transfer studies, revealing the different mechanisms that contribute to the bulk average.
I SOLATION AND CHARACTERIZATION OF QUERCETIN AND KAEMPFEROL IN VIVO AND IN VITRO FROM PEDALIUM MUREX

Phytochemical progress has been aided enormously by the development of rapid and accurate methods of screening plants for particular chemicals. The plants are rich in secondary metabolites. Chemical compounds such as carbohydrates, protein, and lipids and a multitude of compounds like glycosides, alkaloids, flavonoids, etc. are used as food and medicines by people in various ways. Some species of family pedaliaceae are widely used in Indian traditional system and selected for various screening. In the present investigation quercetin and kaempferol have been isolated and identified from stem, leaves and unorganized cultures of P. murex and maintained by frequent subculturings on Murashige and Skoog’s medium (1962) supplemented with BAP(1.0 mg/l). The study showed maximum content of quercetin and kaempferol was observed in 6 weeks old calli and minimum in stem of Pedalium murex. The structure of the isolated compound was established on the basis of physical and chemical test and spectroscopic evidences (TLC, IR, UV, mp).
ATMOSPHERIC OCCURRENCE OF 2-NITROBENZANTHRONE ASSOCIATED WITH AIRBORNE PARTICLES IN CENTRAL TOKYO

2- and 3-Nitrobenzanthrones (NBAs) in airborne particles collected in central Tokyo on a seasonal basis from 1996 to 2001 are quantified and possible sources are investigated. The concentrations of 2- and 3-NBA are found to range from 49 to 831 fmol m–3and 0.5 to 3.5 fmol m–3, while the nitrated polycyclic hydrocarbons 1-nitropyrene and 2-nitrofluoranthene are found at concentrations of 100–492 fmol m–3 and 10–97 fmol m–3. Significant linear correlations are identified between 2-NBA and NO2, a photochemical product, suggesting that 2-NBA is formed by atmospheric reactions of benzanthrone initiated by hydroxyl or nitrate radicals in the presence of NO2. 2-NBA is not correlated with directly emitted compounds such as 1-nitropyrene. The concentration ratio of 2-NBA to 1-nitropyrene is 5 or greater in all samples. Nitrated polycyclic aromatic compounds formed by atmospheric reactions therefore appear to represent a substantial contribution to the mutagenicity of airborne particulate matter.
Wealth and preferences for redistribution: The effects of financial assets and home equity in 31 countries

How does wealth affect preferences for redistribution? In general, social scientists have largely neglected to study the social effects of wealth. This neglect was partially due to a dearth of data on household wealth and social outcomes, and also to greater scholarly interest in how wealth has been accumulated rather than the social effects of wealth. While we would expect household wealth to be an important component of attitudes toward inequality and social welfare policies, research in this area is scarce. In this study, the relationship between wealth and preferences for redistribution is examined in cross-national global and comparative perspective using data on 31 countries from the 2009 wave of the International Social Survey Programme (ISSP), the first wave of that study to include measures of wealth. The findings presented compare the effects of two types of wealth—financial assets and home equity—and demonstrate that there are differences in effects by asset type and by redistributive policy in question. Financial wealth is more closely associated with attitudes about income equality, while home equity is more closely associated with attitudes about unemployment benefits. Moreover, while the upper categories of financial wealth have the largest negative effects on support for income equality, it is the middle categories of home equity that are most strongly associated with opposition to unemployment benefits. Effects also differ by country, but not in patterns that theories of comparative welfare states nor political economy would adequately explain.
Soot Formation in Unstrained Diffusion Flames

The formation of soot particles has been investigated in CH4/O2 diffusion flames using a unique burner design, which allows the creation of a nearly unstrained planar reaction sheet. Spatially resolved soot volume fractions were obtained using laser-induced incandescence. These soot measurements and the sooting limits were obtained as a function of bulk flow across the flame and mixture strength. Samples were collected using thermophoretic sampling and analyzed using electron microscopy, revealing a broad range of microstructures including particles with unusually large primary diameters and carbon nanotubes. A theoretical model is presented, which confirms that under certain conditions the 1D nature of the flow field of the burner and the strong adverse temperature gradient on the fuel side of the flame result in the soot particles being held in place by thermophoretic forces and allowed to grow for very long time periods. Some of these so-called super aggregates reached sizes of tens of microns and became visible to the naked eye in the soot layer.
Theory vs practice: Patterns of the ASEAN-10 agri-food trade

Abstract During the past decades, agricultural trade is enormously expanded. One of its driving factors is the World Trade Organization. However, regional agreements can give further trade opportunities for the participating countries. Association of Southeast Asian Nations (ASEAN) is one of them. This article aims to give a detailed overview of ASEAN members’ agri-food trade by using the world and regional level data. The country level competitiveness is calculated by four different Balassa-type indices and highlights whether the agri-food trade (practice) of these countries is in line with the revealed comparative advantages/competitiveness of the different product groups (theory). According to the results, commodities with the highest comparative advantages overlap with the most important export products. This confirms a tight connection between theory and practice. It should also be noted that world level values are generally higher than that of the regional levels. Moreover, countries with significant agri-food production (Thailand, Indonesia, Vietnam, and Malaysia) can be characterized by higher comparative advantages compared to the other ASEAN member states. These results can help to better understand these countries’ trade specialization and international trade performance.
Preparation and Properties of Boron‐Based Nano‐B/NiO Thermite

Boron particles have several major burning problems, such as incomplete combustion, poor ignitability, and a complex burning process in solid propellants. It is documented that the low ignitability and combustion efficiency of boron are caused by the oxidation of its surface. In order to improve the combustion efficiency of boron particles, a precipitation method was employed to prepare nanometer-sized NiO and coat it on boron particles. The morphology and coating results of the B/NiO nanocomposite thermite were characterized using different approaches such as SEM, X-ray Diffraction (XRD), and EDS. The results indicated that the boron particles were well distributed and coated completely by nanocomposite NiO. The B/NiO nanocomposite thermite reaction process was tested by TG-DTA. The results showed that the reaction temperature of B/NiO particles is about 30 °C lower than that of boron particles. The B/NiO thermite and boron powder were added to Mg/PTFE propellant to be measured for their respective combustion performance. The results showed that the burning rate of the B/NiO-Mg/PTFE propellant increased by 22.8–25.2 %, mass burning rate by 26.7–30.8 %, and combustion temperature increased by 8–56 °C compared to the B-Mg/PTFE propellant. The above results indicate that NiO coating of boron particles has a significant effect on the combustion behavior and increases the combustion performance of the propellant compared with uncoated particles.