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The purpose of this study is to provide an analysis of Genji Monogatari based on certain principles outlined in Chapter 1. I have focussed my attention as much as possible on the style of Murasaki's novel, as opposed to its content, \"message\", or sociological significance. The style of a work cannot be thoroughly examined without reference both to the circumstances in which it was written and to the subject-matter. Parts of this study are accordingly concerned with such topics as Murasaki's life, the development of fiction in Japan prior to her time, and the historical and literary sources of her material. But it is in the presentation of material that Murasaki's originality and greatness manifest themselves, and in the subsequent chapters I stress what seem to be the outstanding qualities of her style: the use of psychological detail, the technique of construction, the use of imagery, and the handling of a central theme. As far as possible, I compare her writing on each point with that of predecessors in order to determine what is traditional and what original. I believe that I have identified certain significant and original elements of Murasaki's style, such as her use of anticipation and of sustained symbolic imagery, which appear to have been overlooked elsewhere. I have also made what I think is an original approach to certain subjects, such as the development of language within Genji, Murasaki's humorous style, her treatment of neurotic characters, and the connexion between her sustained imagery and principal theme. Parts of this study, such as those on Murasaki's literary and religious knowledge and on accidence in the language of Genji, may be of use to future students.

The demand for xylenes is projected to increase over the coming decades. The separation of xylene isomers, particularly p- and m -xylenes, is vital for the production of numerous polymers and materials. However, current state-of-the-art separation is based upon fractional crystallisation at 220 K which is highly energy intensive. Here, we report the discrimination of xylene isomers via refinement of the pore size in a series of porous metal–organic frameworks, MFM-300, at sub-angstrom precision leading to the optimal kinetic separation of all three xylene isomers at room temperature. The exceptional performance of MFM-300 for xylene separation is confirmed by dynamic ternary breakthrough experiments. In-depth structural and vibrational investigations using synchrotron X-ray diffraction and terahertz spectroscopy define the underlying host–guest interactions that give rise to the observed selectivity ( p -xylene < o -xylene < m -xylene) and separation factors of 4.6–18 for p- and m -xylenes. Separation of xylene isomers is essential for the production of a wide range of materials, but current separation methods are energy intensive. Here the authors report separation of the three xylene isomers at room temperature, via refinement of the pore size in a series of porous MOFs at sub-angstrom precision.

The comparatively simple Caenorhabditis elegans intestine fulfills many of the complex functions of the mammalian digestive tract, liver, and fat tissues, while also having roles in pathogen defense, immunity, and longevity. In this review, we describe the structure of the C. elegans gut and how it develops from the embryonic precursor E. We examine what is currently known about how the animal’s microbial diet is moved through the intestinal lumen, and how its enzymatic functions contribute to physiology and metabolism. The underlying gene regulatory networks behind both development and physiology are also described. Finally, we consider recent studies that examine metabolism and digestion and describe emerging areas for future work.

Eukaryotic cells rapidly reduce protein synthesis in response to various stress conditions. This can be achieved by the phosphorylation-mediated inactivation of a key translation initiation factor, eukaryotic initiation factor 2 (eIF2). However, the persistent translation of certain mRNAs is required for deployment of an adequate stress response. We carried out ribosome profiling of cultured human cells under conditions of severe stress induced with sodium arsenite. Although this led to a 5.4-fold general translational repression, the protein coding open reading frames (ORFs) of certain individual mRNAs exhibited resistance to the inhibition. Nearly all resistant transcripts possess at least one efficiently translated upstream open reading frame (uORF) that represses translation of the main coding ORF under normal conditions. Site-specific mutagenesis of two identified stress resistant mRNAs (PPP1R15B and IFRD1) demonstrated that a single uORF is sufficient for eIF2-mediated translation control in both cases. Phylogenetic analysis suggests that at least two regulatory uORFs (namely, in SLC35A4 and MIEF1) encode functional protein products. Proteins carry out essential tasks for living cells and genes contain the instructions to make proteins within their DNA. These instructions are copied to make a molecule of mRNA, and a molecular machine known as a ribosome then reads and translates the mRNA to build the protein. The first step in the translation process is called ‘initiation’ and requires a protein called eIF2 to work together with the ribosome. This step involves identifying an instruction called the start codon that marks the beginning of the mRNA's coding sequence. The section of an mRNA molecule before the start codon is not normally translated by the ribosome and is hence called the 5′ untranslated region. Building proteins requires energy and resources, and so it is carefully regulated. If a cell is stressed, such as by being exposed to harmful chemicals, it makes fewer proteins in order to conserve its resources. This down-regulation of protein production is achieved in part by the cell chemically modifying its eIF2 proteins to make them less able to initiate translation. However, stressed cells still continue to make more of certain proteins that help them to combat stress. The mRNA molecules for some of these proteins contain at least one other start codon in the 5′ untranslated region. The sequence that would be translated from such a start codon is known as an upstream open reading frame (or uORF for short)—and this feature is thought to help certain proteins to still be expressed despite low levels of active eIF2. Andreev, O'Connor et al. have now analysed which mRNAs are translated in human cells that have been treated with a chemical that induces stress and makes the eIF2 protein less able to initiate translation. To do so, a technique called ribosome profiling was used to identify all of the mRNA molecules bound to ribosomes shortly after treatment with this chemical. Overall translation of most mRNAs in stressed cells was reduced to a quarter of the normal level. However, Andreev, O'Connor et al. observed that the translation of a few mRNAs continued almost as normal, or even increased, after the chemical treatment. Notably, most of these mRNAs encoded regulatory proteins, which are not required in large amounts. With one exception, all of these resistant mRNAs contained uORFs. In unstressed cells, these uORFs were efficiently translated, while the same mRNA's coding sequences were translated less efficiently. Andreev, O'Connor et al. suggest that these two features could be used to identify mRNAs that are still translated into working proteins when cells are stressed. Further work is now needed to explore the mechanisms by which translation of these uORFs allows mRNAs to resist the stress.

Pseudomonas syringae is the most frequently emerging group of plant pathogenic bacteria. Because this bacterium is ubiquitous as an epiphyte and on various substrates in non-agricultural settings, there are many questions about how to assess the risk for plant disease posed by strains in the environment. Although P. syringae is considered to have discrete host ranges in defined pathovars, there have been few reports of comprehensive comparisons of host range potential. Here we present results of host range tests for 134 strains, representing eight phylogroups, from epidemics and environmental reservoirs on 15 to 22 plant species per test conducted in four separate tests to determine the patterns and extent of host range. We sought to identify trends that are indicative of distinct pathotypes and to assess if strains in the P. syringae complex are indeed restricted in their host range. We show that for each test, strains display a diversity of host ranges from very restricted to very broad regardless of the gamut of phylogroups used in the test. Overall, strains form an overlapping continuum of host range potential with equal representation of narrow, moderate and broad host ranges. Groups of distinct pathotypes, including strains with currently the same pathovar name, could not be identified. The absence of groupings was validated with statistical tests for pattern recognition. The extent of host range was positively correlated with the capacity of strains to swarm on semi-solid agar medium and with the abundance of genes in biosynthetic clusters and was inversely correlated with the abundance of genes for proteins with transmembrane domains in their genomes. Our results are consistent with the current paradigm that disease symptoms are the result of multiple molecular interactions between P. syringae and its plant host that are modulated by abiotic and biotic conditions. This leads us to propose that pathovar denominations do not correspond to the underlying biology of P. syringae. A new concept of pathogenicity that accounts for the continuum of pathogenic potential in P. syringae would open new perspectives to understand the evolution of pathogenicity in this bacterium and new insights to anticipate disease and to manage plant health.

The generation of haematopoietic stem cells (HSCs) from human pluripotent stem cells (hPSCs) is a major goal for regenerative medicine. During embryonic development, HSCs derive from haemogenic endothelium (HE) in a NOTCH- and retinoic acid (RA)-dependent manner. Although a WNT-dependent (WNTd) patterning of nascent hPSC mesoderm specifies clonally multipotent intra-embryonic-like HOXA + definitive HE, this HE is functionally unresponsive to RA. Here we show that WNTd mesoderm, before HE specification, is actually composed of two distinct KDR + CD34 neg populations. CXCR4 neg CYP26A1 + mesoderm gives rise to HOXA + multilineage definitive HE in an RA-independent manner, whereas CXCR4 + ALDH1A2 + mesoderm gives rise to HOXA + multilineage definitive HE in a stage-specific, RA-dependent manner. Furthermore, both RA-independent (RAi) and RA-dependent (RAd) HE harbour transcriptional similarity to distinct populations found in the early human embryo, including HSC-competent HE. This revised model of human haematopoietic development provides essential resolution to the regulation and origins of the multiple waves of haematopoiesis. These insights provide the basis for the generation of specific haematopoietic populations, including the de novo specification of HSCs. Luff et al. report a distinct human mesoderm cell population that generates definitive haemogenic endothelium in a retinoic acid-dependent manner, thus highlighting the dependence of haematopoietic ontogeny on retinoic acid-responsive mesoderm.

The crystal structure of a complex between the catalytic core of the HOIP subunit of the E3 ligase LUBAC and ubiquitin is reported, yielding insight into the ubiquitin transfer reaction and explaining how HOIP is capable of synthesizing linear ubiquitin chains with high specificity. Linear ubiquitin chain specificity Linear ubiquitin chains are important regulators of cellular signalling pathways involved in innate immunity and inflammation. These chains are synthesized by the E3 ubiquitin ligase HOIP. In this study, Katrin Rittinger and colleagues present the crystal structure of the catalytic core of HOIP in its apo form and in complex with ubiquitin. The structures provide a mechanistic analysis of linear ubiquitin chain formation via the LUBAC ubiquitin ligase complex. Linear ubiquitin chains are important regulators of cellular signalling pathways that control innate immunity and inflammation through nuclear factor (NF)-κB activation and protection against tumour necrosis factor-α-induced apoptosis 1 , 2 , 3 , 4 , 5 . They are synthesized by HOIP, which belongs to the RBR (RING-between-RING) family of E3 ligases and is the catalytic component of LUBAC (linear ubiquitin chain assembly complex), a multisubunit E3 ligase 6 . RBR family members act as RING/HECT hybrids, employing RING1 to recognize ubiquitin-loaded E2 while a conserved cysteine in RING2 subsequently forms a thioester intermediate with the transferred or ‘donor’ ubiquitin 7 . Here we report the crystal structure of the catalytic core of HOIP in its apo form and in complex with ubiquitin. The carboxy-terminal portion of HOIP adopts a novel fold that, together with a zinc-finger, forms a ubiquitin-binding platform that orients the acceptor ubiquitin and positions its α-amino group for nucleophilic attack on the E3∼ubiquitin thioester. The C-terminal tail of a second ubiquitin molecule is located in close proximity to the catalytic cysteine, providing a unique snapshot of the ubiquitin transfer complex containing both donor and acceptor ubiquitin. These interactions are required for activation of the NF-κB pathway in vivo , and they explain the determinants of linear ubiquitin chain specificity by LUBAC.