2,296 research outputs found

    Synthesis of Diarylheptanoid Scaffolds Inspired by Calyxins I and J

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    γ,δ-Unsaturated alcohols are prepared efficiently in two steps from <i>o</i>-hydroxycinnamaldehyde. The TMSOTf-mediated reaction of the γ,δ-unsaturated alcohols with aldehydes creates two oxygen heterocycles and three new stereocenters in a single pot. The approach is versatile, and by varying the boronic acid, Grignard reagent, and aldehyde, different substituents may be introduced, while use of a chiral base in the conjugate addition gives enantioenriched products

    LIN28 is selectively expressed by primordial and pre-meiotic germ cells in the human fetal ovary

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    Germ cell development requires timely transition from primordial germ cell (PGC) self-renewal to meiotic differentiation. This is associated with widespread changes in gene expression, including downregulation of stem cell–associated genes, such as OCT4 and KIT, and upregulation of markers of germ cell differentiation and meiosis, such as VASA, STRA8, and SYCP3. The stem cell–expressed RNA-binding protein Lin28 has recently been demonstrated to be essential for PGC specification in mice, and LIN28 is expressed in human germ cell tumors with phenotypic similarities to human fetal germ cells. We have therefore examined the expression of LIN28 during normal germ cell development in the human fetal ovary, from the PGC stage, through meiosis to the initiation of follicle formation. LIN28 transcript levels were highest when the gonad contained only PGCs, and decreased significantly with increasing gestation, coincident with the onset of germ cell differentiation. Immunohistochemistry revealed LIN28 protein expression to be germ cell–specific at all stages examined. All PGCs expressed LIN28, but at later gestations expression was restricted to a subpopulation of germ cells, which we demonstrate to be primordial and premeiotic germ cells based on immunofluorescent colocalization of LIN28 and OCT4, and absence of overlap with the meiosis marker SYCP3. We also demonstrate the expression of the LIN28 target precursor pri-microRNA transcripts pri-LET7a/f/d and pri-LET-7g in the human fetal ovary, and that expression of these is highest at the PGC stage, mirroring that of LIN28. The spatial and temporal restriction of LIN28 expression and coincident peaks of expression of LIN28 and target pri-microRNAs suggest important roles for this protein in the maintenance of the germline stem cell state and the regulation of microRNA activity in the developing human ovary

    Behavioral and other phenotypes in a cytoplasmic Dynein light intermediate chain 1 mutant mouse

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    The cytoplasmic dynein complex is fundamentally important to all eukaryotic cells for transporting a variety of essential cargoes along microtubules within the cell. This complex also plays more specialized roles in neurons. The complex consists of 11 types of protein that interact with each other and with external adaptors, regulators and cargoes. Despite the importance of the cytoplasmic dynein complex, we know comparatively little of the roles of each component protein, and in mammals few mutants exist that allow us to explore the effects of defects in dynein-controlled processes in the context of the whole organism. Here we have taken a genotype-driven approach in mouse (Mus musculus) to analyze the role of one subunit, the dynein light intermediate chain 1 (Dync1li1). We find that, surprisingly, an N235Y point mutation in this protein results in altered neuronal development, as shown from in vivo studies in the developing cortex, and analyses of electrophysiological function. Moreover, mutant mice display increased anxiety, thus linking dynein functions to a behavioral phenotype in mammals for the first time. These results demonstrate the important role that dynein-controlled processes play in the correct development and function of the mammalian nervous system

    Peeling fingers in an elastic Hele-Shaw channel

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    Using experiments and a depth-averaged numerical model, we study instabilities of two-phase flows in a Hele-Shaw channel with an elastic upper boundary and a non-uniform cross-section prescribed by initial collapse. Experimentally, we find increasingly complex and unsteady modes of air-finger propagation as the dimensionless bubble speed, Ca, and level of collapse are increased, including pointed fingers, indented fingers and the feathered modes first identified by Cuttle et al.(J. Fluid Mech., vol. 886, 2020, A20). By introducing a measure of the viscous contribution to finger propagation, we identify a Ca threshold beyond which viscous forces are superseded by elastic effects. Quantitative prediction of this transition between 'viscous' and 'elastic' reopening regimes across levels of collapse establishes the fidelity of the numerical model. In the viscous regime, we recover the non-monotonic dependence on Ca of the finger pressure, which is characteristic of benchtop models of airway reopening. To explore the elastic regime numerically, we extend the depth-averaged model introduced by Fontana et al. (J. Fluid Mech., vol. 916, 2021, A27) to include an artificial disjoining pressure which prevents the unphysical self-intersection of the interface. Using time simulations, we capture for the first time the majority of experimental finger dynamics, including feathered modes. We show that these disordered states continually evolve, with no evidence of convergence to steady or periodic states. We find that the steady bifurcation structure satisfactorily predicts the bubble pressure as a function of Ca, but that it does not provide sufficient information to predict the transition to unsteady dynamics which appears strongly nonlinear.Comment: 28 pages, 15 figure

    Adjustment of costly extra-group paternity according to inbreeding risk in a cooperative mammal

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    Females of many animal species seek mating opportunities with multiple males, despite being able to obtain sufficient sperm to father their offspring from a single male. In animals that live in stable social groups, females often choose to mate outside their group resulting in extra-group paternity. One reason proposed to explain female choice for extra-group males is to obtain compatible genes, for example in order to avoid inbreeding depression in offspring. The benefits of such extra-group paternities could be substantial if they result in fitter, outbred offspring. However, avoiding inbreeding in this way could be costly for females, for example through retaliation by cuckolded males or through receiving aggression whilst prospecting for extra-group mating opportunities. We investigate the costs and benefits of extra-group paternity in the banded mongoose Mungos mungo, a cooperatively breeding mammal in which within-group mates are sometimes close relatives. We find that pups born to females that mate with extra-group males are more genetically heterozygous, are heavier and are more likely to survive to independence than pups born to females that mate within their group. However, extra-group matings also involve substantial costs as they occur during violent encounters that sometimes result in injury and death. This appears to lead female banded mongooses to adaptively adjust extra-group paternity levels according to the current risk of inbreeding associated with mating within the group. For group-living animals, the costs of inter-group interactions may help to explain variation in both inbreeding rates and extra-group paternity within and between species
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