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&ITSyn &ITvs &ITAnti &ITCarboxylic Acids in Hybrid Peptides: Experimental and Theoretical Charge Density and Chemical Bonding Analysis
No full textA comparative study of syn vs anti carboxylic acids in hybrid peptides based on experimental electron density studies and theoretical calculations shows that, in the anti form, all three bond angles surrounding of the -COOH group are close to similar to 120 degrees, as expected for a C-sp(2) atom, C-carboxyl whereas in the syn form, the angle C-alpha-C(O)-O-hydroxyl angle is significantly smaller by 5-10 degrees. The oxygen atom in the carboxyl group is more electronegative in the anti form, so the polarity of the acidic O-H bond is higher in the anti form compared to the syn form, as observed within the limitations of H atom treatment in X-ray diffraction. Consequently, the investigated anti carboxylic acid forms the strongest O-H center dot center dot center dot O hydrogen bond among all model compounds. Furthermore, according to natural bond orbital analysis, the oxygen lone pairs are clearly nonequivalent, as opposed to the general notion of hybridization of equivalent sp(2) and sp(3) lone pairs on carbonyl or hydroxyl oxygen atoms. The hybridization of the lone pairs is directly related to the directionality and strength of hydrogen bonds
Structural and functional roles of dynamically correlated residues in thymidylate kinase
No full textThymidylate kinase is an important enzyme in DNA synthesis. It catalyzes the conversion of thymidine monophosphate to thymidine diphosphate, with ATP as the preferred phosphoryl donor, in the presence of Mg2+. In this study, the dynamics of the active site and the communication paths between the substrates, ATP and TMP, are reported for thymidylate kinase from Thermus thermophilus. Conformational changes upon ligand binding and the path for communication between the substrates and the protein are important in understanding the catalytic mechanism of the enzyme. High-resolution X-ray crystal structures of thymidylate kinase in apo and ligand-bound states were solved. This is the first report of structures of binary and ternary complexes of thymidylate kinase with its natural substrates ATP and ATP-TMP, respectively. Distinct conformations of the active-site residues, the P-loop and the LID region observed in the apo and ligand-bound structures revealed that their concerted motion is required for the binding and proper positioning of the substrate TMP. Structural analyses provide an insight into the mode of substrate binding at the active site. The residues involved in communication between the substrates were identified through network analysis using molecular-dynamics simulations. The residues identified showed high sequence conservation across species. Biochemical analyses show that mutations of these residues either resulted in a loss of activity or affected the thermal stability of the protein. Further, molecular-dynamics analyses of mutants suggest that the proper positioning of TMP is important for catalysis. These data also provide an insight into the phosphoryl-transfer mechanism
Coevolution of the translational machinery optimizes initiation with unusual initiator tRNAs and initiation codons in mycoplasmas
No full textInitiator tRNAs (i-tRNAs) are characterized by the presence of three consecutive GC base pairs (GC/GC/GC) in their anticodon stems in all domains of life. However, many mycoplasmas possess unconventional i-tRNAs wherein the highly conserved sequence of GC/GC/GC is represented by AU/GC/GC, GC/GC/GU or AU/GC/GU. These mycoplasmas also tend to preferentially utilize non-AUG initiation codons. To investigate if initiation with the unconventional i-tRNAs and non-AUG codons in mycoplasmas correlated with the changes in the other components of the translation machinery, we carried out multiple sequence alignments of genes encoding initiation factors (IF), 16S rRNAs, and the ribosomal proteins such as uS9, uS12 and uS13. In addition, the occurrence of Shine-Dalgarno sequences in mRNAs was analyzed. We observed that in the mycoplasmas harboring AU/GC/GU i-tRNAs, a highly conserved position of R131 in IF3, is represented by P, F or Y and, the conserved C-terminal tail (SKR) of uS9 is represented by the TKR sequence. Using the Escherichia coli model, we show that the change of R131 in IF3 optimizes initiation with the AU/GC/GU i-tRNAs. Also, the SKR to TKR change in uS9 was compatible with the R131P variation in IF3 for initiation with the AU/GC/GU i-tRNA variant. Interestingly, the mycoplasmas harboring AU/GC/GU i-tRNAs are also human pathogens. We propose that these mycoplasmas might have evolved a relaxed translational apparatus to adapt to the environment they encounter in the host
Immunomodulatory activity of glycodelin: implications in allograft rejection
No full textGlycodelin is an immunomodulator, indispensable for the maintenance of pregnancy in humans. The glycoprotein induces apoptosis in activated CD4(+) T cells, monocytes and natural killer (NK) cells, and suppresses the activity of cytotoxic T cells, macrophages and dendritic cells. This study explores the immunosuppressive property of glycodelin for its possible use in preventing graft rejection. Because glycodelin is found only in certain primates, the hypothesis was investigated in an allograft nude mouse model. It is demonstrated that treatment of alloactivated mononuclear cells with glycodelin thwarts graft rejection. Glycodelin decreases the number of activated CD4(+) and CD8(+) cells and down-regulates the expression of key proteins known to be involved in graft demise such as granzyme-B, eomesodermin (EOMES), interleukin (IL)-2 and proinflammatory cytokines tumour necrosis factor (TNF)-alpha and IL-6], resulting in a weakened cell-mediated immune response. Immunosuppressive drugs for treating allograft rejection are associated with severe side effects. Glycodelin, a natural immunomodulator in humans, would be an ideal alternative candidate
Temperature-dependent layer breathing modes in two-dimensional materials
No full textRelative out-of-plane displacements of the constituent layers of two-dimensional materials give rise to unique low-frequency breathing modes. By computing the height-height correlation functions from molecular dynamics simulations, we show that the layer breathing modes (LBMs) can be mapped consistently to vibrations of a simple linear chain model. Our calculated thickness dependence of LBM frequencies for few-layer (FL) graphene and molybdenum disulfide (MoS2) are in excellent agreement with available experiments. Our results show a redshift of LBM frequency with an increase in temperature, which is a direct consequence of anharmonicities present in the interlayer interaction. We also predict the thickness and temperature dependence of LBM frequencies for FL hexagonal boron nitride. Our Rapid Communication provides a simple and efficient way to probe the interlayer interaction for layered materials and their heterostructures with the inclusion of anharmonic effects
Eu/Tb luminescence for alkaline phosphatase and beta-galactosidase assay in hydrogels and on paper devices
No full textSimple technologies for efficient detection of important (bio) molecules are always in great demand. We now report the detection and assay of two biologically important enzymes, alkaline phosphatase and beta-galactosidase, in Eu- or Tb-based cholate hydrogels, respectively, and on filter paper discs coated with such hydrogels. Pro-sensitizers derived from 1-hydroxypyrene and 2,3-dihydroxynaphthalene were incorporated into Eu or Tb cholate hydrogels, respectively. Upon enzyme action, these artificial substrates liberate free sensitizers both in the gel and on gel-coated discs, resulting in turn-on luminescence, red/magenta for Eu, and green for Tb. The detection of enzymes was also demonstrated in natural/biological samples using low-cost systems
Observation of 3D isostructurality in halogen substituted N-benzoylN-phenylbenzamides
No full textThe occurrence of 3D isostructurality in six halogen substituted N-benzoyl-N-phenylbenzamides has been reported and this feature has been quantitatively analyzed in this study. 4-fluoro-N-(4-fluorobenzoyl) N-(fluorphenyl)benzamide (1) was observed to be isostructural with 2-fluoro-N-(2fluorobenzoyl) N-(4-fluorophenyl)benzamide (7), N-(4-bromophenyI)-2-fluoro-N-(2-fluorobenzoyl) benzamide (8) and 2-fluoro-N-(2-fluorobenzoyl) N-(4-iodophenyl)benzamide (9). Similarly, N-(4chlorophenyl)-4-fluoro-N-(4-fluorobenzoyl)benzamide (2) and N-(4-bromophenyl)-4-fluoro-N-(4fluorobenzoyl)benzamide (3) was observed to be isostructural with each other. It was clearly evident from the analysis of structural similarity that 3D supramolecular construct present in 2/3 Set 2] were more identical as compared to those observed in 1/7/8/9 Set 1]. The molecular packing in both sets of isostructural molecules was observed to be governed by the presence of several C-H center dot center dot center dot O=C interactions. In addition to that, C-H center dot center dot center dot F-C and C-H center dot center dot center dot pi interactions also played an important role in the stabilization. However, 2D Fingerprint analysis revealed that the contribution of C-H center dot center dot center dot F-C interaction in a given structure was also dependent on the contribution of other hydrogens bonds involving halogens. (C) 2018 Elsevier B.V. All rights reserved
Never-Ending Learning
No full textWhereas people learn many different types of knowledge from diverse experiences over many years, and become better learners over time, most current machine learning systems are much more narrow, learning just a single function or data model based on statistical analysis of a single data set. We suggest that people learn better than computers precisely because of this difference, and we suggest a key direction for machine learning research is to develop software architectures that enable intelligent agents to also learn many types of knowledge, continuously over many years, and to become better learners over time. In this paper we define more precisely this never-ending learning paradigm for machine learning, and we present one case study: the Never-Ending Language Learner (NELL), which achieves a number of the desired properties of a never-ending learner. NELL has been learning to read the Web 24hrs/day since January 2010, and so far has acquired a knowledge base with 120mn diverse, confidence-weighted beliefs (e.g., servedWith(tea, biscuits)), while learning thousands of interrelated functions that continually improve its reading competence over time. NELL has also learned to reason over its knowledge base to infer new beliefs it has not yet read from those it has, and NELL is inventing new relational predicates to extend the ontology it uses to represent beliefs. We describe the design of NELL, experimental results illustrating its behavior, and discuss both its successes and shortcomings as a case study in never-ending learning. NELL can be tracked online at http://rtw.ml.cmu.edu, and followed on Twitter at @CMUNELL
The role of surface roughness on dislocation bending and stress evolution in low mobility AlGaN films during growth
No full textThe bending and interaction of threading dislocations are essential to reduce their density for applications involving III-nitrides. Bending of dislocation lines also relaxes the compressive growth stress that is essential to prevent cracking on cooling down due to tensile thermal expansion mismatch stress while growing on Si substrates. It is shown in this work that surface roughness plays a key role in dislocation bending. Dislocations only bend and relax compressive stresses when the lines intersect a smooth surface. These films then crack. In rough films, dislocation lines which terminate at the bottom of the valleys remain straight. Compressive stresses are not relaxed and the films are relatively crack-free. The reasons for this difference are discussed in this work along with the implications on simultaneously meeting the requirements of films being smooth, crack free and having low defect density for device applications. Published by AIP Publishing
An incremental off-policy search in a model-free Markov decision process using a single sample path
No full textIn this paper, we consider a modified version of the control problem in a model free Markov decision process (MDP) setting with large state and action spaces. The control problem most commonly addressed in the contemporary literature is to find an optimal policy which maximizes the value function, i.e., the long run discounted reward of the MDP. The current settings also assume access to a generative model of the MDP with the hidden premise that observations of the system behaviour in the form of sample trajectories can be obtained with ease from the model. In this paper, we consider a modified version, where the cost function is the expectation of a non-convex function of the value function without access to the generative model. Rather, we assume that a sample trajectory generated using a priori chosen behaviour policy is made available. In this restricted setting, we solve the modified control problem in its true sense, i.e., to find the best possible policy given this limited information. We propose a stochastic approximation algorithm based on the well-known cross entropy method which is data (sample trajectory) efficient, stable, robust as well as computationally and storage efficient. We provide a proof of convergence of our algorithm to a policy which is globally optimal relative to the behaviour policy. We also present experimental results to corroborate our claims and we demonstrate the superiority of the solution produced by our algorithm compared to the state-of-the-art algorithms under appropriately chosen behaviour policy