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Transcription modulated by the circadian clock is diverse across cell types, underlying circadian control of peripheral metabolism and its observed perturbation in human diseases. We report that knockout of the lineage-specifying Hnf4a gene in mouse liver causes associated reductions in the genome-wide distribution of core clock component BMAL1 and accessible chromatin marks (H3K4me1 and H3K27ac). Ectopically expressing HNF4A remodels chromatin landscape and nucleates distinct tissue-specific BMAL1 chromatin binding events, predominantly in enhancer regions. Circadian rhythms are disturbed in Hnf4a knockout liver and HNF4A-MODY diabetic model cells. Additionally, the epigenetic state and accessibility of the liver genome dynamically change throughout the day, synchronized with chromatin occupancy of HNF4A and clustered expression of circadian outputs. Lastly, Bmal1 knockout attenuates HNF4A genome-wide binding in the liver, likely due to downregulated Hnf4a transcription. Our results may provide a general mechanism for establishing circadian rhythm heterogeneity during development and disease progression, governed by chromatin structure. Genome-wide occupancy of the master circadian clock transcription factor BMAL1::CLOCK varies across tissues and is reprogrammed in cancers, but how specificity is governed is not known. Here the authors show BMAL1::CLOCK in liver tissue is guided by chromatin accessibility remodeled by HNF4A, shedding new lights onto mechanisms of dysregulated circadian rhythms in hepatocarcinoma.

PARP1 and PARP2 play critical roles in regulating DNA repair and PARP inhibitors have been approved for the treatment of BRCA1/2-mutated ovarian and breast cancers. It has long been known that PARP inhibition sensitizes cancer cells to DNA-damaging cytotoxic agents independent of BRCA status, however, clinical use of PARP inhibitors in combination with DNA-damaging chemotherapy is limited by the more-than-additive cytotoxicity. The natural compound alantolactone (ATL) inhibits the thioredoxin reductase to induce ROS accumulation and oxidative DNA damage selectively in cancer cells. Here, we showed that nontoxic doses of ATL markedly synergized with the PARP inhibitor olaparib to result in synthetic lethality irrespective of homologous recombination status. Synergistic cytotoxicity was seen in cancer but not noncancerous cells and was reduced by the ROS inhibitor NAC or knockdown of OGG1, demonstrating that the cytotoxicity resulted from the repair of ATL-induced oxidative DNA damage. PARP1 knockdown suppressed the synergistic lethality and olaparib was much more toxic than veliparib when combined with ATL, suggesting PARP-trapping as the primary inducer of cytotoxicity. Consistently, combined use of ATL and olaparib caused intense signs of replication stress and formation of double strand DNA breaks, leading to S and G2 arrest followed by apoptosis. In vivo, the combination effectively induced regression of tumor xenografts, while either agent alone had no effect. Hence, PARP trapping combined with specific pro-oxidative agents may provide safe and effective ways to broaden the therapeutic potential of PARP inhibitors.

Seahorses have a circum-global distribution in tropical to temperate coastal waters. Yet, seahorses show many adaptations for a sedentary, cryptic lifestyle: they require specific habitats, such as seagrass, kelp or coral reefs, lack pelvic and caudal fins, and give birth to directly developed offspring without pronounced pelagic larval stage, rendering long-range dispersal by conventional means inefficient. Here we investigate seahorses’ worldwide dispersal and biogeographic patterns based on a de novo genome assembly of Hippocampus erectus as well as 358 re-sequenced genomes from 21 species. Seahorses evolved in the late Oligocene and subsequent circum-global colonization routes are identified and linked to changing dynamics in ocean currents and paleo-temporal seaway openings. Furthermore, the genetic basis of the recurring “bony spines” adaptive phenotype is linked to independent substitutions in a key developmental gene. Analyses thus suggest that rafting via ocean currents compensates for poor dispersal and rapid adaptation facilitates colonizing new habitats. A new seahorse genome and the re-sequenced genomes of 21 other species shed new light on the evolutionary origin and global dispersal routes of seahorses, and show that bony spines—a key adaptation against predation—probably evolved multiple times via independent substitutions in the bmp3 gene.

Either expression level or transcriptional activity of various nuclear receptors (NRs) have been demonstrated to be under circadian control. With a few exceptions, little is known about the roles of NRs as direct regulators of the circadian circuitry. Here we show that the nuclear receptor HNF4A strongly transrepresses the transcriptional activity of the CLOCK:BMAL1 heterodimer. We define a central role for HNF4A in maintaining cell-autonomous circadian oscillations in a tissue-specific manner in liver and colon cells. Not only transcript level but also genome-wide chromosome binding of HNF4A is rhythmically regulated in the mouse liver. ChIP-seq analyses revealed cooccupancy of HNF4A and CLOCK: BMAL1 at a wide array of metabolic genes involved in lipid, glucose, and amino acid homeostasis. Taken together, we establish that HNF4A defines a feedback loop in tissue-specific mammalian oscillators and demonstrate its recruitment in the circadian regulation of metabolic pathways.

This paper examines how creativity-based social entrepreneurship and entrepreneurial networks in the context of small-scale rural art festivals can advance social and regional revitalization goals in peripheral island communities. This qualitative- and action-based research explores the effects of artistic activities on rural revitalization through the analysis of four small-scale rural events: a traditional matsuri (festival), and three contemporary art, music, and film festivals. The adaptability and diversity of the festivals’ entrepreneurial networks are investigated in greater depth by combining the literatures on rural revitalization, social entrepreneurship, bricolage and resourcefulness with the embedded and relational aspects of creative entrepreneurial networks. The study also analyzes the complex relationship between the individual actions of creative festival entrepreneurs and the socially engaged creative networks that facilitate population retention and resource exchanges in a community, and therefore rural revitalization.

Disruption of the cellular pathway modulating endogenous 24-h rhythms, referred to as “the circadian clock”, has been recently proven to be associated with cancer risk, development, and progression. This pathway operates through a complex network of transcription-translation feedback loops generated by a set of interplaying proteins. The expression of core circadian clock genes is frequently dysregulated in human tumors; however, the specific effects and underlying mechanisms seem to vary depending on the cancer types and are not fully understood. In addition, specific oncogenes may differentially induce the dysregulation of the circadian clock in tumors. Pharmacological modulation of clock components has been shown to result in specific lethality in certain types of cancer cells, and thus holds great promise as a novel anti-cancer therapeutic approach. Here we present an overview of the rationale and current evidence for targeting the clock in cancer treatment.

World semantics refers to how individuals comprehend and ascribe meaning to phenomena within specific sociocultural and environmental contexts. And it significantly influences how people conceptualize numerical properties, such as quantity (“how many”) and order (“which”), influencing their resolution of cardinal and ordinal numerical task. In order to reveal the influence of world semantics on the joint effects of encoding spatial-numerical responses related to cardinal and ordinal numbers, this study conducted three experimental contexts with distinct numerical representations: (1) a non-symbolic context, where numbers were represented using dot arrays; (2) a symbolic context, where numbers were presented as Chinese characters; and (3) a word problem solving context, where numerical values were embedded in real-world mathematical scenarios. To investigate how numerical attributes (cardinality vs. ordinality) influence on the SNARC effect under varying level of world semantics across these three contexts. Results showed that in the non-symbolic context, the SNARC effect is primarily observed for cardinal numbers. In the symbolic context, ordinal number elicited a stronger SNARC effect. However, in the word problem context, no significant SNARC effect was observed. The findings suggest that as world semantics become more prominent, the SNARC effect diminishes, particularly in applied numerical contexts. Additionally, ordinal numbers exhibited a stronger SNARC effect than cardinal numbers, supporting the role of sequential processing in spatial-numerical associations.

Groupers of the family Epinephelidae are a diverse and economically valuable group of reef fishes. To investigate the evolution of their mitochondrial genomes we characterized and compared these genomes among 22 species, 17 newly sequenced. Among these fishes we identified three distinct genome organizations, two of them never previously reported in vertebrates. In 19 of these species, mitochondrial genomes followed the typical vertebrate canonical organization with 13 protein-coding genes, 22 tRNAs, two rRNAs, and a non-coding control region. Differing from this, members of genus Variola have an extra tRNA-Ile between tRNA-Val and 16S rRNA. Evidence suggests that this evolved from tRNA-Val via a duplication event due to slipped strand mispairing during replication. Additionally, Cephalopholisargus has an extra tRNA-Asp in the midst of the control region, likely resulting from long-range duplication of the canonical tRNA-Asp through illicit priming of mitochondrial replication by tRNAs. Along with their gene contents, we characterized the regulatory elements of these mitochondrial genomes' control regions, including putative termination-associated sequences and conserved sequence blocks. Looking at the mitochondrial genomic constituents, rRNA and tRNA are the most conserved, followed by protein-coding genes, and non-coding regions are the most divergent. Divergence rates vary among the protein-coding genes, and the three cytochrome oxidase subunits (COI, II, III) are the most conserved, while NADH dehydrogenase subunit 6 (ND6) and the ATP synthase subunit 8 (ATP8) are the most divergent. We then tested the phylogenetic utility of this new mt genome data using 12 protein-coding genes of 48 species from the suborder Percoidei. From this, we provide further support for the elevation of the subfamily Epinephelinae to family Epinephelidae, the resurrection of the genus Hyporthodus, and the combination of the monotypic genera Anyperodon and Cromileptes to genus Epinephelus, and Aethaloperca to genus Cephalopholis.

Three wood-inhabiting fungal species, Xylodon gossypinus, X. macrosporus, and X. sinensis spp. nov. were collected from southern China, with the similar function to decompose rotten wood, which are here proposed as new taxa based on a combination of morphological features and molecular evidence. Xylodon gossypinus is characterized by the resupinate basidiomata with cotton hymenophore, and ellipsoid basidiospores; X.macrosporus is characterized by the resupinate basidiomata having the cracking hymenophore with pale yellowish hymenial surface, and larger basidiospores 8–10.5 × 7.5–9 µm; and X. sinensis differs by its grandinioid hymenial surface and subglobose basidiospores measuring as 3–5 × 2.5–4 µm. Sequences of ITS and nLSU rRNA markers of the studied samples were generated, and phylogenetic analyses were performed with maximum likelihood, maximum parsimony, and Bayesian inference methods. The ITS+nLSU analysis in Hymenochaetales revealed that the three new species clustered into the Schizoporaceae family, located in genus Xylodon; based on the ITS dataset, X. gossypinus was a sister to X. ussuriensis; X. macrosporus closely grouped with X.follis with a high support; and X.sinensis was retrieved as two sisters to X. attenuatus and X. yarraensis with a lower support.

Background Antiretroviral therapy (ART) can reduce viral load in individuals infected with human immunodeficiency virus (HIV); however, some HIV-infected individuals still cannot achieve optimal immune recovery even after ART. Hence, we described the profile of peripheral immune cells and explored the association with disease progression in patients infected with HIV-1. Methods Mass cytometry analysis was used to characterize the circulating immune cells of 20 treatment-naïve (TNs), 20 immunological non-responders (INRs), 20 immunological responders (IRs), and 10 healthy controls (HCs). Correlation analysis was conducted between cell subpopulation percentages and indicators including HIV-1 cell-associated (CA)-RNA, DNA, CD4 + T cell count, and CD4/CD8 ratio. Results Global activation, immunosenescence, and exhaustion phenotypes were observed in myeloid cells and T cells from individuals with HIV-1 infection. We also found that specific subsets or clusters of myeloid, CD4 + T, and CD8 + T cells were significantly lost or increased in TN individuals, which could be partially restored after receiving ART. The percentages of several subpopulations correlated with HIV-1 CA-RNA, DNA, CD4 + T cell count, and CD4/CD8 ratio, suggesting that changes in immune cell composition were associated with therapeutic efficacy. Conclusion These data provide a complete profile of immune cell subpopulations or clusters that are associated with disease progression during chronic HIV-1 infection, which will improve understanding regarding the mechanism of incomplete immune recovery in INRs.