Improved Detection of Remote Homologues Using Cascade PSI-BLAST: Influence of Neighbouring Protein Families on Sequence Coverage

Background: Development of sensitive sequence search procedures for the detection of distant relationships between proteins at superfamily/fold level is still a big challenge. The intermediate sequence search approach is the most frequently employed manner of identifying remote homologues effectively. In this study, examination of serine proteases of prolyl oligopeptidase, rhomboid and subtilisin protein families were carried out using plant serine proteases as queries from two genomes including A. thaliana and O. sativa and 13 other families of unrelated folds to identify the distant homologues which could not be obtained using PSI-BLAST. Methodology/Principal Findings: We have proposed to start with multiple queries of classical serine protease members to identify remote homologues in families, using a rigorous approach like Cascade PSI-BLAST. We found that classical sequence based approaches, like PSI-BLAST, showed very low sequence coverage in identifying plant serine proteases. The algorithm was applied on enriched sequence database of homologous domains and we obtained overall average coverage of 88% at family, 77% at superfamily or fold level along with specificity of similar to 100% and Mathew's correlation coefficient of 0.91. Similar approach was also implemented on 13 other protein families representing every structural class in SCOP database. Further investigation with statistical tests, like jackknifing, helped us to better understand the influence of neighbouring protein families. Conclusions/Significance: Our study suggests that employment of multiple queries of a family for the Cascade PSI-BLAST searches is useful for predicting distant relationships effectively even at superfamily level. We have proposed a generalized strategy to cover all the distant members of a particular family using multiple query sequences. Our findings reveal that prior selection of sequences as query and the presence of neighbouring families can be important for covering the search space effectively in minimal computational time. This study also provides an understanding of the `bridging' role of related families.

Tethering preferences of domain families co-occurring in multi-domain proteins

Genomic data of several organisms have revealed the presence of a vast repertoire of multi-domain proteins. The role played by individual domains in a multi-domain protein has a profound influence on the overall function of the protein. In the present analysis an attempt has been made to better understand the tethering preferences of domain families that occur in multi-domain proteins. The analysis has been carried out on an exhaustive dataset of 2 961 898 sequences of proteins from 930 organisms, where 741 274 proteins are comprised of at least two domain families. For every domain family, the number of other domain families with which it co-occurs within a protein in this dataset has been enumerated and is referred to as the tethering number of the domain family. It was found that, in the general dataset, the AAA ATPase family and the family of Ser/Thr kinases have the highest tethering numbers of 450 and 444 respectively. Further analysis reveals significant correlation between the number of members in a family and its tethering number. Positive correlation was also observed for the extent of a sequence and functional diversity within a family and the tethering numbers of domain families. Domain families that are present ubiquitously in diverse organisms tend to have large tethering numbers, while organism/kingdom-specific families have low tethering numbers. Thus, the analysis uncovers how domain families recombine and evolve to give rise to multi-domain proteins.

DMT of parallel-path and layered networks under the half-duplex constraint

In this paper, we study the diversity-multiplexing-gain tradeoff (DMT) of wireless relay networks under the half-duplex constraint. It is often unclear what penalty if any, is imposed by the half-duplex constraint on the DMT of such networks. We study two classes of networks; the first class, called KPP(I) networks, is the class of networks with the relays organized in K parallel paths between the source and the destination. While we assume that there is no direct source-destination path, the K relaying paths can interfere with each other. The second class, termed as layered networks, is comprised of relays organized in layers, where links exist only between adjacent layers. We present a communication scheme based on static schedules and amplify-and-forward relaying for these networks. We also show that for KPP(I) networks with K >= 3, the proposed schemes can achieve full-duplex DMT performance, thus demonstrating that there is no performance hit on the DMT due to the half-duplex constraint. We also show that, for layered networks, a linear DMT of d(max)(1 - r)(+) between the maximum diversity d(max) and the maximum MG, r(max) = 1 is achievable. We adapt existing DMT optimal coding schemes to these networks, thus specifying the end-to-end communication strategy explicitly.

Mutation analysis of the SLC4A11 gene in Indian families with congenital hereditary endothelial dystrophy 2 and a review of the literature

Purpose: Congenital hereditary endothelial dystrophy 2 (CHED2) is an autosomal recessive disorder caused by mutations in the solute carrier family 4, sodium borate transporter, member 11 (SLC4A11) gene. The purpose of this study was to identify the genetic cause of CHED2 in six Indian families and catalog all known mutations in the SLC4A11 gene. Methods: Peripheral blood samples were collected from individuals of the families with CHED2 and used in genomic DNA isolation. PCR primers were used to amplify the entire coding region including intron-exon junctions of SLC4A11. Amplicons were subsequently sequenced to identify the mutations. Results: DNA sequence analysis of the six families identified four novel (viz., p.Thr262Ile, p.Gly417Arg, p.Cys611Arg, and p.His724Asp) mutations and one known p.Arg869His homozygous mutation in the SLC4A11 gene. The mutation p.Gly417Arg was identified in two families. Conclusions: This study increases the mutation spectrum of the SLC4A11 gene. A review of the literature showed that the total number of mutations in the SLC4A11 gene described to date is 78. Most of the mutations are missense, followed by insertions-deletions. The present study will be helpful in genetic diagnosis of the families reported here.

Generalized distributive law for ML decoding of STBCs: further results

The problem of designing good Space-Time Block Codes (STBCs) with low maximum-likelihood (ML) decoding complexity has gathered much attention in the literature. All the known low ML decoding complexity techniques utilize the same approach of exploiting either the multigroup decodable or the fast-decodable (conditionally multigroup decodable) structure of a code. We refer to this well known technique of decoding STBCs as Conditional ML (CML) decoding. In [1], we introduced a framework to construct ML decoders for STBCs based on the Generalized Distributive Law (GDL) and the Factor-graph based Sum-Product Algorithm, and showed that for two specific families of STBCs, the Toepltiz codes and the Overlapped Alamouti Codes (OACs), the GDL based ML decoders have strictly less complexity than the CML decoders. In this paper, we introduce a `traceback' step to the GDL decoding algorithm of STBCs, which enables roughly 4 times reduction in the complexity of the GDL decoders proposed in [1]. Utilizing this complexity reduction from `traceback', we then show that for any STBC (not just the Toeplitz and Overlapped Alamouti Codes), the GDL decoding complexity is strictly less than the CML decoding complexity. For instance, for any STBC obtained from Cyclic Division Algebras that is not multigroup or conditionally multigroup decodable, the GDL decoder provides approximately 12 times reduction in complexity compared to the CML decoder. Similarly, for the Golden code, which is conditionally multigroup decodable, the GDL decoder is only about half as complex as the CML decoder.

Energy Loss in the Impact of Elastic Spheres on a Rigid Half-Space in Presence of Adhesion

Adhesion can cause energy losses in asperities or particles coming into dynamic contact resulting in frictional dissipation, even if the deformation occurring is purely elastic. Such losses are of special significance in impact of nanoparticles and friction between surfaces under low contact pressure to hardness ratio. The objective of this work is to study the effect of adhesion during the normal impact of elastic spheres on a rigid half-space, with an emphasis on understanding the mechanism of energy loss. We use finite element method for modeling the impact phenomenon, with the adhesion due to van der Waals force and the short-range repulsion included as body forces distributed over the volume of the sphere. This approach, in contrast with commonly used surface force approximation, helps to model the interactions in a more precise way. We find that the energy loss in impact of elastic spheres is negligible unless there are adhesion-induced instabilities. Significant energy loss through elastic stress waves occurs due to jump-to-contact and jump-out-of-contact instabilities and can even result in capture of the elastic sphere on the half-space.

Self-assembly of discrete metallamacrocycles employing half-sandwich octahedral diruthenium(II) building units and imidazole-based ligands

Equimolar combination of a series of binuclear half-sandwich p-cymene ruthenium(II) building units Ru-2(mu-eta(4)-C2O4)(MeOH)(2)(eta(6)-p-cymene)(2)](OTf)(2) 1a](OTf)(2), Ru-2(mu-eta(4)-N,N'-diphenyloxamidato)( MeOH)(2)(eta(6)-p-cymene)(2)](OTf)(2) 1b](OTf)(2) and Ru-2(mu-eta(4)-C6H2O4)(MeOH)(2)(eta(6)-p-cymene)(2)](OTf)(2) 1c](OTf)(2) separately with imidazole-based ditopic ligands (L-1-L-2) in methanol yielded a series of tetranuclear metallamacrocycles 2-7](OTf)(4), respectively L-1 = 1,4-bis(imidazole-1-yl)benzene; L-2 = 4,4'-bis(imidazole-1-yl)biphenyl; OTf- = O3SCF3-]. Similarly, the reaction of Ru-2(mu-eta(4)-C2O4)(MeOH)(2)(eta(6)-p-cymene)2](OTf)(2) 1a](OTf)(2) with a triazine-based tritopic ligand 1,3,5-tris(imidazole-1-yl) triazine (L3) in 3: 2 M ratio afforded an unexpected tetranuclear macrocycle 8](OTf)(4) instead of an expected trigonal prismatic cage 8a](OTf)(6). All the self-assembled macrocycles 2-8](OTf)(4) were isolated in moderate to high yields and were fully characterized by multinuclear H-1, F-19] NMR, IR and electrospray ionization mass spectrometry (ESI-MS). In addition, X-ray diffraction study on the single crystals of 3](OTf)(4) and 8](OTf)(4) also indicated the formation 2 + 2] self-assembled macrocycles. Despite the possibility of formation of different conformational isomeric macrocycles (syn-and anti) and polymeric product due to free rotation of ligand sites of imidazole linkers, the selective formation of single conformational isomer (anti) as the only product is quite interesting. Furthermore, the photo-and electrochemical properties of these assemblies have been studied using UV/Vis absorption and cyclic voltammetry analysis. (c) 2013 Elsevier B.V. All rights reserved.

Investigations of Ramachandran disallowed conformations in protein domain families

In peptide and protein structures, occurrence of (phi,psi.) angles in the disallowed region of the Ramachandran map almost always suggests local regions of error or poor accuracy. However, very rarely genuine disallowed conformations occur as noted in the current study in proteins of known structure available at ultra-high resolution (<= 1.2 (A) over circle). In the current work, extent of conservation of genuine disallowed conformations in homologous proteins of known structures has been analyzed. From a dataset of 124 protein domain families, with structure of at least one constituent member in each family available at a resolution of 1.2 (A) over circle or better, we have analyzed the conservation of 221 disallowed conformations. It is observed that the disallowed conformation is only moderately conservedin protein domain families. In the gross dataset no particular residue type adopting disallowed conformation elicit high conservation of residue type though there are alignment positions in the dataset with complete conservation of both the residue type and the disallowed conformation. Conserved disallowed conformation in protein domain families play biologically significant role in roughly 50% of the cases. The residues with the disallowed conformation or its flanking residues are often located within or around the functional site of the protein. (C) 2013 Elsevier B.V. All rights reserved.

Common recognition principles across diverse sequence and structural families of sialic acid binding proteins

Sialic acids form a large family of 9-carbon monosaccharides and are integral components of glycoconjugates. They are known to bind to a wide range of receptors belonging to diverse sequence families and fold classes and are key mediators in a plethora of cellular processes. Thus, it is of great interest to understand the features that give rise to such a recognition capability. Structural analyses using a non-redundant data set of known sialic acid binding proteins was carried out, which included exhaustive binding site comparisons and site alignments using in-house algorithms, followed by clustering and tree computation, which has led to derivation of sialic acid recognition principles. Although the proteins in the data set belong to several sequence and structure families, their binding sites could be grouped into only six types. Structural comparison of the binding sites indicates that all sites contain one or more different combinations of key structural features over a common scaffold. The six binding site types thus serve as structural motifs for recognizing sialic acid. Scanning the motifs against a non-redundant set of binding sites from PDB indicated the motifs to be specific for sialic acid recognition. Knowledge of determinants obtained from this study will be useful for detecting function in unknown proteins. As an example analysis, a genome-wide scan for the motifs in structures of Mycobacterium tuberculosis proteome identified 17 hits that contain combinations of the features, suggesting a possible function of sialic acid binding by these proteins.

Minimizing total weighted tardiness on heterogeneous batch processors with incompatible job families

In this paper, we address a scheduling problem for minimizing total weighted tardiness. The background for the paper is derived from the automobile gear manufacturing process. We consider the bottleneck operation of heat treatment stage of gear manufacturing. Real-life scenarios like unequal release times, incompatible job families, nonidentical job sizes, heterogeneous batch processors, and allowance for job splitting have been considered. We have developed a mathematical model which takes into account dynamic starting conditions. The problem considered in this study is NP-hard in nature, and hence heuristic algorithms have been proposed to address it. For real-life large-size problems, the performance of the proposed heuristic algorithms is evaluated using the method of estimated optimal solution available in literature. Extensive computational analyses reveal that the proposed heuristic algorithms are capable of consistently obtaining near-optimal statistically estimated solutions in very reasonable computational time.

Doping a Correlated Band Insulator: A New Route to Half-Metallic Behavior

We demonstrate in a simple model the surprising result that turning on an on-site Coulomb interaction U in a doped band insulator leads to the formation of a half-metallic state. In the undoped system, we show that increasing U leads to a first order transition at a finite value U-AF between a paramagnetic band insulator and an antiferomagnetic Mott insulator. Upon doping, the system exhibits half-metallic ferrimagnetism over a wide range of doping and interaction strengths on either side of U-AF. Our results, based on dynamical mean field theory, suggest a new route to half metallicity, and will hopefully motivate searches for new materials for spintronics.

Mitigating UVA light induced reactivity of 6-thioguanine through formation of a Ru(II) half-sandwich complex

The organometallic complex of (eta(6)-cymene)Ru(II)Br with 6-thioguanine (6-TG) shows better photostability than the biologically active 6-thioguanine which is used as an immunosuppressant and as an anticancer agent.

Substitution-Modulated Anticancer Activity of Half-Sandwich Ruthenium(II) Complexes with Heterocyclic Ancillary Ligands

Ten new organometallic half-sandwich ruthenium complexes with heterocyclic ligands have been synthesized (H1-H10). The substituents on the ancillary heterocyclic ligands were varied to understand the effect of substitution on anticancer activity. The crystallographic characterization of five complexes confirms that they adopt three-legged piano-stool structures and are stabilized by intramolecular hydrogen bonding. Complexes H2 and H3 also exhibit halogen bonding in the solid state. In aqueous media, the complexes form dinuclear ruthenium species. Complex H1 with a noncytotoxic heterocycle, 6-fluoro-2-mercaptobenzothiazole, and complex H11 with the unsubstituted 2-mercaptobenzothiazole are the most active against A2780 and KB cell lines. The substitution of the H atoms on the ancillary ligand with Cl or Br atoms leads to a decrease in the anticancer activity. With the exception of fluorine-substituted H5, the complexes with mercaptobenzoxazole (H6-H9) are inactive against all of the tested cell lines. Ruthenium complexes with mercaptonaphthimidazole (H10) and mercaptobenzimidazole (H13) do not show any anticancer activity. The active complexes show a biphasic melting curve when incubated with calf thymus (CT) DNA. These complexes only inhibit thioredoxin reductase (TrxR) enzyme activity to a small extent. The substitution of hydrogen atoms with fluorine atoms in the aromatic heterocyclic ligands on organometallic half-sandwich ruthenium complexes has the most beneficial effect on their anticancer activity.

Seleno-Nucleobases and Their Water-Soluble Ruthenium-Arene Half-Sandwich Complexes: Chemistry and Biological Activity

Half-sandwich organometallic ruthenium complexes of seleno-nucleobases, 3 and 4, were synthesized and characterized. The structures of both complexes were determined by X-ray crystallography and are the first crystal structures of ruthenium complexes with seleno-nucleobases. Interestingly, 3 self-assembles aided by adventitious water in DMF to give a tetranuclear square 3a center dot 6H(2)O. Complex 4 is active against Jurkat and Molt-4 cell lines but inactive against the K562 cell line, whereas 3 is completely inactive against all three cell lines. The free ligand 6-selenopurine (1) and 6-selenoguanine (2) are highly active against these cell lines. Compound 2, like its thio analogue, is unstable under UVA light, whereas 4 is stable under similar conditions, which suggests that the ruthenium complex could reduce problems associated with the instability of the free ligand, 2, under irradiation.

THEORY OF NEWFORMS OF HALF-INTEGRAL WEIGHT

We set up the theory of newforms of half-integral weight on Gamma(0)(8N) and Gamma(0)(16N), where N is odd and squarefree. Further, we extend the definition of the Kohnen plus space in general for trivial character and also study the theory of newforms in the plus spaces on Gamma(0)(8N), Gamma(0)(16N), where N is odd and squarefree. Finally, we show that the Atkin-Lehner W-operator W-4 acts as the identity operator on S-2k(new)(4N), where N is odd and squarefree. This proves that S-2k(-)(4) = S-2k(4).