Rapid evolution of protein kinase PKR alters sensitivity to viral inhibitors.

Protein kinase PKR (also known as EIF2AK2) is activated during viral infection and phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 (eIF2), leading to inhibition of translation and viral replication. We report fast evolution of the PKR kinase domain in vertebrates, coupled with positive selection of specific sites. Substitution of positively selected residues in human PKR with residues found in related species altered sensitivity to PKR inhibitors from different poxviruses. Species-specific differences in sensitivity to poxviral pseudosubstrate inhibitors were identified between human and mouse PKR, and these differences were traced to positively selected residues near the eIF2alpha binding site. Our findings indicate how an antiviral protein evolved to evade viral inhibition while maintaining its primary function. Moreover, the identified species-specific differences in the susceptibility to viral inhibitors have important implications for studying human infections in nonhuman model systems

Incommensurate-commensurate transition in the geometric ferroelectric LaTaO4

Funding: UK Engineering and Physical Sciences Research Council (Grant Number(s): EP/P022637/1, EP/K503162/1), Science and Technology Facilities Council (Grant Number(s): RB1820307), China Scholarship Council (CN).The layered perovskite LaTaO4 has been synthesized to be stable in both (polar) orthorhombic and (nonpolar) monoclinic polymorphs at ambient conditions. Although the structural transition between monoclinic and orthorhombic phases has been well established, there is some controversy regarding a further, unidentified transition around 500 K. Here this is identified as an incommensurate–commensurate first‐order transition between incommensurate Cmc21(α00)0s0 and commensurate Cmc21 orthorhombic phases. Transmission electron microscopy indicates partially ordered stacking of different structural units in a, identifying the local cause for the modulation, whereas variable temperature powder neutron diffraction has shown the overall macroscopic modulation vector, q ≈ (0.456, 0, 0)—roughly a 2.2 × expansion in a, corresponding to an approximate 11a commensurate superunit cell dimension. The modulation shows a continuous temperature dependence until transitioning to the basic (commensurate) cell at TIC‐C. Doping the interlayer La sites with smaller Nd cations stabilizes the incommensuration to higher temperature, suggesting the modulation is geometrically driven at the A site.Publisher PDFPeer reviewe

Structural phase transitions in the geometric ferroelectric LaTa O4

Funding: School of Chemistry, University of St Andrews for funding of a studentship to GWH through the EPSRC doctoral training grant (Grant No. EP/N509759/1). This work was also facilitated by funding provided by the EPSRC (Grant No. EP/P024637/1). K.K.M. and R.S.K. acknowledge financial support from the Department of Defense, USA (DoD Grant No. FA9550-20-1-0064). The RUS component of this work was funded by EPSRC Grant No. EP/P024904/1.The recent report of an intermediate incommensurately modulated orthorhombic phase in LaTaO4 has prompted a re-examination of the phase transition sequence in LaTaO4 as a function of temperature. With falling temperature, the sequence of phases examined is (orthorhombic) Cmc21(C)↔Cmc21(IC)↔(monoclinic)P21/c, with C and IC denoting commensurate and incommensurate phases, respectively. The orthorhombic to monoclinic transition, Tm-o, is a first order reconstructive transition occurring at 440 K and TIC-C is a first-order displacive transition occurring at 500-530 K. Strain and elasticity data confirm a first-order transition between the basic and modulated Cmc21 phases, with similarities to the isostructural fluoride BaMnF4. A Raman spectroscopic study of the LaTaO4 phase transition indicates that the IC-C phase transition is driven by a soft zone-boundary phonon (unstable) of the commensurate orthorhombic (Cmc21) phase. The soft phonon is found to appear (underdamped) above 443 K and vanishes (overdamped) around 528 K. A large supercell of the monoclinic phase below Tm-o is proposed based on the Raman spectroscopic results.Publisher PDFPeer reviewe

Influenza A Virus Hemagglutinin Antibody Escape Promotes Neuraminidase Antigenic Variation and Drug Resistance

Drugs inhibiting the influenza A virus (IAV) neuraminidase (NA) are the cornerstone of anti-IAV chemotherapy and prophylaxis in man. Drug-resistant mutations in NA arise frequently in human isolates, limiting the therapeutic application of NA inhibitors. Here, we show that antibody-driven antigenic variation in one domain of the H1 hemagglutinin Sa site leads to compensatory mutations in NA, resulting in NA antigenic variation and acquisition of drug resistance. These findings indicate that influenza A virus resistance to NA inhibitors can potentially arise from antibody driven HA escape, confounding analysis of influenza NA evolution in nature

Killing of endothelial cells and release of arachidonic acid

51 hromium-labeled rat pulmonary artery endothelial cells (EC) cultivated in MEM medium were killed, in a synergistic manner, by mixtures of subtoxic amounts of glucose oxidase-generated H 2 O 2 and subtoxic amounts of the following agents: the cationic substances, nuclear histone, defensins, lysozyme, poly- l -arginine, spermine, pancreatic ribonuclease, polymyxin B, chlorhexidine, cetyltrimethyl ammonium bromide, as well as by the membrane-damaging agents phospholipases A 2 (PLA 2 ) and C (PLC), lysolecithin (LL), and by streptolysin S (SLS) of group A streptococci. Cytotoxicity induced by such mixtures was further enhanced by subtoxic amounts either of trypsin or of elastase. Glucose-oxidase cationized by complexing to poly- l -histidine proved an excellent deliverer of membrane-directed H 2 O 2 capable of enhancing EC killing by other agonists. EC treated with rabbit anti-streptococcal IgG were also killed, in a synergistic manner, by H 2 O 2 , suggesting the presence in the IgG preparation of cross-reactive antibodies. Killing of EC by the various mixtures of agonists was strongly inhibited by scavengers of hydrogen peroxide (catalase, dimethylthiourea, MnCl 2 ), by soybean trypsin inhibitor, by polyanions, as well as by putative inhibitors of phospholipases. Strong inhibition of cell killing was also observed with tannic acid and by extracts of tea, but less so by serum. On the other hand, neither deferoxamine, HClO, TNF, nor GTP-γS had any modulating effects on the synergistic cell killing. EC exposed either to 6-deoxyglucose, puromycin, or triflupromazin became highly susceptible to killing by mixtures of hydrogen peroxide with several of the membrane-damaging agents. While maximal synergistic EC killing was achieved by mixtures of H 2 O 2 with either PLA 2 , PLC, LL, or with SLS, a very substantial release of [ 3 H]arachidonic acid (AA), PGE 3 , and 6-keto-PGF occurred only if a proteinase was also added to the mixture of agonists. The release of AA from EC was markedly inhibited either by scavengers of H 2 O 2 , by proteinase inhibitors, by cationic agents,by HClO, by tannic acid, and by quinacrin. We suggest that cellular injury induced in inflammatory and infectious sites might be the result of synergistic effects among leukocyte-derived oxidants, lysosomal hydrolases, cytotoxic cationic polypeptides, proteinases, and microbial toxins, which might be present in exudates. These “cocktails” not only kill cells, but also solubilize AA and several of its metabolites. However, AA release by the various agonists can be also achieved following attack by leukocyte-derived agonists on dead cells. It is proposed that treatment by “cocktails” of adequate antagonists might be beneficial to protect against cellular injury in vivo.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44512/1/10753_2004_Article_BF00918992.pd

Lung injury-induced skeletal muscle wasting in aged mice is linked to alterations in long chain fatty acid metabolism

Older patients are more likely to acquire and die from acute respiratory distress syndrome (ARDS) and muscle weakness may be more clinically significant in older persons. Recent data implicate muscle ring finger protein 1 (MuRF1) in lung injury-induced skeletal muscle atrophy in young mice and identify an alternative role for MuRF1 in cardiac metabolism regulation through inhibition of fatty acid oxidation

Decoherent Histories Quantum Mechanics with One 'Real' Fine-Grained History

Decoherent histories quantum theory is reformulated with the assumption that there is one "real" fine-grained history, specified in a preferred complete set of sum-over-histories variables. This real history is described by embedding it in an ensemble of comparable imagined fine-grained histories, not unlike the familiar ensemble of statistical mechanics. These histories are assigned extended probabilities, which can sometimes be negative or greater than one. As we will show, this construction implies that the real history is not completely accessible to experimental or other observational discovery. However, sufficiently and appropriately coarse-grained sets of alternative histories have standard probabilities providing information about the real fine-grained history that can be compared with observation. We recover the probabilities of decoherent histories quantum mechanics for sets of histories that are recorded and therefore decohere. Quantum mechanics can be viewed as a classical stochastic theory of histories with extended probabilities and a well-defined notion of reality common to all decoherent sets of alternative coarse-grained histories.Comment: 11 pages, one figure, expanded discussion and acknowledgment

The significance of motivation in student-centred learning : a reflective case study

The theoretical underpinnings of student-centred learning suggest motivation to be an integral component. However, lack of clarification of what is involved in motivation in education often results in unchallenged assumptions that fail to recognise that what motivates some students may alienate others. This case study, using socio-cognitive motivational theory to analyse previously collected data, derives three fuzzy propositions which, collectively, suggest that motivation interacts with the whole cycle of episodes in the teachinglearning process. It argues that the development of the higherlevel cognitive competencies that are implied by the term, student-centred learning, must integrate motivational constructs such as goal orientation, volition, interest and attributions into pedagogical practices

Literature review on the use of action research in higher education

This literature review considers the use of action research in higher education. It specifically looks at two areas of higher education activity. The first concerns academic teaching practice and includes a discussion of research and pedagogy practice, and staff development. The second considers student engagement. In both these core features of higher education, action research has proved to be a central approach to the investigation, reflection and improvement of practice. Each of these main foci includes a discussion of the limitations of the literature. The review illustrates the extent and range of uses to have benefited from an action research approach

Elementary Forms of the Metaphorical Life : Tropes at Work in Durkheim’s Theory of the Religious

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