Rescue with an anti-inflammatory peptide of chickens infected H5N1 avian flu

Chickens suffering from avian flu caused by H5N1 influenza virus are destined to die within 2 days due to a systemic inflammatory response. Since HVJ infection (1,2) and influenza virus infection (3,4) cause infected cells to activate homologous serum complement, the systemic inflammatory response elicited could be attributed to the unlimited generation of C5a anaphylatoxin of the complement system, which is a causative peptide of serious inflammation. In monkeys inoculated with a lethal dose of LPS (4 mg/kg body weight), inhibition of C5a by an inhibitory peptide termed AcPepA (5) rescued these animals from serious septic shock which would have resulted in death within a day (6). Therefore, we tested whether AcPepA could also have a beneficial effect on chickens with bird flu. On another front, enhanced production of endothelin-1 (ET-1) and the activation of mast cells (MCs) have been implicated in granulocyte sequestration (7). An endothelin receptor derived antisense homology box peptide (8) designated ETR-P1/fl was shown to antagonize endothelin A receptor (ET-A receptor) (9) and reduce such inflammatory responses as endotoxin-shock (10) and hemorrhagic shock (11), thereby suppressing histamine release in the circulation (12). Thus, we also administered ETR-P1/fl to bird flu chickens expecting suppression of a systemic inflammatory response

Universality test of the charged Higgs boson couplings at the LHC and at B factories

Many extensions of the Standard Model (SM) of particle physics predict the existence of charged Higgs bosons with substantial couplings to SM particles, which would render them observable both directly at the LHC and indirectly at B-factories. For example, the charged Higgs boson couplings to fermions in two doublet Higgs models of type II, are proportional to the ratio of the two Higgs doublet vacuum expectation values (tan(beta)) and fermionic mass factors and could thus be substantial at large tan(beta) and/or for heavy fermions. In this work we perform a model-independent study of the charged Higgs boson couplings at the LHC and at B-factories for large values of tan(beta). We have shown that at high luminosity it is possible to measure the couplings of a charged Higgs boson to the third generation of quarks up to an accuracy of 10%. We further argue that by combining the possible measurements of the LHC and the B-factories, it is possible to perform a universality test of charged Higgs boson couplings to quarks.Comment: 20 pages, 7 figures, LaTeX (style changed to PRD format, text expanded, references added

Unparticle Searches Through Compton Scattering

We investigate the effects of unparticles on Compton scattering, e gamma -> e gamma based on a future e^+e^- linear collider such as the CLIC. For different polarization configurations, we calculate the lower limits of the unparticle energy scale Lambda_U for a discovery reach at the center of mass energies sqrt(s)=0.5 TeV- 3 TeV. It is shown that, especially, for smaller values of the mass dimension d, (1 <d <1.3), and for high energies and luminosities of the collider these bounds are very significant. As a stringent limit, we find Lambda_U>80 TeV for d<1.3 at sqrt(s)=3 TeV, and 1 ab^(-1) integrated luminosity per year, which is comparable with the limits calculated from other low and high energy physics implications.Comment: Table 1 and 2 have been combined as Table 1, references updated, minor typos have been correcte

Constraints from Solar and Reactor Neutrinos on Unparticle Long-Range Forces

We have investigated the impact of long-range forces induced by unparticle operators of scalar, vector and tensor nature coupled to fermions in the interpretation of solar neutrinos and KamLAND data. If the unparticle couplings to the neutrinos are mildly non-universal, such long-range forces will not factorize out in the neutrino flavour evolution. As a consequence large deviations from the observed standard matter-induced oscillation pattern for solar neutrinos would be generated. In this case, severe limits can be set on the infrared fix point scale, Lambda_u, and the new physics scale, M, as a function of the ultraviolet (d_UV) and anomalous (d) dimension of the unparticle operator. For a scalar unparticle, for instance, assuming the non-universality of the lepton couplings to unparticles to be of the order of a few per mil we find that, for d_UV=3 and d=1.1, M is constrained to be M > O(10^9) TeV (M > O(10^10) TeV) if Lambda_u= 1 TeV (10 TeV). For given values of Lambda_u and d, the corresponding bounds on M for vector [tensor] unparticles are approximately 100 [3/Sqrt(Lambda_u/TeV)] times those for the scalar case. Conversely, these results can be translated into severe constraints on universality violation of the fermion couplings to unparticle operators with scales which can be accessible at future colliders.Comment: 13 pages, 3 figures. Minor changes due to precision in numerical factors and correction in figure labels. References added. Conclusions remain unchange

Constraints on Astro-unparticle Physics from SN 1987A

SN 1987A observations have been used to place constraints on the interactions between standard model particles and unparticles. In this study we calculate the energy loss from the supernovae core through scalar, pseudo scalar, vector, pseudo vector unparticle emission from nuclear bremsstrahlung for degenerate nuclear matter interacting through one pion exchange. In order to examine the constraints on $d_{\cal U}=1$ we considered the emission of scalar, pseudo scalar, vector, pseudo vector and tensor through the pair annihilation process $e^+e^-\to {\cal U} \gamma$. In addition we have re-examined other pair annihilation processes. The most stringent bounds on the dimensionless coupling constants for $d_{\cal U} =1$ and $\Lambda_{\cal U}= m_Z$ are obtained from nuclear bremsstrahlung process for the pseudo scalar and pseudo-vector couplings $\bigl|\lambda^{\cal P}_{0,1}\bigr|\leq 4\times 10^{-11}$ and for tensor interaction, the best limit on dimensionless coupling is obtained from $e^+ e^-\to {\cal U} \gamma$ and we get $\bigl|\lambda^{\cal T}\bigr| \leq 6\times 10^{-6}$.Comment: 12 pages, 2 postscript figure

Simultaneous disruption of two DNA polymerases, Polη and Polζ, in Avian DT40 cells unmasks the role of Polη in cellular response to various DNA lesions

Replicative DNA polymerases are frequently stalled by DNA lesions. The resulting replication blockage is released by homologous recombination (HR) and translesion DNA synthesis (TLS). TLS employs specialized TLS polymerases to bypass DNA lesions. We provide striking in vivo evidence of the cooperation between DNA polymerase η, which is mutated in the variant form of the cancer predisposition disorder xeroderma pigmentosum (XP-V), and DNA polymerase ζ by generating POLη−/−/POLζ−/− cells from the chicken DT40 cell line. POLζ−/− cells are hypersensitive to a very wide range of DNA damaging agents, whereas XP-V cells exhibit moderate sensitivity to ultraviolet light (UV) only in the presence of caffeine treatment and exhibit no significant sensitivity to any other damaging agents. It is therefore widely believed that Polη plays a very specific role in cellular tolerance to UV-induced DNA damage. The evidence we present challenges this assumption. The phenotypic analysis of POLη−/−/POLζ−/− cells shows that, unexpectedly, the loss of Polη significantly rescued all mutant phenotypes of POLζ−/− cells and results in the restoration of the DNA damage tolerance by a backup pathway including HR. Taken together, Polη contributes to a much wide range of TLS events than had been predicted by the phenotype of XP-V cells

Interobserver Agreement Among Uveitis Experts on Uveitic Diagnoses:The Standardization of Uveitis Nomenclature Experience

• PURPOSE: To evaluate the interobserver agreement among uveitis experts on the diagnosis of the specific uveitic disease. • DESIGN: Interobserver agreement analysis. • METHODS: Five committees, each comprised of 9 individuals and working in parallel, reviewed cases from a preliminary database of 25 uveitic diseases, collected by disease, and voted independently online whether the case was the disease in question or not. The agreement statistic, κ, was calculated for the 36 pairwise comparisons for each disease, and a mean κ was calculated for each disease. After the independent online voting, committee consensus conference calls, using nominal group techniques, reviewed all cases not achieving supermajority agreement (> 75%) on the diagnosis in the online voting to attempt to arrive at a supermajority agreement. • RESULTS: A total of 5766 cases for the 25 diseases were evaluated. The overall mean κ for the entire project was 0.39, with disease-specific variation ranging from 0.23 to 0.79. After the formalized consensus conference calls to address cases that did not achieve supermajority agreement in the online voting, supermajority agreement overall was reached on approximately 99% of cases, with disease-specific variation ranging from 96% to 100%. • CONCLUSIONS: Agreement among uveitis experts on diagnosis is moderate at best but can be improved by discussion among them. These data suggest the need for validated and widely used classification criteria in the field of uveitis

Autoinflammatory periodic fever, immunodeficiency, and thrombocytopenia (PFIT) caused by mutation in actin-regulatory gene WDR1

The importance of actin dynamics in the activation of the inflammasome is becoming increasingly apparent. IL-1β, which is activated by the inflammasome, is known to be central to the pathogenesis of many monogenic autoinflammatory diseases. However, evidence from an autoinflammatory murine model indicates that IL-18, the other cytokine triggered by inflammasome activity, is important in its own right. In this model, autoinflammation was caused by mutation in the actin regulatory gene WDR1 We report a homozygous missense mutation in WDR1 in two siblings causing periodic fevers with immunodeficiency and thrombocytopenia. We found impaired actin dynamics in patient immune cells. Patients had high serum levels of IL-18, without a corresponding increase in IL-18-binding protein or IL-1β, and their cells also secreted more IL-18 but not IL-1β in culture. We found increased caspase-1 cleavage within patient monocytes indicative of increased inflammasome activity. We transfected HEK293T cells with pyrin and wild-type and mutated WDR1 Mutant protein formed aggregates that appeared to accumulate pyrin; this could potentially precipitate inflammasome assembly. We have extended the findings from the mouse model to highlight the importance of WDR1 and actin regulation in the activation of the inflammasome, and in human autoinflammation

Acquired resistance to anti-EGFR mAb ICR62 in cancer cells is accompanied by an increased EGFR expression, HER-2/HER-3 signalling and sensitivity to pan HER blockers

Our results provide a novel mechanistic insight into the development of acquired resistance to EGFR antibody-based therapy in colorectal cancer cells and justify further investigations on the therapeutic benefits of pan-HER family inhibitors in the treatment of colorectal cancer patients once acquired resistance to EGFR antibody-based therapy is developed

Genome-Wide Association Study of White Blood Cell Count in 16,388 African Americans: the Continental Origins and Genetic Epidemiology Network (COGENT)

Total white blood cell (WBC) and neutrophil counts are lower among individuals of African descent due to the common African-derived “null” variant of the Duffy Antigen Receptor for Chemokines (DARC) gene. Additional common genetic polymorphisms were recently associated with total WBC and WBC sub-type levels in European and Japanese populations. No additional loci that account for WBC variability have been identified in African Americans. In order to address this, we performed a large genome-wide association study (GWAS) of total WBC and cell subtype counts in 16,388 African-American participants from 7 population-based cohorts available in the Continental Origins and Genetic Epidemiology Network. In addition to the DARC locus on chromosome 1q23, we identified two other regions (chromosomes 4q13 and 16q22) associated with WBC in African Americans (P<2.5×10−8). The lead SNP (rs9131) on chromosome 4q13 is located in the CXCL2 gene, which encodes a chemotactic cytokine for polymorphonuclear leukocytes. Independent evidence of the novel CXCL2 association with WBC was present in 3,551 Hispanic Americans, 14,767 Japanese, and 19,509 European Americans. The index SNP (rs12149261) on chromosome 16q22 associated with WBC count is located in a large inter-chromosomal segmental duplication encompassing part of the hydrocephalus inducing homolog (HYDIN) gene. We demonstrate that the chromosome 16q22 association finding is most likely due to a genotyping artifact as a consequence of sequence similarity between duplicated regions on chromosomes 16q22 and 1q21. Among the WBC loci recently identified in European or Japanese populations, replication was observed in our African-American meta-analysis for rs445 of CDK6 on chromosome 7q21 and rs4065321 of PSMD3-CSF3 region on chromosome 17q21. In summary, the CXCL2, CDK6, and PSMD3-CSF3 regions are associated with WBC count in African American and other populations. We also demonstrate that large inter-chromosomal duplications can result in false positive associations in GWAS