Rheumatoid arthritis sera react with a phage-displayed peptide selected by a monoclonal antibody to type II collagen that has homology to EBNA-1

Antibodies to type II collagen, and to Epstein Barr virus nuclear antigen-1 (EBNA-1) have been associated with rheumatoid arthritis (RA). In studies involving probing of phage-displayed random peptide libraries with an antibody to type II collagen, CII-C1, we observed that among 17 phagotopes selected 5 expressed peptides with homology with the sequence of EBNA-1. The residues in common were RLPFG. Hence we tested sera from 50 patients with RA, of whom 26 had antibodies to native type II collagen, and 43 healthy controls, for reactivity by ELISA with a phagotope selected 4 times, which expressed the peptide RRLPFGSQM. Eight RA sera (16%) but no normal sera reacted with the phagotope (p = 0.025). This reactivity could not be correlated with reactivity of RA sera with EBNA-1 by semi-quantitative western blot, with which reactivity occurred in 78% of RA patients and 81% of controls. Evidence for molecular mimicry was not found insofar as the phagotope did not inhibit reactivity of RA sera with EBNA-1 and CII-C1 was not reactive with EBNA-1. We conclude that the reactivity of the RA sera with the phagotope is most likely due to the phagotope being a mimic of an epitope of type II collagen for a proportion of RA sera.

Mimotopes identified by phage display for the monoclonal antibody CII- C1 to type II collagen

The characterization of B cell epitopes has been advanced by the use of random peptide libraries displayed within the coat protein of bacteriophage. This technique was applied to the monoclonal antibody (mAb) C1 to type II collagen (CII-C1). CII-C1 is known to react with a conformational epitope on type II collagen that includes residues 359-363. Three rounds of selection were used to screen two random nonameric phage libraries and 18 phagotopes were isolated. CII-C1 reacted by ELISA with 17 of the 18 phagotopes: one phagotope contained a stop codon. Of the eight most reactive phage, seven inhibited the reactivity by ELISA of CII-C1 with type II collagen. Of the 18 phage isolated, 11 encoded the motif F-G-x-Q with the sequence F-G-S-Q in 6, 2 encoded F-G-Q, and one the reverse motif Q-x-y-F. Most phagotopes that inhibited the reactivity of CII-C1 encoded two particular motifs consisting of two basic amino acid residues and a hydrophobic residue in the first part of the insert and the F-G-x-Q or F-G-Q motif ill the second part; phagotopes which contained only one basic residue in the first part of the sequence were less reactive. These motifs are not represented in the linear sequence of type II collagen and thus represent mimotopes of the epitope for CII-C1 on type II collagen. There were five phagotopes with peptide inserts containing the sequence RLPFG occurring in the Epstein-Barr virus nuclear antigen, EBNA- 1. This is of interest because EBV has been implicated in the initiation of rheumatoid arthritis (RA) by reason of increased reactivity to EBNA-1 in RA sera. In conclusion, the phage display technique disclosed mimotopes for a conformational epitope of type II collagen, and revealed an interesting homology with a sequence of the EBNA-1 antigen from Epstein Barr virus.

High threshold of β1 integrin inhibition required to block collagen I-induced membrane type-1 matrix metalloproteinase (MT1-MMP) activation of matrix metalloproteinase 2 (MMP-2)

Background Matrix metalloproteinase-2 (MMP-2) is an endopeptidase that facilitates extracellular matrix remodeling and molecular regulation, and is implicated in tumor metastasis. Type I collagen (Col I) regulates the activation of MMP-2 through both transcriptional and post-transcriptional means; however gaps remain in our understanding of the involvement of collagen-binding ?1 integrins in collagen-stimulated MMP-2 activation. Methods Three ?1 integrin siRNAs were used to elucidate the involvement of ?1 integrins in the Col I-induced MMP-2 activation mechanism. ?1 integrin knockdown was analyzed by quantitative RT-PCR, Western Blot and FACS analysis. Adhesion assay and collagen gel contraction were used to test the biological effects of ?1 integrin abrogation. MMP-2 activation levels were monitored by gelatin zymography. Results All three ?1 integrin siRNAs were efficient at ?1 integrin knockdown and FACS analysis revealed commensurate reductions of integrins ?2 and ?3, which are heterodimeric partners of ?1, but not ?V, which is not. All three ?1 integrin siRNAs inhibited adhesion and collagen gel contraction, however only the siRNA showing the greatest magnitude of ?1 knockdown inhibited Col I-induced MMP-2 activation and reduced the accompanying upregulation of MT1-MMP, suggesting a dose response threshold effect. Re-transfection with codon-swapped ?1 integrin overcame the reduction in MMP-2 activation induced by Col-1, confirming the ?1 integrin target specificity. MMP-2 activation induced by TPA or Concanavalin A (Con A) was not inhibited by ?1 integrin siRNA knockdown. Conclusion Together, the data reveals that strong abrogation of ?1 integrin is required to block MMP-2 activation induced by Col I, which may have implications for the therapeutic targeting of ?1 integrin.

A CCG virtual system for big data application communication costs analysis

Network topology and routing are two important factors in determining the communication costs of big data applications at large scale. As for a given Cluster, Cloud, or Grid system, the network topology is fixed and static or dynamic routing protocols are preinstalled to direct the network traffic. Users cannot change them once the system is deployed. Hence, it is hard for application developers to identify the optimal network topology and routing algorithm for their applications with distinct communication patterns. In this study, we design a CCG virtual system (CCGVS), which first uses container-based virtualization to allow users to create a farm of lightweight virtual machines on a single host. Then, it uses software-defined networking (SDN) technique to control the network traffic among these virtual machines. Users can change the network topology and control the network traffic programmingly, thereby enabling application developers to evaluate their applications on the same system with different network topologies and routing algorithms. The preliminary experimental results through both synthetic big data programs and NPB benchmarks have shown that CCGVS can represent application performance variations caused by network topology and routing algorithm.

Cardiometabolic effects of genetic upregulation of the interleukin 1 receptor antagonist: A Mendelian randomisation analysis

Background To investigate potential cardiovascular and other effects of long-term pharmacological interleukin 1 (IL-1) inhibition, we studied genetic variants that produce inhibition of IL-1, a master regulator of inflammation. Methods We created a genetic score combining the effects of alleles of two common variants (rs6743376 and rs1542176) that are located upstream of IL1RN, the gene encoding the IL-1 receptor antagonist (IL-1Ra; an endogenous inhibitor of both IL-1α and IL-1β); both alleles increase soluble IL-1Ra protein concentration. We compared effects on inflammation biomarkers of this genetic score with those of anakinra, the recombinant form of IL-1Ra, which has previously been studied in randomised trials of rheumatoid arthritis and other inflammatory disorders. In primary analyses, we investigated the score in relation to rheumatoid arthritis and four cardiometabolic diseases (type 2 diabetes, coronary heart disease, ischaemic stroke, and abdominal aortic aneurysm; 453 411 total participants). In exploratory analyses, we studied the relation of the score to many disease traits and to 24 other disorders of proposed relevance to IL-1 signalling (746 171 total participants). Findings For each IL1RN minor allele inherited, serum concentrations of IL-1Ra increased by 0·22 SD (95% CI 0·18–0·25; 12·5%; p=9·3 × 10−33), concentrations of interleukin 6 decreased by 0·02 SD (−0·04 to −0·01; −1·7%; p=3·5 × 10−3), and concentrations of C-reactive protein decreased by 0·03 SD (−0·04 to −0·02; −3·4%; p=7·7 × 10−14). We noted the effects of the genetic score on these inflammation biomarkers to be directionally concordant with those of anakinra. The allele count of the genetic score had roughly log-linear, dose-dependent associations with both IL-1Ra concentration and risk of coronary heart disease. For people who carried four IL-1Ra-raising alleles, the odds ratio for coronary heart disease was 1·15 (1·08–1·22; p=1·8 × 10−6) compared with people who carried no IL-1Ra-raising alleles; the per-allele odds ratio for coronary heart disease was 1·03 (1·02–1·04; p=3·9 × 10−10). Per-allele odds ratios were 0·97 (0·95–0·99; p=9·9 × 10−4) for rheumatoid arthritis, 0·99 (0·97–1·01; p=0·47) for type 2 diabetes, 1·00 (0·98–1·02; p=0·92) for ischaemic stroke, and 1·08 (1·04–1·12; p=1·8 × 10−5) for abdominal aortic aneurysm. In exploratory analyses, we observed per-allele increases in concentrations of proatherogenic lipids, including LDL-cholesterol, but no clear evidence of association for blood pressure, glycaemic traits, or any of the 24 other disorders studied. Modelling suggested that the observed increase in LDL-cholesterol could account for about a third of the association observed between the genetic score and increased coronary risk. Interpretation Human genetic data suggest that long-term dual IL-1α/β inhibition could increase cardiovascular risk and, conversely, reduce the risk of development of rheumatoid arthritis. The cardiovascular risk might, in part, be mediated through an increase in proatherogenic lipid concentrations. Funding UK Medical Research Council, British Heart Foundation, UK National Institute for Health Research, National Institute for Health Research Cambridge Biomedical Research Centre, European Research Council, and European Commission Framework Programme 7.

The v-MFG test: Investigating maternal, offspring and maternal-fetal genetic incompatibility effects on disease and viability

The MFG test is a family-based association test that detects genetic effects contributing to disease in offspring, including offspring allelic effects, maternal allelic effects and MFG incompatibility effects. Like many other family-based association tests, it assumes that the offspring survival and the offspring-parent genotypes are conditionally independent provided the offspring is affected. However, when the putative disease-increasing locus can affect another competing phenotype, for example, offspring viability, the conditional independence assumption fails and these tests could lead to incorrect conclusions regarding the role of the gene in disease. We propose the v-MFG test to adjust for the genetic effects on one phenotype, e.g., viability, when testing the effects of that locus on another phenotype, e.g., disease. Using genotype data from nuclear families containing parents and at least one affected offspring, the v-MFG test models the distribution of family genotypes conditional on offspring phenotypes. It simultaneously estimates genetic effects on two phenotypes, viability and disease. Simulations show that the v-MFG test produces accurate genetic effect estimates on disease as well as on viability under several different scenarios. It generates accurate type-I error rates and provides adequate power with moderate sample sizes to detect genetic effects on disease risk when viability is reduced. We demonstrate the v-MFG test with HLA-DRB1 data from study participants with rheumatoid arthritis (RA) and their parents, we show that the v-MFG test successfully detects an MFG incompatibility effect on RA while simultaneously adjusting for a possible viability loss.

Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A

The major histocompatibility complex (MHC) on chromosome 6 is associated with susceptibility to more common diseases than any other region of the human genome, including almost all disorders classified as autoimmune. In type 1 diabetes the major genetic susceptibility determinants have been mapped to the MHC class II genes HLA-DQB1 and HLA-DRB1 (refs 1–3), but these genes cannot completely explain the association between type 1 diabetes and the MHC region4, 5, 6, 7, 8, 9, 10, 11. Owing to the region's extreme gene density, the multiplicity of disease-associated alleles, strong associations between alleles, limited genotyping capability, and inadequate statistical approaches and sample sizes, which, and how many, loci within the MHC determine susceptibility remains unclear. Here, in several large type 1 diabetes data sets, we analyse a combined total of 1,729 polymorphisms, and apply statistical methods—recursive partitioning and regression...

Rattling modes and the intrinsic vibrational spectrum of beetle-type scanning tunneling microscopes

It is known that the vibrational spectra of beetle-type scanning tunneling microscopes with a total mass of ≈3–4 g contain extrinsic ‘rattling’ modes in the frequency range extending from 500 to 1700 Hz that interfere with image acquisition. These modes lie below the lowest calculated eigenfrequency of the beetle and it has been suggested that they arise from the inertial sliding of the beetle between surface asperities on the raceway. In this paper we describe some cross-coupling measurements that were performed on three home-built beetle-type STMs of two different designs. We provide evidence that suggests that for beetles with total masses of 12–15 g all the modes in the rattling range are intrinsic. This provides additional support for the notion that the vibrational properties of beetle-type scanning tunneling microscopes can be improved by increasing the contact pressure between the feet of the beetle and the raceway.

SPSA Based Feature Relevance Estimation For Video Retrieval

With the availability of a huge amount of video data on various sources, efficient video retrieval tools are increasingly in demand. Video being a multi-modal data, the perceptions of ``relevance'' between the user provided query video (in case of Query-By-Example type of video search) and retrieved video clips are subjective in nature. We present an efficient video retrieval method that takes user's feedback on the relevance of retrieved videos and iteratively reformulates the input query feature vectors (QFV) for improved video retrieval. The QFV reformulation is done by a simple, but powerful feature weight optimization method based on Simultaneous Perturbation Stochastic Approximation (SPSA) technique. A video retrieval system with video indexing, searching and relevance feedback (RF) phases is built for demonstrating the performance of the proposed method. The query and database videos are indexed using the conventional video features like color, texture, etc. However, we use the comprehensive and novel methods of feature representations, and a spatio-temporal distance measure to retrieve the top M videos that are similar to the query. In feedback phase, the user activated iterative on the previously retrieved videos is used to reformulate the QFV weights (measure of importance) that reflect the user's preference, automatically. It is our observation that a few iterations of such feedback are generally sufficient for retrieving the desired video clips. The novel application of SPSA based RF for user-oriented feature weights optimization makes the proposed method to be distinct from the existing ones. The experimental results show that the proposed RF based video retrieval exhibit good performance.

The crystal structure of eulytite Pb3BiV3O12

The crystal structure of Pb3BiV3O12 was solved using single-crystal X-ray diffraction technique. The compound crystallizes in the cubic system View the MathML source (No. 220) with eulytite structure with a = 10.7490(7) Å, V = 1241.95(14) Å3 and Z = 4. The final R1 value of 0.0198 (wR2=0.0384) was achieved for 359 independent reflections during the structure refinement. The Pb2+ and Bi3+ cations occupy the special position (16c) while the oxygen anions occupy the general position (48e) in the crystal structure. Unlike many other eulytite compounds, all the crystallographic positions are fully occupied. The structure consists of edge-shared Pb/Bi octahedra linked at the corners to independent [VO4]3− tetrahedra units, generating a eulytite-type network in the crystal lattice.

Anthranilate Hydroxylase from Aspergillus niger: New Type of NADPH-Linked Nonheme Iron Monooxygenase

Anthranilate hydroxylase from Aspergillus niger catalyzes the oxidative deamination and dihydroxylation of anthranilic acid to 2,3-dihydroxybenzoic acid. This enzyme has been purified to homogeneity and has a molecular weight of 89,000. The enzyme is composed of two subunits of 42,000 with 2 gram-atoms of nonheme iron per mol. Fe2+-chelators like alpha,alpha'-dipyridyl and o-phenanthroline are potent inhibitors of the enzyme activity. Absorption and fluorescence spectra of the enzyme offer no evidence for the presence of other cofactors like flavin. Flavins and flavin-specific inhibitors like atebrin have no effect on the activity of the enzyme. The enzyme incorporates one atom of oxygen each from 18O2 and H218O into the product 2,3-dihydroxybenzoic acid. Based on these studies, it is concluded that anthranilate hydroxylase from A. niger is a new type of NADPH-linked nonheme iron monooxygenase.

Primestoimenno-otnositel'nye konstrukcii v sovremennom russkom jazyke

Relative Constructions with Pronominal Heads in Contemporary Russian Chapter 1 introduces the distinctive syntactic and semantic properties of Russian relative constructions (RCs), which are then divided into two main classes according to the type of the head phrase. The study concentrates on RCs with pronominal heads, which are systematically compared with noun-headed RCs. Chapter 2 clarifies the categorization of pronouns in Russian. The conclusion is that Russian pronouns include only personal, reflexive and wh-pronouns. The remaining words that are traditionally seen as pronouns are actually functional equivalents of determiners. This idea leads to the suggestion that RCs with these determiner-like words as the only constituent of the head phrase are actually headed by zero pronouns. In the other type of RCs with pronominal heads, the head position is occupied by wh-pronouns with clitics expressing different types of indefiniteness and quantification. Comparison of the two types of pronoun-headed RCs shows that the wh-heads and zero-heads share a number of common properties with respect to the grammatical gender, number and person as well as to the semantic distinction between animates and inanimates. The rest of Chapter 2 gives an overview of various uses of wh-pronouns in Russian and an experimental analysis of RCs headed by pronominal adverbs. Chapter 3 discusses fundamental differences between RCs with noun and pronominal heads. One of the main findings is that the choice of the relative pronoun (kto 'who' and chto 'what' versus kotoryj 'which') is motivated by a tendency to reproduce maximally the essential grammatical and semantic properties of the antecedent. Chapter 4 gives a detailed description of the determiner-like words and wh-based heads used in the two types of RCs with pronominal heads. In addition, several issues related to the syntax and semantics of free relatives are discussed. The conclusion is that there is no need to establish a separate category of free relatives in Russian. Chapter 5 discusses the syntax and semantics of correlative and free concessive constructions. They share a number of properties with pronoun-headed RCs and the two are often confused in Russian linguistics. However, a detailed analysis shows that these constructions must be distinguished from RCs. The study combines the methods of functionally-oriented Russian structuralism with some insights from generative syntax.

The Broad-Line Type Ic Supernoava SN 2007ru: Adding To The Diversity Of Type Ic Supernovae

Photometric and spectral evolution of the Type Ic supernova SN 2007ru until around 210 days after maximum are presented. The spectra show broad spectral features due to very high expansion velocity, normally seen in hypernovae. The photospheric velocity is higher than other normal Type Ic supernovae (SNe Ic). It is lower than SN 1998bw at similar to 8 days after the explosion, but is comparable at later epochs. The light curve (LC) evolution of SN 2007ru indicates a fast rise time of 8 +/- 3 days to B-band maximum and postmaximum decline more rapid than other broad-line SNe Ic. With an absolute V magnitude of -19.06, SN 2007ru is comparable in brightness with SN 1998bw and lies at the brighter end of the observed SNe Ic. The ejected mass of Ni-56 is estimated to be similar to 0.4 M-circle dot. The fast rise and decline of the LC and the high expansion velocity suggest that SN 2007ru is an explosion with a high kinetic energy/ejecta mass ratio (E-K/M-ej). This adds to the diversity of SNe Ic. Although the early phase spectra are most similar to those of broad-line SN 2003jd, the [O I] line profile in the nebular spectrum of SN 2007ru shows the singly peaked profile, in contrast to the doubly peaked profile in SN 2003jd. The singly peaked profile, together with the high luminosity and the high expansion velocity, may suggest that SN 2007ru could be an aspherical explosion viewed from the polar direction. Estimated oxygen abundance 12 + log(O/H) of similar to 8.8 indicates that SN 2007ru occurred in a region with nearly solar metallicity.

Recipient v russkom razgovore : o raspredelenii funkcij mezhdu otvetami da, nu i tak

The study investigates actions by recipients in spontaneous Russian conversations by focusing on DA, NU and TAK, when they are used as responses to the main speaker's larger on-going turn. The database for the study consists of some 7 hours of spontaneous conversations. The participants of the conversations come from different parts of Russia. The use of DA, NU and TAK was analyzed by applying the method of ethnomethodological conversation analysis from the point of view of the type of the context, the sequential placement of the response and its manner of production. The particles were analyzed both in contexts in which they responded to an informing and in affective contexts. The particles NU and TAK were used by the speakers almost exclusively in informing contexts, whereas DA was the central response type in affective contexts. DA was also the most common response to information with affective implications. The information, to which the particle NU provided as response, was often unspesific and projected a spesification or explanation by its speaker as the next action. DA and TAK, by contrast, treated the information as one that could be followed and was sufficient in its local context. As a response to parenthetical information NU responded to information that was only loosely connected with the mainline of talk. The particle DA, by contrast, was used as a response to such parenthetical information, which was more crucial for the larger on-going activity. Only NU was used as a response that invited the main speaker to continue a turn that she or he had offered as possibly complete. NU was also used by the recipient after her or his own contribution as a continuer. In affective contexts, DA expressed, depending on its more spesific context, not only agreement but also other functions, such as giving up arguing or prior knowledge on the topic being discussed. In addition DA responses were used to display empathy and identification with the state of affairs expressed by the co-participant. NU, by contrast, was seldom used as a response to a turn that expressed affect. When it was used in affective contexts, it displayed agreement with the co-participant or just registered an assessment by her or him.

Èvoljucija sistemy glasnyh fonem v nekotoryh russkih govorah Vologodskoj oblasti

The present dissertation analyses 36 local vernaculars of villages surrounding the northern Russian city of Vologda in relation to the system of the vowels in the stressed syllables and those preceding the stressed syllables by using the available dialectological researches. The system in question differs from the corresponding standard Russian system by that the palatalisation of the surrounding consonants affects the vowels much more significantly in the vernaculars, whereas the phonetic difference between the stressed and non-stressed vowels is less obvious in them. The detailed information on the local vernaculars is retrieved from the Dialektologičeskij Atlas Russkogo Jazyka dialect atlas, the data for which were collected, for the most part, in the 1940 s and 1950 s. The theoretical framework of the research consists of a brief cross-section of western sociolinguistic theory related to language change and that of historical linguistics related to the Slavonic vowel development, which includes some new theories concerning the development of the Russian vowel phonemes. The author has collected dialect data in one of the 36 villages and three villages surrounding it. During the fieldwork, speech of nine elderly persons and ten school children was recorded. The speech data were then transcribed with coded information on the corresponding etymological vowels, the phonetic position, and the factual pronunciation at each appearance of vowels in the phonetic positions named above. The data from both of the dialect strata were then systematised to two corresponding systems that were compared with the information retrievable from the dialect atlas and other dialectological literature on the vowel phoneme system of the traditional local vernacular. As a result, it was found out (as hypothesised) that the vernacular vowel phoneme system has approached that of the standard language but has nonetheless not become similar to it. The phoneme quantity of the traditional vernacular is by one greater than that of the standard language, whereas the vowel phoneme quantity in the speech of the school children coincides with that in the standard language, although the phonetic realisations differ to some extent. The analysis of the speech of the elderly people resulted in that it is quite difficult to define the exact phoneme quantity of this stratum due to the fluctuation and irregularities in the realisation of the old phoneme that has ceased to exist in the newest stratum. It was noticed that the effect of the quality of the surrounding consonants on the phonetic realisation of the vowel phonemes has diminished, and the dependence of the phonetic realisation of a vowel phoneme on its place in a word in relation to the word stress has become more and more obvious, which is the state of affairs in the standard language as well.