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    Cohesin couples transcriptional bursting probabilities of inducible enhancers and promoters.
    Robles-Rebollo, I ; Cuartero, S ; Canellas-Socias, A ; Wells, S ; Karimi, MM ; Mereu, E ; Chivu, AG ; Heyn, H ; Whilding, C ; Dormann, D ; Marguerat, S ; Rioja, I ; Prinjha, RK ; Stumpf, MPH ; Fisher, AG ; Merkenschlager, M (Springer Science and Business Media LLC, 2022-07-27)
    Innate immune responses rely on inducible gene expression programmes which, in contrast to steady-state transcription, are highly dependent on cohesin. Here we address transcriptional parameters underlying this cohesin-dependence by single-molecule RNA-FISH and single-cell RNA-sequencing. We show that inducible innate immune genes are regulated predominantly by an increase in the probability of active transcription, and that probabilities of enhancer and promoter transcription are coordinated. Cohesin has no major impact on the fraction of transcribed inducible enhancers, or the number of mature mRNAs produced per transcribing cell. Cohesin is, however, required for coupling the probabilities of enhancer and promoter transcription. Enhancer-promoter coupling may not be explained by spatial proximity alone, and at the model locus Il12b can be disrupted by selective inhibition of the cohesinopathy-associated BET bromodomain BD2. Our data identify discrete steps in enhancer-mediated inducible gene expression that differ in cohesin-dependence, and suggest that cohesin and BD2 may act on shared pathways.
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    Systematics and Plastome Evolution in Schizaeaceae.
    Ke, B-F ; Wang, G-J ; Labiak, PH ; Rouhan, G ; Chen, C-W ; Shepherd, LD ; Ohlsen, DJ ; Renner, MAM ; Karol, KG ; Li, F-W ; Kuo, L-Y (Frontiers Media SA, 2022)
    While the family Schizaeaceae (Schizaeales) represents only about 0.4% of the extant fern species diversity, it differs from other ferns greatly in gross morphologies, niche preferences, and life histories. One of the most notable features in this family is its mycoheterotrophic life style in the gametophytic stage, which appears to be associated with extensive losses of plastid genes. However, the limited number of sequenced plastomes, and the lack of a well-resolved phylogenetic framework of Schizaeaceae, makes it difficult to gain any further insight. Here, with a comprehensive sampling of ~77% of the species diversity of this family, we first inferred a plastid phylogeny of Schizaeaceae using three DNA regions. To resolve the deep relationships within this family, we then reconstructed a plastome-based phylogeny focusing on a selection of representatives that covered all the major clades. From this phylogenomic backbone, we traced the evolutionary histories of plastid genes and examined whether gene losses were associated with the evolution of gametophytic mycoheterotrophy. Our results reveal that extant Schizaeaceae is comprised of four major clades-Microschizaea, Actinostachys, Schizaea, and Schizaea pusilla. The loss of all plastid NADH-like dehydrogenase (ndh) genes was confirmed to have occurred in the ancestor of extant Schizaeaceae, which coincides with the evolution of mycoheterotrophy in this family. For chlorophyll biosynthesis genes (chl), the losses were interpreted as convergent in Schizaeaceae, and found not only in Actinostachys, a clade producing achlorophyllous gametophytes, but also in S. pusilla with chlorophyllous gametophytes. In addition, we discovered a previously undescribed but phylogenetically distinct species hidden in the Schizaea dichotoma complex and provided a taxonomic treatment and morphological diagnostics for this new species-Schizaea medusa. Finally, our phylogenetic results suggest that the current PPG I circumscription of Schizaea is non-monophyletic, and we therefore proposed a three-genus classification moving a subset of Schizaea species sensu PPG I to a third genus-Microschizaea.
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    Germline mutations in mitochondrial complex I reveal genetic and targetable vulnerability in IDH1-mutant acute myeloid leukaemia (vol 13, 2614, 2022)
    Bassal, MA ; Samaraweera, SE ; Lim, K ; Benard, BA ; Bailey, S ; Kaur, S ; Leo, P ; Toubia, J ; Thompson-Peach, C ; Nguyen, T ; Maung, KZY ; Casolari, DA ; Iarossi, DG ; Pagani, IS ; Powell, J ; Pitson, S ; Natera, S ; Roessner, U ; Lewis, ID ; Brown, AL ; Tenen, DG ; Robinson, N ; Ross, DM ; Majeti, R ; Gonda, TJ ; Thomas, D ; D'Andrea, RJ (NATURE PORTFOLIO, 2022-07-15)
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    beta-hydroxybutyrate reduces blastocyst viability via trophectoderm-mediated metabolic aberrations in mice
    Whatley, EG ; Truong, TT ; Wilhelm, D ; Harvey, AJ ; Gardner, DK (OXFORD UNIV PRESS, 2022-07-20)
    STUDY QUESTION: What is the effect of the ketone β-hydroxybutyrate (βOHB) on preimplantation mouse embryo development, metabolism, epigenetics and post-transfer viability? SUMMARY ANSWER: In vitro βOHB exposure at ketogenic diet (KD)-relevant serum concentrations significantly impaired preimplantation mouse embryo development, induced aberrant glycolytic metabolism and reduced post-transfer fetal viability in a sex-specific manner. WHAT IS KNOWN ALREADY: A maternal KD in humans elevates gamete and offspring βOHB exposure during conception and gestation, and in rodents is associated with an increased time to pregnancy, and altered offspring organogenesis, post-natal growth and behaviour, suggesting a developmental programming effect. In vitro exposure to βOHB at supraphysiological concentrations (8-80 mM) perturbs preimplantation mouse embryo development. STUDY DESIGN, SIZE, DURATION: A mouse model of embryo development and viability was utilized for this laboratory-based study. Embryo culture media were supplemented with βOHB at KD-relevant concentrations, and the developmental competence, physiology, epigenetic state and post-transfer viability of in vitro cultured βOHB-exposed embryos was assessed. PARTICIPANTS/MATERIALS, SETTING, METHODS: Mouse embryos were cultured in vitro with or without βOHB at concentrations representing serum levels during pregnancy (0.1 mM), standard diet consumption (0.25 mM), KD consumption (2 mM) and diabetic ketoacidosis (4 mM). The impact of βOHB exposure on embryo development (blastocyst formation rate, morphokinetics and blastocyst total, inner cell mass and trophectoderm (TE) cell number), physiology (redox state, βOHB metabolism, glycolytic metabolism), epigenetic state (histone 3 lysine 27 β-hydroxybutyrylation, H3K27bhb) and post-transfer viability (implantation rate, fetal and placental development) was assessed. MAIN RESULTS AND THE ROLE OF CHANCE: All βOHB concentrations tested slowed embryo development (P < 0.05), and βOHB at KD-relevant serum levels (2 mM) delayed morphokinetic development, beginning at syngamy (P < 0.05). Compared with unexposed controls, βOHB exposure reduced blastocyst total and TE cell number (≥0.25 mM; P < 0.05), reduced blastocyst glucose consumption (2 mM; P < 0.01) and increased lactate production (0.25 mM; P < 0.05) and glycolytic flux (0.25 and 2 mM; P < 0.01). Consumption of βOHB by embryos, mediated via monocarboxylate transporters, was detected throughout preimplantation development. Supraphysiological (20 mM; P < 0.001), but not physiological (0.25-4 mM) βOHB elevated H3K27bhb levels. Preimplantation βOHB exposure at serum KD levels (2 mM) reduced post-transfer viability. Implantation and fetal development rates of βOHB-treated embryos were 50% lower than controls (P < 0.05), and resultant fetuses had a shorter crown-rump length (P < 0.01) and placental diameter (P < 0.05). A strong sex-specific effect of βOHB was detected, whereby female fetuses from βOHB-treated embryos weighed less (P < 0.05), had a shorter crown-rump length (P < 0.05), and tended to have accelerated ear development (P < 0.08) compared with female control fetuses. LIMITATIONS, REASONS FOR CAUTION: This study only assessed embryo development, physiology and viability in a mouse model utilizing in vitro βOHB exposure; the impact of in vivo exposure was not assessed. The concentrations of βOHB utilized were modelled on blood/serum levels as the true oviduct and uterine concentrations are currently unknown. WIDER IMPLICATIONS OF THE FINDINGS: These findings indicate that the development, physiology and viability of mouse embryos is detrimentally impacted by preimplantation exposure to βOHB within a physiological range. Maternal diets which increase βOHB levels, such as a KD, may affect preimplantation embryo development and may therefore impair subsequent viability and long-term health. Consequently, our initial observations warrant follow-up studies in larger human populations. Furthermore, analysis of βOHB concentrations within human and rodent oviduct and uterine fluid under different nutritional states is also required. STUDY FUNDING/COMPETING INTEREST(S): This work was funded by the University of Melbourne and the Norma Hilda Schuster (nee Swift) Scholarship. The authors have no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.
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    Ultrastructure of Antennal Sensory Organs in Nine Flesh Flies (Diptera: Sarcophagidae): New Insight into the Definition of Family Sarcophagidae.
    Xu, W ; Liu, G ; Wang, Q ; Yan, L ; Liu, X ; Li, X ; Pape, T ; Zhang, D (MDPI AG, 2022-06-30)
    The antennae are the main olfactory organ of flies, playing key roles in their survival and the success of all life stages. Antennal ultrastructural morphology has been well described in the representative species of most calyptrate families, yet only a few studies have focused on Sarcophagidae species, those with ecological and medical relevance. Antennal morphology and the types, shapes, distribution, and density of the antennal sensilla of nine Sarcophagidae species are studied in detail with scanning electron microscopy, including Miltogramminae: Metopia campestris (Fallén) and Mesomelena mesomelaena (Loew), Paramacronychiinae: Agria mihalyii (Rohdendorf & Verves), Wohlfahrtia bella (Macquart), and W. magnifica (Schiner); Sarcophaginae: Sarcophaga (Parasarcophaga) albiceps Meigen, S. (Bercaea) africa (Wiedemann), S. (Boettcherisca) peregrina (Robineau-Desvoidy), and S. (Liosarcophaga) portschinskyi (Rohdendorf), covering all three subfamilies of this family. The morphology of the three segments of the antennae has been described. The scape has only one type of chaetic sensilla, while three subtypes of chaetic sensilla were detected on the pedicel. The postpedicel has four types of sensilla: trichoid sensilla, coeloconic sensilla, clavate sensilla, and three subtypes of basiconic sensilla. Bottle-shaped sensilla were observed in sensory pits on the postpedicel in all nine species. These sensilla have not been discovered in other calyptrate species, suggesting that they are a potential sarcophagid synapomorphy.
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    A new family of structurally conserved fungal effectors displays epistatic interactions with plant resistance proteins.
    Lazar, N ; Mesarich, CH ; Petit-Houdenot, Y ; Talbi, N ; Li de la Sierra-Gallay, I ; Zélie, E ; Blondeau, K ; Gracy, J ; Ollivier, B ; Blaise, F ; Rouxel, T ; Balesdent, M-H ; Idnurm, A ; van Tilbeurgh, H ; Fudal, I ; Kobe, B (Public Library of Science (PLoS), 2022-07)
    Recognition of a pathogen avirulence (AVR) effector protein by a cognate plant resistance (R) protein triggers a set of immune responses that render the plant resistant. Pathogens can escape this so-called Effector-Triggered Immunity (ETI) by different mechanisms including the deletion or loss-of-function mutation of the AVR gene, the incorporation of point mutations that allow recognition to be evaded while maintaining virulence function, and the acquisition of new effectors that suppress AVR recognition. The Dothideomycete Leptosphaeria maculans, causal agent of oilseed rape stem canker, is one of the few fungal pathogens where suppression of ETI by an AVR effector has been demonstrated. Indeed, AvrLm4-7 suppresses Rlm3- and Rlm9-mediated resistance triggered by AvrLm3 and AvrLm5-9, respectively. The presence of AvrLm4-7 does not impede AvrLm3 and AvrLm5-9 expression, and the three AVR proteins do not appear to physically interact. To decipher the epistatic interaction between these L. maculans AVR effectors, we determined the crystal structure of AvrLm5-9 and obtained a 3D model of AvrLm3, based on the crystal structure of Ecp11-1, a homologous AVR effector candidate from Fulvia fulva. Despite a lack of sequence similarity, AvrLm5-9 and AvrLm3 are structural analogues of AvrLm4-7 (structure previously characterized). Structure-informed sequence database searches identified a larger number of putative structural analogues among L. maculans effector candidates, including the AVR effector AvrLmS-Lep2, all produced during the early stages of oilseed rape infection, as well as among effector candidates from other phytopathogenic fungi. These structural analogues are named LARS (for Leptosphaeria AviRulence and Suppressing) effectors. Remarkably, transformants of L. maculans expressing one of these structural analogues, Ecp11-1, triggered oilseed rape immunity in several genotypes carrying Rlm3. Furthermore, this resistance could be suppressed by AvrLm4-7. These results suggest that Ecp11-1 shares a common activity with AvrLm3 within the host plant which is detected by Rlm3, or that the Ecp11-1 structure is sufficiently close to that of AvrLm3 to be recognized by Rlm3.
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    High-resolution spatial and genomic characterization of coral-associated microbial aggregates in the coral Stylophora pistillata
    Wada, N ; Hsu, M-T ; Tandon, K ; Hsiao, SS-Y ; Chen, H-J ; Chen, Y-H ; Chiang, P-W ; Yu, S-P ; Lu, C-Y ; Chiou, Y-J ; Tu, Y-C ; Tian, X ; Chen, B-C ; Lee, D-C ; Yamashiro, H ; Bourne, DG ; Tang, S-L (AMER ASSOC ADVANCEMENT SCIENCE, 2022-07-08)
    Bacteria commonly form aggregates in a range of coral species [termed coral-associated microbial aggregates (CAMAs)], although these structures remain poorly characterized despite extensive efforts studying the coral microbiome. Here, we comprehensively characterize CAMAs associated with Stylophora pistillata and quantify their cell abundance. Our analysis reveals that multiple Endozoicomonas phylotypes coexist inside a single CAMA. Nanoscale secondary ion mass spectrometry imaging revealed that the Endozoicomonas cells were enriched with phosphorus, with the elemental compositions of CAMAs different from coral tissues and endosymbiotic Symbiodiniaceae, highlighting a role in sequestering and cycling phosphate between coral holobiont partners. Consensus metagenome-assembled genomes of the two dominant Endozoicomonas phylotypes confirmed their metabolic potential for polyphosphate accumulation along with genomic signatures including type VI secretion systems allowing host association. Our findings provide unprecedented insights into Endozoicomonas-dominated CAMAs and the first direct physiological and genomic linked evidence of their biological role in the coral holobiont.
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    DEB-IBM for predicting climate change and anthropogenic impacts on population dynamics of hairtail Trichiurus lepturus in the East China Sea
    Yang, T ; Han, Q ; Gorfine, H ; Shan, X ; Ren, JS ; Cooke, S (OXFORD UNIV PRESS, 2022-01-01)
    The hairtail Trichiurus lepturus supports the largest fisheries in the East China Sea. The stock has fluctuated in the past few decades and this variation has been attributed to human pressures and climate change. To investigate energetics of individuals and population dynamics of the species in responses to environmental variations and fishing efforts, we have developed a DEB-IBM by coupling a dynamic energy budget (DEB) model to an individual-based model (IBM). The parameter estimation of DEB model shows an acceptable goodness of fit. The DEB-IBM was validated with histological data for a period of 38 years. High fishing pressure was largely responsible for the dramatic decline of the stock in middle 1980s. The stock recovered from early 1990s, which coincided with introduction of fishing moratorium on spawning stocks in inshore waters and substantial decrease of fishing efforts from large fisheries companies. In addition, the population average age showed a trend of slight decrease. The model successfully reproduced these observations of interannual variations in the population dynamics. The model was then implemented to simulate the effect of climate change on the population performance under greenhouse gas emission scenarios projected for 2100. It was also used to explore population responses to changing fishing mortalities. These scenario simulations have shown that the population biomass under SSP1-1.9, SSP2-4.5 and SSP5-8.5 would decline by 7.5%, 16.6% and 30.1%, respectively, in 2100. The model predicts that increasing fishing mortality by 10% will cause 5.3% decline of the population biomass, whereas decrease of fishing mortality by 10% will result in 6.8% increase of the biomass. The development of the DEB-IBM provides a predictive tool to inform management decisions for sustainable exploitation of the hairtail stock in the East China Sea.
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    Gestational heat stress alters skeletal muscle gene expression profiles and vascularity in fetal pigs in a sexually dimorphic manner
    Zhao, W ; Green, MP ; Marth, CD ; Liu, F ; Le, HH ; Lynch, GS ; Bell, AW ; Leury, BJ ; Dunshea, FR ; Cottrell, JJ (BMC, 2022-07-15)
    BACKGROUND: There is evidence that sow heat stress (HS) during gestation affects fetal development with implications for impaired muscle growth. We have previously demonstrated that maternal HS during early to mid-gestation compromised muscle fibre hyperplasia in developing fetal pigs. Thus, we hypothesised these phenotypic changes are associated with a change in expression of genes regulating fetal skeletal muscle development and metabolism. To test this, at d 60 of gestation, RNA sequencing and immunohistochemistry were performed on fetal longissimus dorsi (LD) muscle biopsies collected from pregnant gilts that had experienced either thermoneutral control (CON, 20 °C, n = 7 gilts, 18 LD samples) or controlled HS (cyclic 28 to 33 °C, n = 8 gilts, 23 LD samples) conditions for 3 weeks. RESULTS: A total of 282 genes were differentially expressed between the HS and CON groups in female LD muscles (false discovery rate (FDR) ≤ 0.05), whereas no differentially expressed genes were detected in male LD muscles between the two groups (FDR > 0.05). Gestational HS increased the expression of genes associated with transcription corepressor activity, adipogenesis cascades, negative regulation of angiogenesis and pro-inflammatory signalling in female LD muscles. Immunohistochemical analyses revealed a decreased muscle vascularity density in fetuses from HS group for both sexes compared to those from the CON group (P = 0.004). CONCLUSIONS: These results reveal gilt HS during early to mid-gestation altered gene expression profiles in fetal LD muscles in a sexually dimorphic manner. The molecular responses, including transcription and angiogenesis repressions and enhanced adipogenesis cascades, were exclusively observed in females. However, the associated reductions in muscle vascularity were observed independently of sexes. Collectively this may indicate female fetal pigs are more adaptive to gestational HS in terms of gene expression changes, and/or there may be sexually dimorphic differences with respect to the timing of muscle molecular responses to gestational HS.
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    Phytochemical and Safety Evaluations of Finger Lime, Mountain Pepper, and Tamarind in Zebrafish Embryos
    Caceres-Velez, PR ; Ali, A ; Fournier-Level, A ; Dunshea, FR ; Jusuf, PR (MDPI, 2022-07-01)
    Plants play a pivotal role in drug discovery, constituting 50% of modern pharmacopeia. Many human diseases, including age-related degenerative diseases, converge onto common cellular oxidative stress pathways. This provides an opportunity to develop broad treatments to treat a wide range of diseases in the ageing population. Here, we characterize and assess the toxicological effects of finger lime (Citrus australasica), mountain pepper (Tasmannia lanceolata), and small-leaved tamarind (Diploglottis australis) extracts. The characterization demonstrates that these Australian native plants have antioxidant potential and, importantly, they have high concentrations of distinct combinations of different antioxidant classes. Using zebrafish larvae as a high-throughput pre-clinical in vivo toxicology screening model, our experiment effectively discriminates which of these extracts (and at what exposure levels) are suitable for development towards future therapies. The LC50-96h for finger lime and tamarind were >480 mg/L, and 1.70 mg/L for mountain pepper. Critically, this work shows that adverse effects are not correlated to the properties of these antioxidants, thus highlighting the need for combining characterization and in vivo screening to identify the most promising plant extracts for further development. Thus, we present a high-throughput pre-clinical screening that robustly tests natural plant products to utilize the diversity of antioxidant compounds for drug development.