Antigenic Complementarity in the Origins of Autoimmunity: A General Theory Illustrated With a Case Study of Idiopathic Thrombocytopenia Purpura

We describe a novel, testable theory of autoimmunity, outline novel predictions made by the theory, and illustrate its application to unravelling the possible causes of idiopathic thrombocytopenia purpura (ITP). Pairs of stereochemically complementary antigens induce complementary immune responses (antibody or T-cell) that create loss of regulation and civil war within the immune system itself. Antibodies attack antibodies creating circulating immune complexes; T-cells attack T-cells creating perivascular cuffing. This immunological civil war abrogates the self-nonself distinction. If at least one of the complementary antigens mimics a self antigen, then this unregulated immune response will target host tissues as well. Data demonstrating that complementary antigens are found in some animal models of autoimmunity and may be present in various human diseases, especially ITP, are reviewed. Specific mechanisms for preventing autoimmunity or suppressing existing autoimmunity are derived from the theory, and critical tests proposed. Finally, we argue that Koch's postulates are inadequate for establishing disease causation for multiple-antigen diseases and discuss the possibility that current research has failed to elucidate the causes of human autoimmune diseases because we are using the wrong criteria

Parasite Species Associated With Wild Plateau Pika (Ochotona Curzoniae) In Southeastern Qinghai Province, China

A survey was conducted to determine the prevalence and seasonal abundance of egg, larval, and adult stages of helminths; oocyts of protozoans; and ectoparasites of plateau pikas (Ochotona curzoniae) in seven areas of southeastern Qinghai Province, China, during August 2006 and May 2007. Fecal samples collected from 430 plateau pikas were examined by the modified McMaster technique, which revealed that 83% of the samples contained eggs from two or more helminth species. Mean fecal egg counts were generally moderate and showed the same trend irrespective of the age or sex of the pikas. The prevalence and counts of cestode eggs showed strong seasonal relationships that corresponded with the rainfall pattern in the study area during the study period. Of the 430 plateau pika examined at necropsy, 89% contained adult nematode or cestode species, but none of these contained adult trematode species or protozoans. Overall, six genera of adult nematodes including Oesophagostomum sp., Cephaluris coloradensis, Eugenuris schumakowiescsi, Haemonchus sp., Trichuris sp., and Chbertiinae sp.; three genera of adult cestodes including Schizorchis sp., Ochotonae sp., and Hymenolepis nana; three ectoparasite species including Hypoderma curzonial, Pulex sp., and Ixodes ovatus; and one proscolex stage of a cestode, Echinococcus multilocularis or Echinococcus shiquicus, were encountered during the study. Other genera examined occurred in low numbers, which did not allow any meaningful comparisons. Overall, results suggest that four parasite species, Hypoderma curzonial, Pulex sp., Ixodes ovatus Neumann, and Cephaluris coloradensis, may be regulating factors in controlling future numbers of plateau pika in this study area. These data provide evidence of a natural biologic control mechanism of plateau pika on grassland habitats, and may be of use for identifying the mechanism of transmission of parasites between plateau pika, livestock, and humans

Determining the top-antitop and ZZZZ Couplings of a Neutral Higgs Boson of Arbitrary CP Nature at the NLC

The optimal procedure for extracting the coefficients of different components of a cross section which takes the form of unknown coefficients times functions of known kinematical form is developed. When applied to \epem\to t\anti t+Higgs production at \rts=1\tev and integrated luminosity of 200\fbi, we find that the t\anti t\toHiggs CP-even and CP-odd couplings and, to a lesser extent, the $ZZ\to$Higgs (CP-even) coupling can be extracted with reasonable errors, assuming the Higgs sector parameter choices yield a significant production rate. Indeed, the composition of a mixed-CP Higgs eigenstate can be determined with sufficient accuracy that a SM-like CP-even Higgs boson can be distinguished from a purely CP-odd Higgs boson at a high level of statistical significance, and vice versa.Comment: 8 pages, full postscript file also available via anonymous ftp at ftp://ucdhep.ucdavis.edu/gunion/eetottbh.p

Small-molecule targeting of brachyury transcription factor addiction in chordoma.

Chordoma is a primary bone cancer with no approved therapy1. The identification of therapeutic targets in this disease has been challenging due to the infrequent occurrence of clinically actionable somatic mutations in chordoma tumors2,3. Here we describe the discovery of therapeutically targetable chordoma dependencies via genome-scale CRISPR-Cas9 screening and focused small-molecule sensitivity profiling. These systematic approaches reveal that the developmental transcription factor T (brachyury; TBXT) is the top selectively essential gene in chordoma, and that transcriptional cyclin-dependent kinase (CDK) inhibitors targeting CDK7/12/13 and CDK9 potently suppress chordoma cell proliferation. In other cancer types, transcriptional CDK inhibitors have been observed to downregulate highly expressed, enhancer-associated oncogenic transcription factors4,5. In chordoma, we find that T is associated with a 1.5-Mb region containing 'super-enhancers' and is the most highly expressed super-enhancer-associated transcription factor. Notably, transcriptional CDK inhibition leads to preferential and concentration-dependent downregulation of cellular brachyury protein levels in all models tested. In vivo, CDK7/12/13-inhibitor treatment substantially reduces tumor growth. Together, these data demonstrate small-molecule targeting of brachyury transcription factor addiction in chordoma, identify a mechanism of T gene regulation that underlies this therapeutic strategy, and provide a blueprint for applying systematic genetic and chemical screening approaches to discover vulnerabilities in genomically quiet cancers

Measurement of the Branching Fraction for B->eta' K and Search for B->eta'pi+

We report measurements for two-body charmless B decays with an eta' meson in the final state. Using 11.1X10^6 BBbar pairs collected with the Belle detector, we find BF(B^+ ->eta'K^+)=(79^+12_-11 +-9)x10^-6 and BF(B^0 -> eta'K^0)=(55^+19_-16 +-8)x10^-6, where the first and second errors are statistical and systematic, respectively. No signal is observed in the mode B^+ -> eta' pi^+, and we set a 90% confidence level upper limit of BF(B^+-> eta'pi^+) eta'K^+- decays is investigated and a limit at 90% confidence level of -0.20<Acp<0.32 is obtained.Comment: Submitted to Physics Letters

Improved Measurement of the Partial-Rate CP Asymmetry in B+ -> K0pi+ and B- -> K0bar pi- Decays

We report an improved measurement of the partial-rate CP asymmetry in B+ => K0pi+ and B- => K0bar pi- decays. The analysis is based on a data sample of 85 million BBbar pairs collected at the Upsilon(4S) resonance with the Belle detector at the KEKB e+ e- storage ring. We measure Acp(K0pi+-) = 0.07^{+0.09 +0.01}_{-0.08 -0.03}, where the first and second errors are statistical and systematic, respectively; the corresponding 90% confidence-level interval is -0.10 < Acp(K0pi+-) < 0.22 .Comment: 7 pages, 8 figures, submitted to Phys. Rev.

Genome-wide analysis of YY2 versus YY1 target genes

Yin Yang 1 (YY1) is a critical transcription factor controlling cell proliferation, development and DNA damage responses. Retrotranspositions have independently generated additional YY family members in multiple species. Although Drosophila YY1 [pleiohomeotic (Pho)] and its homolog [pleiohomeotic-like (Phol)] redundantly control homeotic gene expression, the regulatory contributions of YY1-homologs have not yet been examined in other species. Indeed, targets for the mammalian YY1 homolog YY2 are completely unknown. Using gene set enrichment analysis, we found that lentiviral constructs containing short hairpin loop inhibitory RNAs for human YY1 (shYY1) and its homolog YY2 (shYY2) caused significant changes in both shared and distinguishable gene sets in human cells. Ribosomal protein genes were the most significant gene set upregulated by both shYY1 and shYY2, although combined shYY1/2 knock downs were not additive. In contrast, shYY2 reversed the anti-proliferative effects of shYY1, and shYY2 particularly altered UV damage response, platelet-specific and mitochondrial function genes. We found that decreases in YY1 or YY2 caused inverse changes in UV sensitivity, and that their combined loss reversed their respective individual effects. Our studies show that human YY2 is not redundant to YY1, and YY2 is a significant regulator of genes previously identified as uniquely responding to YY1

Theoretical foundations of equity based foreign market entry decisions: a review of the literature and recommendations for future research

This paper reviews the theoretical foundations of the equity based foreign market entry (FME) decisions literature. We analyse 1055 academic FME papers published over four decades (1970–2013). We identify and analyse the theories that informed and guided FME research over time. Our review indicates that scholars have recently started to challenge some of the core assumptions of established theories, draw on and integrate insights from multiple theoretical perspectives which, in turn, generated a multiplicity of approaches for studying FME decisions and their performance outcomes. The paper discusses the explanatory power of the different theories, assesses the relevance of the different theoretical perspectives to our understanding of current FME phenomena and recommends directions for further research

Cerebrospinal fluid biomarker candidates associated with human WNV neuroinvasive disease

During the last decade, the epidemiology of WNV in humans has changed in the southern regions of Europe, with high incidence of West Nile fever (WNF) cases, but also of West Nile neuroinvasive disease (WNND). The lack of human vaccine or specific treatment against WNV infection imparts a pressing need to characterize indicators associated with neurological involvement. By its intimacy with central nervous system (CNS) structures, modifications in the cerebrospinal fluid (CSF) composition could accurately reflect CNS pathological process. Until now, few studies investigated the association between imbalance of CSF elements and severity of WNV infection. The aim of the present study was to apply the iTRAQ technology in order to identify the CSF proteins whose abundances are modified in patients with WNND. Forty-seven proteins were found modified in the CSF of WNND patients as compared to control groups, and most of them are reported for the first time in the context of WNND. On the basis of their known biological functions, several of these proteins were associated with inflammatory response. Among them, Defensin-1 alpha (DEFA1), a protein reported with anti-viral effects, presente

Changing patterns in diagnostic strategies and the treatment of blunt injury to solid abdominal organs

Background: In recent years there has been increasing interest shown in the nonoperative management (NOM) of blunt traumatic injury. The growing use of NOM for blunt abdominal organ injury has been made possible because of the progress made in the quality and availability of the multidetector computed tomography (MDCT) scan and the development of minimally invasive intervention options such as angioembolization. Aim: The purpose of this review is to describe the changes that have been made over the past decades in the management of blunt trauma to the liver, spleen and kidney. Results: The management of blunt abdominal injury has changed considerably. Focused assessment with sonography for trauma (FAST) examination has replaced diagnostic peritoneal lavage as diagnostic modality in the primary survey. MDCT scanning with intravenous contrast is now the gold standard diagnostic modality in hemodynamically stable patients with intra-abdominal fluid detected with FAST. One of the current discussions in the l erature is whether a whole body MDCT survey should be implemented in the primary survey. Conclusions The progress in imaging techniques has contributed to NOM being currently the treatment of choice for hemodynamically stable patients. Angioembolization can be used as an adjunct to NOM and has increased the succe