Crystallographic Study of Novel Transthyretin Ligands Exhibiting Negative-Cooperativity between Two Thyroxine Binding Sites

Background: Transthyretin (TTR) is a homotetrameric serum and cerebrospinal fluid protein that transports thyroxine (T4) and retinol by binding to retinol binding protein. Rate-limiting tetramer dissociation and rapid monomer misfolding and disassembly of TTR lead to amyloid fibril formation in different tissues causing various amyloid diseases. Based on the current understanding of the pathogenesis of TTR amyloidosis, it is considered that the inhibition of amyloid fibril formation by stabilization of TTR in native tetrameric form is a viable approach for the treatment of TTR amyloidosis. Methodology and Principal Findings: We have examined interactions of the wtTTR with a series of compounds containing various substitutions at biphenyl ether skeleton and a novel compound, previously evaluated for binding and inhibiting tetramer dissociation, by x-ray crystallographic approach. High resolution crystal structures of five ligands in complex with wtTTR provided snapshots of negatively cooperative binding of ligands in two T4 binding sites besides characterizing their binding orientations, conformations, and interactions with binding site residues. In all complexes, the ligand has better fit and more potent interactions in first T4 site i.e. (AC site) than the second T4 site (BD site). Together, these results suggest that AC site is a preferred ligand binding site and retention of ordered water molecules between the dimer interfaces further stabilizes the tetramer by bridging a hydrogen bond interaction between Ser117 and its symmetric copy. Conclusion: Novel biphenyl ether based compounds exhibit negative-cooperativity while binding to two T4 sites which suggests that binding of only single ligand molecule is sufficient to inhibit the TTR tetramer dissociation.

A soluble-lead redox flow battery with corrugated graphite sheet and reticulated vitreous carbon as positive and negative current collectors

A soluble-lead redox flow battery with corrugated-graphite sheet and reticulated-vitreous carbon as positive and negative current collectors is assembled and performance tested. In the cell, electrolyte comprising of 1 center dot 5 M lead (II) methanesulfonate and 0 center dot 9 M methanesulfonic acid with sodium salt of lignosulfonic acid as additive is circulated through the reaction chamber at a flow rate of 50 ml min (-aEuro parts per thousand 1). During the charge cycle, pure lead (Pb) and lead dioxide (PbO2) from the soluble lead (II) species are electrodeposited onto the surface of the negative and positive current collectors, respectively. Both the electrodeposited materials are characterized by XRD, XPS and SEM. Phase purity of synthesized lead (II) methanesulfonate is unequivocally established by single crystal X-ray diffraction followed by profile refinements using high resolution powder data. During the discharge cycle, electrodeposited Pb and PbO2 are dissolved back into the electrolyte. Since lead ions are produced during oxidation and reduction at the negative and positive plates, respectively there is no risk of crossover during discharge cycle, preventing the possibility of lowering the overall efficiency of the cell. As the cell employs a common electrolyte, the need of employing a membrane is averted. It has been possible to achieve a capacity value of 114 mAh g (-aEuro parts per thousand 1) at a load current-density of 20 mA cm (-aEuro parts per thousand 2) with the cell at a faradaic efficiency of 95%. The cell is tested for 200 cycles with little loss in its capacity and efficiency.

Hybrid online non-negative matrix factorization for clustering of documents

When document corpus is very large, we often need to reduce the number of features. But it is not possible to apply conventional Non-negative Matrix Factorization(NMF) on billion by million matrix as the matrix may not fit in memory. Here we present novel Online NMF algorithm. Using Online NMF, we reduced original high-dimensional space to low-dimensional space. Then we cluster all the documents in reduced dimension using k-means algorithm. We experimentally show that by processing small subsets of documents we will be able to achieve good performance. The method proposed outperforms existing algorithms.

Negative differential resistance and effect of defects and deformations in MoS2 armchair nanoribbon metal-oxide-semiconductor field effect transistor

In this work, we present a study on the negative differential resistance (NDR) behavior and the impact of various deformations (like ripple, twist, wrap) and defects like vacancies and edge roughness on the electronic properties of short-channel MoS2 armchair nanoribbon MOSFETs. The effect of deformation (3 degrees-7 degrees twist or wrap and 0.3-0.7 angstrom ripple amplitude) and defects on a 10 nm MoS2 ANR FET is evaluated by the density functional tight binding theory and the non-equilibrium Green's function approach. We study the channel density of states, transmission spectra, and the I-D-V-D characteristics of such devices under the varying conditions, with focus on the NDR behavior. Our results show significant change in the NDR peak to valley ratio and the NDR window with such minor intrinsic deformations, especially with the ripple. (C) 2013 AIP Publishing LLC.

Metal-organic chemical vapor-deposited cobalt oxide films as negative electrodes for thin film Li-ion battery

In this study, thin films of cobalt oxide (Co3O4) have been grown by the metal-organic chemical vapor deposition (MOCVD) technique on stainless steel substrate at two preferred temperatures (450 degrees C and 500 degrees C), using cobalt acetylacetonate dihydrate as precursor. Spherical as well as columnar microstructures of Co3O4 have been observed under controlled growth conditions. Further investigations reveal these films are phase-pure, well crystallized and carbon-free. High-resolution TEM analysis confirms that each columnar structure is a continuous stack of minute crystals. Comparative study between these Co3O4 films grown at 450 degrees C and 500 degrees C has been carried out for their application as negative electrodes in Li-ion batteries. Our method of electrode fabrication leads to a coating of active material directly on current collector without any use of external additives. A high specific capacity of 1168 micro Ah cm(-2) mu m(-1) has been measured reproducibly for the film deposited at 500 degrees C with columnar morphology. Further, high rate capability is observed when cycled at different current densities. The Co3O4 electrode with columnar structure has a specific capacity 38% higher than the electrode with spherical microstructure (grown at 450 degrees C). Impedance measurements on the Co3O4 electrode grown at 500 degrees C also carried out to study the kinetics of the electrode process. (C) 2014 Published by Elsevier B.V.

Demonstration of helicase activity in the nonstructural protein, NSs, of the negative-sense RNA virus, Groundnut bud necrosis virus

The nonstructural protein NSs, encoded by the S RNA of groundnut bud necrosis virus (GBNV) (genus Tospovirus, family Bunyaviridae) has earlier been shown to possess nucleic-acid-stimulated NTPase and 50 a phosphatase activity. ATP hydrolysis is an essential function of a true helicase. Therefore, NSs was tested for DNA helicase activity. The results demonstrated that GBNV NSs possesses bidirectional DNA helicase activity. An alanine mutation in the Walker A motif (K189A rNSs) decreased DNA helicase activity substantially, whereas a mutation in the Walker B motif resulted in a marginal decrease in this activity. The parallel loss of the helicase and ATPase activity in the K189A mutant confirms that NSs acts as a non-canonical DNA helicase. Furthermore, both the wild-type and K189A NSs could function as RNA silencing suppressors, demonstrating that the suppressor activity of NSs is independent of its helicase or ATPase activity. This is the first report of a true helicase from a negative-sense RNA virus.

Negative hyperconjugation and red-, blue- or zero-shift in X-Z center dot center dot center dot Y complexes

A generalized explanation is provided for the existence of the red-and blue-shifting nature of X-Z bonds (Z = H, halogens, chalcogens, pnicogens, etc.) in X-Z center dot center dot center dot Y complexes based on computational studies on a selected set of weakly bonded complexes and analysis of existing literature data. The additional electrons and orbitals available on Z in comparison to H make for dramatic differences between the H-bond and the rest of the Z-bonds. The nature of the X-group and its influence on the X-Z bond length in the parent X-Z molecule largely controls the change in the X-Z bond length on X-Z center dot center dot center dot Y bond formation; the Y-group usually influences only the magnitude of the effects controlled by X. The major factors which control the X-Z bond length change are: (a) negative hyperconjugative donation of electron density from X-group to X-Z sigma* antibonding molecular orbital (ABMO) in the parent X-Z, (b) induced negative hyperconjugation from the lone pair of electrons on Z to the antibonding orbitals of the X-group, and (c) charge transfer (CT) from the Y-group to the X-Z sigma* orbital. The exchange repulsion from the Y-group that shifts partial electron density at the X-Z sigma* ABMO back to X leads to blue-shifting and the CT from the Y-group to the sigma* ABMO of X-Z leads to red-shifting. The balance between these two opposing forces decides red-, zero- or blue-shifting. A continuum of behaviour of X-Z bond length variation is inevitable in X-Z center dot center dot center dot Y complexes.

SUB1 Plays a Negative Role during Starvation Induced Sporulation Program in Saccharomyces cerevisiae

Saccharomyces cerevisiae Sub1 is involved in several cellular processes such as, transcription initiation, elongation, mRNA processing and DNA repair. It has also been reported to provide cellular resistance during conditions of oxidative DNA damage and osmotic stress. Here, we report a novel role of SUB1 during starvation stress-induced sporulation, which leads to meiosis and spore formation in diploid yeast cells. Deletion of SUB1 gene significantly increased sporulation efficiency as compared to the wild-type cells in S288c genetic background. Whereas, the sporulation functions of the sub1(Y66A) missense mutant were similar to Sub1. SUB1 transcript and protein levels are downregulated during sporulation, in highly synchronized and sporulation proficient wild-type SK1 cells. The changes in Sub1 levels during sporulation cascade correlate with the induction of middle sporulation gene expression. Deletion of SUB1 increased middle sporulation gene transcript levels with no effect on their induction kinetics. In wild-type cells, Sub1 associates with chromatin at these loci in a temporal pattern that correlates with their enhanced gene expression seen in sub1. cells. We show that SUB1 genetically interacts with HOS2, which led us to speculate that Sub1 might function with Set3 repressor complex during sporulation. Positive Cofactor 4, human homolog of Sub1, complemented the sub1. sporulation phenotype, suggesting conservation of function. Taken together, our results suggest that SUB1 acts as a negative regulator of sporulation.

Average Overlap for Clustering Incomplete Data using Symmetric Non-Negative Matrix Factorization

Clustering techniques which can handle incomplete data have become increasingly important due to varied applications in marketing research, medical diagnosis and survey data analysis. Existing techniques cope up with missing values either by using data modification/imputation or by partial distance computation, often unreliable depending on the number of features available. In this paper, we propose a novel approach for clustering data with missing values, which performs the task by Symmetric Non-Negative Matrix Factorization (SNMF) of a complete pair-wise similarity matrix, computed from the given incomplete data. To accomplish this, we define a novel similarity measure based on Average Overlap similarity metric which can effectively handle missing values without modification of data. Further, the similarity measure is more reliable than partial distances and inherently possesses the properties required to perform SNMF. The experimental evaluation on real world datasets demonstrates that the proposed approach is efficient, scalable and shows significantly better performance compared to the existing techniques.

Negative Cooperativity and High Affinity in Chitooligosaccharide Binding by a Mycobacterium smegmatis Protein Containing LysM and Lectin Domains

LysM domains have been recognized in bacteria and eukaryotes as carbohydrate-binding protein modules, but the mechanism of their binding to chitooligosaccharides has been underexplored. Binding of a Mycobacterium smegmatis protein containing a lectin (MSL) and one LysM domain to chitooligosaccharides has been studied using isothermal titration calorimetry and fluorescence titration that demonstrate the presence of two binding sites of nonidentical affinities per dimeric MSL-LysM molecule. The affinity of the molecule for chitooligosaccharides correlates with the length of the carbohydrate chain. Its binding to chitooligosaccharides is characterized by negative cooperativity in the interactions of the two domains. Apparently, the flexibility of the long linker that connects the LysM and MSL domains plays a facilitating role in this recognition. The LysM domain in the MSL-LysM molecule, like other bacterial domains but unlike plant LysM domains, recognizes equally well peptidoglycan fragments as well as chitin polymers. Interestingly, in the case presented here, two LysM domains are enough for binding to peptidoglycan in contrast to the three reportedly required by the LysM domains of Bacillus subtilis and Lactococcus lactis. Also, the affinity of the MSL-LysM molecule for chitooligosaccharides is higher than that of LysM-chitooligosaccharide interactions reported so far.