System Evolution, Feedback and Compliant Architectures

Proceedings, International Workshop on Feedback and Evolution in Software and Business Processes (FEAST 2000), Imperial College, London. Supported by EPSRCPostprintNon peer reviewe

Safety and Immunogenicity of a Replication-Defective Adenovirus Type 5 HIV Vaccine in Ad5-Seronegative Persons: A Randomized Clinical Trial (HVTN 054)

BACKGROUND: Individuals without prior immunity to a vaccine vector may be more sensitive to reactions following injection, but may also show optimal immune responses to vaccine antigens. To assess safety and maximal tolerated dose of an adenoviral vaccine vector in volunteers without prior immunity, we evaluated a recombinant replication-defective adenovirus type 5 (rAd5) vaccine expressing HIV-1 Gag, Pol, and multiclade Env proteins, VRC-HIVADV014-00-VP, in a randomized, double-blind, dose-escalation, multicenter trial (HVTN study 054) in HIV-1-seronegative participants without detectable neutralizing antibodies (nAb) to the vector. As secondary outcomes, we also assessed T-cell and antibody responses. METHODOLOGY/PRINCIPAL FINDINGS: Volunteers received one dose of vaccine at either 10(10) or 10(11) adenovector particle units, or placebo. T-cell responses were measured against pools of global potential T-cell epitope peptides. HIV-1 binding and neutralizing antibodies were assessed. Systemic reactogenicity was greater at the higher dose, but the vaccine was well tolerated at both doses. Although no HIV infections occurred, commercial diagnostic assays were positive in 87% of vaccinees one year after vaccination. More than 85% of vaccinees developed HIV-1-specific T-cell responses detected by IFN-γ ELISpot and ICS assays at day 28. T-cell responses were: CD8-biased; evenly distributed across the three HIV-1 antigens; not substantially increased at the higher dose; and detected at similar frequencies one year following injection. The vaccine induced binding antibodies against at least one HIV-1 Env antigen in all recipients. CONCLUSIONS/SIGNIFICANCE: This vaccine appeared safe and was highly immunogenic following a single dose in human volunteers without prior nAb against the vector. TRIAL REGISTRATION: ClinicalTrials.gov NCT00119873

Axion Protection from Flavor

The QCD axion fails to solve the strong CP problem unless all explicit PQ violating, Planck-suppressed, dimension n<10 operators are forbidden or have exponentially small coefficients. We show that all theories with a QCD axion contain an irreducible source of explicit PQ violation which is proportional to the determinant of the Yukawa interaction matrix of colored fermions. Generically, this contribution is of low operator dimension and will drastically destabilize the axion potential, so its suppression is a necessary condition for solving the strong CP problem. We propose a mechanism whereby the PQ symmetry is kept exact up to n=12 with the help of the very same flavor symmetries which generate the hierarchical quark masses and mixings of the SM. This "axion flavor protection" is straightforwardly realized in theories which employ radiative fermion mass generation and grand unification. A universal feature of this construction is that the heavy quark Yukawa couplings are generated at the PQ breaking scale.Comment: 16 pages, 2 figure

Extremely high He isotope ratios in MORB-source mantle from the proto-Iceland plume

The high &lt;sup&gt;3&lt;/sup&gt;He/&lt;sup&gt;4&lt;/sup&gt;He ratio of volcanic rocks thought to be derived from mantle plumes is taken as evidence for the existence of a mantle reservoir that has remained largely undegassed since the Earth's accretion. The helium isotope composition of this reservoir places constraints on the origin of volatiles within the Earth and on the evolution and structure of the Earth's mantle. Here we show that olivine phenocrysts in picritic basalts presumably derived from the proto-Iceland plume at Baffin Island, Canada, have the highest magmatic &lt;sup&gt;3&lt;/sup&gt;He/&lt;sup&gt;4&lt;/sup&gt;He ratios yet recorded. A strong correlation between &lt;sup&gt;3&lt;/sup&gt;He/&lt;sup&gt;4&lt;/sup&gt;He and &lt;sup&gt;87&lt;/sup&gt;Sr/&lt;sup&gt;86&lt;/sup&gt;Sr, &lt;sup&gt;143&lt;/sup&gt;Nd/&lt;sup&gt;144&lt;/sup&gt;Nd and trace element ratios demonstrate that the &lt;sup&gt;3&lt;/sup&gt;He-rich end-member is present in basalts that are derived from large-volume melts of depleted upper-mantle rocks. This reservoir is consistent with the recharging of depleted upper-mantle rocks by small volumes of primordial volatile-rich lower-mantle material at a thermal boundary layer between convectively isolated reservoirs. The highest &lt;sup&gt;3&lt;/sup&gt;He/&lt;sup&gt;4&lt;/sup&gt;He basalts from Hawaii and Iceland plot on the observed mixing trend. This indicates that a &lt;sup&gt;3&lt;/sup&gt;He-recharged depleted mantle (HRDM) reservoir may be the principal source of high &lt;sup&gt;3&lt;/sup&gt;He/&lt;sup&gt;4&lt;/sup&gt;He in mantle plumes, and may explain why the helium concentration of the 'plume' component in ocean island basalts is lower than that predicted for a two-layer, steady-state model of mantle structure

Identification and validation of oncologic miRNA biomarkers for Luminal A-like breast cancer

Introduction: Breast cancer is a common disease with distinct tumor subtypes phenotypically characterized by ER and HER2/neu receptor status. MiRNAs play regulatory roles in tumor initiation and progression, and altered miRNA expression has been demonstrated in a variety of cancer states presenting the potential for exploitation as cancer biomarkers. Blood provides an excellent medium for biomarker discovery. This study investigated systemic miRNAs differentially expressed in Luminal A-like (ER+PR+HER2/neu-) breast cancer and their effectiveness as oncologic biomarkers in the clinical setting. Methods: Blood samples were prospectively collected from patients with Luminal A-like breast cancer (n=54) and controls (n=56). RNA was extracted, reverse transcribed and subjected to microarray analysis (n=10 Luminal A-like; n=10 Control). Differentially expressed miRNAs were identified by artificial neural network (ANN) data-mining algorithms. Expression of specific miRNAs was validated by RQ-PCR (n=44 Luminal A; n=46 Control) and potential relationships between circulating miRNA levels and clinicopathological features of breast cancer were investigated. Results: Microarray analysis identified 76 differentially expressed miRNAs. ANN revealed 10 miRNAs for further analysis ( miR-19b, miR-29a, miR-93, miR-181a, miR-182, miR-223, miR-301a, miR-423-5p, miR-486-5 and miR-652 ). The biomarker potential of 4 miRNAs ( miR-29a, miR-181a , miR-223 and miR-652 ) was confirmed by RQ-PCR, with significantly reduced expression in blood of women with Luminal A-like breast tumors compared to healthy controls (p=0.001, 0.004, 0.009 and 0.004 respectively). Binary logistic regression confirmed that combination of 3 of these miRNAs ( miR-29a, miR-181a and miR-652 ) could reliably differentiate between cancers and controls with an AUC of 0.80. Conclusion: This study provides insight into the underlying molecular portrait of Luminal A-like breast cancer subtype. From an initial 76 miRNAs, 4 were validated with altered expression in the blood of women with Luminal A-like breast cancer. The expression profiles of these 3 miRNAs, in combination with mammography, has potential to facilitate accurate subtype- specific breast tumor detection