Modeling Molecular-Line Emission from Circumstellar Disks

Molecular lines hold valuable information on the physical and chemical composition of disks around young stars, the likely progenitors of planetary systems. This invited contribution discusses techniques to calculate the molecular emission (and absorption) line spectrum based on models for the physical and chemical structure of protoplanetary disks. Four examples of recent research illutrate these techniques in practice: matching resolved molecular-line emission from the disk around LkCa15 with theoertical models for the chemistry; evaluating the two-dimensional transfer of ultraviolet radiation into the disk, and the effect on the HCN/CN ratio; far-infrared CO line emission from a superheated disk surface layer; and inward motions in the disk around L1489 IRS.Comment: 6 pages, no figures. To appear in "The Dense Interstellar Medium in Galaxies", Procs. Fourth Cologne-Bonn-Zermatt-Symposiu

Accessing a Hidden Conformation of the Maltose Binding Protein Using Accelerated Molecular Dynamics

Periplasmic binding proteins (PBPs) are a large family of molecular transporters that play a key role in nutrient uptake and chemotaxis in Gram-negative bacteria. All PBPs have characteristic two-domain architecture with a central interdomain ligand-binding cleft. Upon binding to their respective ligands, PBPs undergo a large conformational change that effectively closes the binding cleft. This conformational change is traditionally viewed as a ligand induced-fit process; however, the intrinsic dynamics of the protein may also be crucial for ligand recognition. Recent NMR paramagnetic relaxation enhancement (PRE) experiments have shown that the maltose binding protein (MBP) - a prototypical member of the PBP superfamily - exists in a rapidly exchanging (ns to µs regime) mixture comprising an open state (approx 95%), and a minor partially closed state (approx 5%). Here we describe accelerated MD simulations that provide a detailed picture of the transition between the open and partially closed states, and confirm the existence of a dynamical equilibrium between these two states in apo MBP. We find that a flexible part of the protein called the balancing interface motif (residues 175–184) is displaced during the transformation. Continuum electrostatic calculations indicate that the repacking of non-polar residues near the hinge region plays an important role in driving the conformational change. Oscillations between open and partially closed states create variations in the shape and size of the binding site. The study provides a detailed description of the conformational space available to ligand-free MBP, and has implications for understanding ligand recognition and allostery in related proteins

Structural Biology by NMR: Structure, Dynamics, and Interactions

The function of bio-macromolecules is determined by both their 3D structure and conformational dynamics. These molecules are inherently flexible systems displaying a broad range of dynamics on time-scales from picoseconds to seconds. Nuclear Magnetic Resonance (NMR) spectroscopy has emerged as the method of choice for studying both protein structure and dynamics in solution. Typically, NMR experiments are sensitive both to structural features and to dynamics, and hence the measured data contain information on both. Despite major progress in both experimental approaches and computational methods, obtaining a consistent view of structure and dynamics from experimental NMR data remains a challenge. Molecular dynamics simulations have emerged as an indispensable tool in the analysis of NMR data

Fluoxetine reverses the memory impairment and reduction in proliferation and survival of hippocampal cells caused by methotrexate chemotherapy

RATIONALE: Adjuvant cancer chemotherapy can cause long-lasting, cognitive deficits. It is postulated that these impairments are due to these drugs targeting neural precursors within the adult hippocampus, the loss of which has been associated with memory impairment. OBJECTIVES: The present study investigates the effects of the chemotherapy, methotrexate (MTX) on spatial working memory and the proliferation and survival of the neural precursors involved in hippocampal neurogenesis, and the possible neuroprotective properties of the antidepressant fluoxetine. METHODS: Male Lister hooded rats were administered MTX (75 mg/kg, two i.v. doses a week apart) followed by leucovorin rescue (i.p. 18 h after MTX at 6 mg/kg and at 26, 42 and 50 h at 3 mg/kg) and/or fluoxetine (10 mg/kg/day in drinking water for 40 days). Memory was tested using the novel location recognition (NLR) test. Using markers, cell proliferation (Ki67) and survival (bromodeoxyuridine/BrdU), in the dentate gyrus were quantified. RESULTS: MTX-treated rats showed a cognitive deficit in the NLR task compared with the vehicle and fluoxetine-treated groups. Cognitive ability was restored in the group receiving both MTX and fluoxetine. MTX reduced both the number of proliferating cells in the SGZ and their survival. This was prevented by the co-administration of fluoxetine, which alone increased cell numbers. CONCLUSIONS: These results demonstrate that MTX induces an impairment in spatial working memory and has a negative long-term effect on hippocampal neurogenesis, which is counteracted by the co-administration of fluoxetine. If translatable to patients, this finding has the potential to prevent the chemotherapy-induced cognitive deficits experienced by many cancer survivors

Discovering Conformational Sub-States Relevant to Protein Function

Background: Internal motions enable proteins to explore a range of conformations, even in the vicinity of native state. The role of conformational fluctuations in the designated function of a protein is widely debated. Emerging evidence suggests that sub-groups within the range of conformations (or sub-states) contain properties that may be functionally relevant. However, low populations in these sub-states and the transient nature of conformational transitions between these substates present significant challenges for their identification and characterization. Methods and Findings: To overcome these challenges we have developed a new computational technique, quasianharmonic analysis (QAA). QAA utilizes higher-order statistics of protein motions to identify sub-states in the conformational landscape. Further, the focus on anharmonicity allows identification of conformational fluctuations that enable transitions between sub-states. QAA applied to equilibrium simulations of human ubiquitin and T4 lysozyme reveals functionally relevant sub-states and protein motions involved in molecular recognition. In combination with a reaction pathway sampling method, QAA characterizes conformational sub-states associated with cis/trans peptidyl-prolyl isomerization catalyzed by the enzyme cyclophilin A. In these three proteins, QAA allows identification of conformational sub-states, with critical structural and dynamical features relevant to protein function. Conclusions: Overall, QAA provides a novel framework to intuitively understand the biophysical basis of conformational diversity and its relevance to protein function. © 2011 Ramanathan et al

Expression of two barley proteinase inhibitors in tomato promotes endogenous defensive response and enhances resistance to Tuta absoluta

[EN] Background: For as long as 350 million years, plants and insects have coexisted and developed a set of relationships which affect both organisms at different levels. Plants have evolved various morphological and biochemical adaptations to cope with herbivores attacks. However, Tuta absoluta (Meyrick) (Lepidoptera: Gelechiidae) has become the major pest threatening tomato crops worldwide and without the appropriated management it can cause production losses between 80 to 100%. Results: The aim of this study was to investigate the in vivo effect of a serine proteinase inhibitor (BTI-CMe) and a cysteine proteinase inhibitor (Hv-CPI2) from barley on this insect and to examine the effect their expression has on tomato defensive response. We found that larvae fed on the double transgenic plants showed a notable reduction in weight. Moreover, only 56% of the larvae reached the adult stage. The emerged adults showed wings deformities and reduced fertility. We also investigated the effect of proteinase inhibitors ingestion on the insect digestive enzymes. Our results showed a decrease in larval trypsin activity. Transgenes expression had no harmful effect on Nesidiocoris tenuis (Reuter) (Heteroptera: Miridae), a predator of Tuta absoluta, despite transgenic tomato plants attracted the mirid. We also found that barley cystatin expression promoted plant defense by inducing the expression of the tomato endogenous wound inducible Proteinase inhibitor 2 (Pin2) gene, increasing the production of glandular trichomes and altering the emission of volatile organic compounds. Conclusion: Our results demonstrate the usefulness of the co-expression of different proteinase inhibitors for the enhancement of plant resistance to Tuta absoluta.This work was partly supported by grants BIO2013-40747-R and AGL2014-55616-C3 from the Spanish Ministry of Economy and Competitiveness (MINECO)Hamza, R.; Pérez-Hedo, M.; Urbaneja, A.; Rambla Nebot, JL.; Granell Richart, A.; Gaddour, K.; Beltran Porter, JP.... (2018). Expression of two barley proteinase inhibitors in tomato promotes endogenous defensive response and enhances resistance to Tuta absoluta. BMC Plant Biology. 18. https://doi.org/10.1186/s12870-018-1240-6S18Oerke EC. Crop losses to pests. J Agric Sci. 2005;144(01):31.Jouanin L, Bonadé-Bottino M, Girard C, Morrot G, Giband M. Transgenic plants for insect resistance. Plant Sci. 1998;131(1):1–11.Markwick NP, Docherty LC, Phung MM, Lester MT, Murray C, Yao JL, Mitra DS, Cohen D, Beuning LL, Kutty-Amma S, et al. 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Attitudes to atypical and conventional antipsychotic drug treatment in clinicians participating in the cutlass study.

Objectives To examine clinicians' attitudes regarding the relative benefits and risks of conventional and atypical antipsychotic medication, and the perceived validity of the CUtLASS study. To examine the attitudes of participant clinicians' regarding the operation and administration, and the potential clinical impact of the findings. Method Two hundred and sixty-two clinicians were each sent an anonymous questionnaire, and invited to indicate whether they agreed or disagreed with each of to nine statements (from agree to disagree). Results Of the 112 clinicians who responded, 71% supported the CUtLASS study. Thirty-nine percent agreed with the statement that the clinical efficacy of atypicals was superior to conventional antipsychotics, while 27% disagreed and 34% were undecided. Thus, two-thirds of participating clinicians revealed no uncertainty on a key question being tested in the CUtLASS study. Further, the vast majority (97%) considered that atypicals were associated with less severe side effects. Conclusions In clinical studies, recruitment strategies relying on referrals from clinicians may find that some clinicians identify fewer patients than expected. This can lead to a relatively low yield of potential study subjects and possibly a selection bias. Surveys of clinicians approached to participate in clinical studies provide a potential mechanism to explore attitudes relevant to participant recruitment

Early Jurassic North Atlantic sea-surface temperatures from TEX86 palaeothermometry

Early Jurassic marine palaeotemperatures have been typically quantified by oxygen-isotope palaeothermometry of benthic and nektonic carbonate and phosphatic macrofossils. However, records of Early Jurassic sea-surface temperatures (SSTs) that can be directly compared with General Circulation Model (GCM) simulations of past climates are currently unavailable. The TEX86 SST proxy is based upon the relative abundance of glycerol dialkyl glycerol tetraethers (GDGTs) preserved in organic-carbon-bearing sediments. This proxy has been used extensively on Cretaceous and Cenozoic materials and, in one study, Middle and Upper Jurassic sediments. Here TEX86 is applied, for the first time, to Lower Jurassic (Sinemurian–Pliensbachian) sediments cored at Deep Sea Drilling Project Site 547 in the North Atlantic. The abundance of GDGTs in these sediments is very low, despite biomarker and Rock-Eval data suggesting that thermal maturity is, generally, low. Sea-floor oxygenation and a high input of reworked terrestrially sourced organic matter may explain the low concentrations. For samples from which it was possible to quantify the relative abundance of GDGTs, TEX86 values range from 0.78 to 0.88, equating to SSTs in excess of >28˚C. These temperatures are broadly comparable with new GCM simulations of the Sinemurian and Pliensbachian stages and support the general view of a predominantly warm climate. The new proxy data suggest that, under favourable geological conditions, it is possible to extend the record of TEX86-based SSTs back into the Early Jurassic