A Case of Crohn's Disease with Improvement after Azathioprine-Induced Pancytopenia

The immunosuppressant azathioprine (AZA) is widely used in the treatment of inflammatory bowel disease (IBD) for both inducing and maintaining remission. However, the adverse effects of AZA can often necessitate a dose reduction or discontinuation. Bone marrow suppression is one of the most serious complications with AZA treatment. On the other hand, some reports have suggested that neutropenia during AZA therapy reduced the relapse rates of IBD patients, and there have been some cases where eradication of the sensitized leukocytes by leukapheresis or bone marrow transplantation improved the IBD, which may explain the relevant role of neutropenia in controlling disease activity. This report describes the case of a 22-year-old male patient who had Crohn's colitis and complicated perianal fistulas that required immunosuppression; he achieved endoscopically determined remission and showed accelerated mucosal healing as well as clinical remission following the AZA-induced pancytopenia

Solitary waves in the Nonlinear Dirac Equation

In the present work, we consider the existence, stability, and dynamics of solitary waves in the nonlinear Dirac equation. We start by introducing the Soler model of self-interacting spinors, and discuss its localized waveforms in one, two, and three spatial dimensions and the equations they satisfy. We present the associated explicit solutions in one dimension and numerically obtain their analogues in higher dimensions. The stability is subsequently discussed from a theoretical perspective and then complemented with numerical computations. Finally, the dynamics of the solutions is explored and compared to its non-relativistic analogue, which is the nonlinear Schr{\"o}dinger equation. A few special topics are also explored, including the discrete variant of the nonlinear Dirac equation and its solitary wave properties, as well as the PT-symmetric variant of the model

Atomically-thin micas as proton conducting membranes

Monolayers of graphene and hexagonal boron nitride (hBN) are highly permeable to thermal protons. For thicker two-dimensional (2D) materials, proton conductivity diminishes exponentially so that, for example, monolayer MoS2 that is just three atoms thick is completely impermeable to protons. This seemed to suggest that only one-atom-thick crystals could be used as proton conducting membranes. Here we show that few-layer micas that are rather thick on the atomic scale become excellent proton conductors if native cations are ion-exchanged for protons. Their areal conductivity exceeds that of graphene and hBN by one-two orders of magnitude. Importantly, ion-exchanged 2D micas exhibit this high conductivity inside the infamous gap for proton-conducting materials, which extends from 100 C to 500 C. Areal conductivity of proton-exchanged monolayer micas can reach above 100 S cm-2 at 500 C, well above the current requirements for the industry roadmap. We attribute the fast proton permeation to 5 A-wide tubular channels that perforate micas' crystal structure which, after ion exchange, contain only hydroxyl groups inside. Our work indicates that there could be other 2D crystals with similar nm-scale channels, which could help close the materials gap in proton-conducting applications

A novel de novo BRCA1 mutation in a Chinese woman with early onset breast cancer

Germline mutations in the two breast cancer susceptibility genes, BRCA1 and BRCA2 account for a significant portion of hereditary breast/ovarian cancer. De novo mutations such as multiple exon deletion are rarely occurred in BRCA1 and BRCA2. During our mutation screening for BRCA1/2 genes to Chinese women with risk factors for hereditary breast/ovarian cancer, we identified a novel germline mutation, consisting of a deletion from exons 1 to 12 in BRCA1 gene, in a patient diagnosed with early onset triple negative breast cancer with no family history of cancer. None of her parents carried the mutation and molecular analysis showed that this novel de novo germline mutation resulted in down-regulation of BRCA1 gene expression

Genome sequencing and comparative genomics of the broad host-range pathogen Rhizoctonia solani AG8

Rhizoctonia solani is a soil-borne basidiomycete fungus with a necrotrophic lifestyle which is classified into fourteen reproductively incompatible anastomosis groups (AGs). One of these, AG8, is a devastating pathogen causing bare patch of cereals, brassicas and legumes. R. solani is a multinucleate heterokaryon containing significant heterozygosity within a single cell. This complexity posed significant challenges for the assembly of its genome. We present a high quality genome assembly of R. solani AG8 and a manually curated set of 13,964 genes supported by RNA-seq. The AG8 genome assembly used novel methods to produce a haploid representation of its heterokaryotic state. The whole-genomes of AG8, the rice pathogen AG1-IA and the potato pathogen AG3 were observed to be syntenic and co-linear. Genes and functions putatively relevant to pathogenicity were highlighted by comparing AG8 to known pathogenicity genes, orthology databases spanning 197 phytopathogenic taxa and AG1-IA.We also observed SNP-level “hypermutation” of CpG dinucleotides to TpG between AG8 nuclei, with similarities to repeat-induced point mutation (RIP). Interestingly, gene-coding regions were widely affected along with repetitive DNA, which has not been previously observed for RIP in mononuclear fungi of the Pezizomycotina. The rate of heterozygous SNP mutations within this single isolate of AG8 was observed to be higher than SNP mutation rates observed across populations of most fungal species compared. Comparative analyses were combined to predict biological processes relevant to AG8 and 308 proteins with effector-like characteristics, forming a valuable resource for further study of this pathosystem. Predicted effector-like proteins had elevated levels of non-synonymous point mutations relative to synonymous mutations (dN/dS), suggesting that they may be under diversifying selection pressures. In addition, the distant relationship to sequenced necrotrophs of the Ascomycota suggests the R. solani genome sequence may prove to be a useful resource in future comparative analysis of plant pathogens

Rare mutations in N-methyl-D-aspartate glutamate receptors in autism spectrum disorders and schizophrenia

Pharmacological, genetic and expression studies implicate N-methyl-D-aspartate (NMDA) receptor hypofunction in schizophrenia (SCZ). Similarly, several lines of evidence suggest that autism spectrum disorders (ASD) could be due to an imbalance between excitatory and inhibitory neurotransmission. As part of a project aimed at exploring rare and/or de novo mutations in neurodevelopmental disorders, we have sequenced the seven genes encoding for NMDA receptor subunits (NMDARs) in a large cohort of individuals affected with SCZ or ASD (n=429 and 428, respectively), parents of these subjects and controls (n=568). Here, we identified two de novo mutations in patients with sporadic SCZ in GRIN2A and one de novo mutation in GRIN2B in a patient with ASD. Truncating mutations in GRIN2C, GRIN3A and GRIN3B were identified in both subjects and controls, but no truncating mutations were found in the GRIN1, GRIN2A, GRIN2B and GRIN2D genes, both in patients and controls, suggesting that these subunits are critical for neurodevelopment. The present results support the hypothesis that rare de novo mutations in GRIN2A or GRIN2B can be associated with cases of sporadic SCZ or ASD, just as it has recently been described for the related neurodevelopmental disease intellectual disability. The influence of genetic variants appears different, depending on NMDAR subunits. Functional compensation could occur to counteract the loss of one allele in GRIN2C and GRIN3 family genes, whereas GRIN1, GRIN2A, GRIN2B and GRIN2D appear instrumental to normal brain development and function

Autonomy and Its Role in English Language Learning: Practice and Research

This chapter picks up discussion in the previous edition of this handbook of how the concept of autonomy has influenced language education and applied linguistics in recent years. It begins by discussing the philosophical and practical origins of learner autonomy in language education and particularly in English language teaching and how these have developed over the last 10 years. Key practical initiatives and research findings are reviewed to illuminate how autonomy has been interpreted in relation to learners, teachers, and the learning situation; how it has been linked or contrasted with other constructs; and how fostering autonomy has been seen as a part of pedagogy. Recent developments from the earlier edition are discussed regarding metacognition and, in particular, various contextual dimensions of learner autonomy. Other emerging topics are also reviewed, including learner autonomy in the world of digital/social media, learner autonomy in curriculum design and published materials, and the relation of learner autonomy to plurilingual perspectives. The chapter discusses issues in each of these areas, potential strategies for developing autonomy and effective learning, and possible future directions for research and practice

A Systematic Proteomic Study of Irradiated DNA Repair Deficient Nbn-Mice

BACKGROUND: The NBN gene codes for the protein nibrin, which is involved in the detection and repair of DNA double strand breaks (DSBs). The NBN gene is essential in mammals. METHODOLOGY/PRINCIPAL FINDINGS: We have used a conditional null mutant mouse model in a proteomics approach to identify proteins with modified expression levels after 4 Gy ionizing irradiation in the absence of nibrin in vivo. Altogether, amongst approximately 8,000 resolved proteins, 209 were differentially expressed in homozygous null mutant mice in comparison to control animals. One group of proteins significantly altered in null mutant mice were those involved in oxidative stress and cellular redox homeostasis (p<0.0001). In substantiation of this finding, analysis of Nbn null mutant fibroblasts indicated an increased production of reactive oxygen species following induction of DSBs. CONCLUSIONS/SIGNIFICANCE: In humans, biallelic hypomorphic mutations in NBN lead to Nijmegen breakage syndrome (NBS), an autosomal recessive genetic disease characterised by extreme radiosensitivity coupled with growth retardation, immunoinsufficiency and a very high risk of malignancy. This particularly high cancer risk in NBS may be attributable to the compound effect of a DSB repair defect and oxidative stress

Conserved Expression of the Glutamate NMDA Receptor 1 Subunit Splice Variants during the Development of the Siberian Hamster Suprachiasmatic Nucleus

Glutamate neurotransmission and the N-methyl-D-aspartate receptor (NMDAR) are central to photic signaling to the master circadian pacemaker located in the hypothalamic suprachiasmatic nucleus (SCN). NMDARs also play important roles in brain development including visual input circuits. The functional NMDAR is comprised of multiple subunits, but each requiring the NR1 subunit for normal activity. The NR1 can be alternatively spliced to produce isoforms that confer different functional properties on the NMDAR. The SCN undergoes extensive developmental changes during postnatal life, including synaptogenesis and acquisition of photic signaling. These changes are especially important in the highly photoperiodic Siberian hamster, in which development of sensitivity to photic cues within the SCN could impact early physiological programming. In this study we examined the expression of NR1 isoforms in the hamster at different developmental ages. Gene expression in the forebrain was quantified by in situ hybridization using oligonucleotide probes specific to alternatively spliced regions of the NR1 heteronuclear mRNA, including examination of anterior hypothalamus, piriform cortex, caudate-putamen, thalamus and hippocampus. Gene expression analysis within the SCN revealed the absence of the N1 cassette, the presence of the C2 cassette alone and the combined absence of C1 and C2 cassettes, indicating that the dominant splice variants are NR1-2a and NR1-4a. Whilst we observe changes at different developmental ages in levels of NR1 isoform probe hybridization in various forebrain structures, we find no significant changes within the SCN. This suggests that a switch in NR1 isoform does not underlie or is not produced by developmental changes within the hamster SCN. Consistency of the NR1 isoforms would ensure that the response of the SCN cells to photic signals remains stable throughout life, an important aspect of the function of the SCN as a responder to environmental changes in quality/quantity of light over the circadian day and annual cycle

Unraveling the forcings controlling the vegetation and climate of the best orbital analogues for the present interglacial in SW Europe

The suitability of MIS 11c and MIS 19c as analogues of our present interglacial and its natural evolution is still debated. Here we examine the regional expression of the Holocene and its orbital analogues over SW Iberia using a model-data comparison approach. Regional tree fraction and climate based on snapshot and transient experiments using the LOVECLIM model are evaluated against the terrestrial-marine profiles from Site U1385 documenting the regional vegetation and climatic changes. The pollen-based reconstructions show a larger forest optimum during the Holocene compared to MIS 11c and MIS 19c, putting into question their analogy in SW Europe. Pollen-based and model results indicate reduced MIS 11c forest cover compared to the Holocene primarily driven by lower winter precipitation, which is critical for Mediterranean forest development. Decreased precipitation was possibly induced by the amplified MIS 11c latitudinal insolation and temperature gradient that shifted the westerlies northwards. In contrast, the reconstructed lower forest optimum at MIS 19c is not reproduced by the simulations probably due to the lack of Eurasian ice sheets and its related feedbacks in the model. Transient experiments with time-varying insolation and CO2 reveal that the SW Iberian forest dynamics over the interglacials are mostly coupled to changes in winter precipitation mainly controlled by precession, CO2 playing a negligible role. Model simulations reproduce the observed persistent vegetation changes at millennial time scales in SW Iberia and the strong forest reductions marking the end of the interglacial "optimum".SFRH/BD/9079/2012, SFRH/BPD/108712/2015, SFRH/BPD/108600/2015info:eu-repo/semantics/publishedVersio