A concise and convergent (formal) total synthesis of huperzine A

The first convergent synthesis of the tricyclic skeleton of huperzine A is described and includes, as the key step, an efficient regioselective intramolecular Heck reaction of 2-(tert-butyldimethylsillyoxymethyl)-6-(2-methoxy-5-bromopyridin-6-yl)methylcyclohex-2-enol.

BRCA1 Regulates IFN-γ Signaling through a Mechanism Involving the Type I IFNs

BRCA1 encodes a tumor suppressor gene that is mutated in the germ line of women with a genetic predisposition to breast and ovarian cancer. BRCA1 has been implicated in a number of important cellular functions including DNA damage repair, transcriptional regulation, cell cycle control, and ubiquitination. Using an Affymetrix U95A microarray, IRF-7 was identified as a BRCA1 transcriptional target and was also shown to be synergistically up-regulated by BRCA1 specifically in the presence of IFN-gamma, coincident with the synergistic induction of apoptosis. We show that BRCA1, signal transducer and activator of transcription (STAT)-1, and STAT2 are all required for the induction of IRF-7 following stimulation with IFN-gamma. We also show that the induction of IRF-7 by BRCA1 and IFN-gamma is dependent on the type I IFNs, IFN-alpha and IFN-beta. We show that BRCA1 is required for the up-regulation of STAT1, STAT2, and the type I IFNs in response to IFN-gamma. We show that BRCA1 is localized at the promoters of the molecules involved in type I IFN signaling leading to their up-regulation. Blocking this intermediary type I IFN step using specific antisera shows the requirement for IFN-alpha and IFN-beta in the induction of IRF-7 and apoptosis. Finally, we outline a mechanism for the BRCA1/IFN-gamma regulation of target genes involved in the innate immune response, which is dependent on type I IFN signaling.

Molecular Computational Elements Encode Large Populations of Small Objects

Since the introduction of molecular computation1, 2, experimental molecular computational elements have grown3, 4, 5 to encompass small-scale integration6, arithmetic7 and games8, among others. However, the need for a practical application has been pressing. Here we present molecular computational identification (MCID), a demonstration that molecular logic and computation can be applied to a widely relevant issue. Examples of populations that need encoding in the microscopic world are cells in diagnostics or beads in combinatorial chemistry (tags). Taking advantage of the small size9 (about 1 nm) and large 'on/off' output ratios of molecular logic gates and using the great variety of logic types, input chemical combinations, switching thresholds and even gate arrays in addition to colours, we produce unique identifiers for members of populations of small polymer beads (about 100 m) used for synthesis of combinatorial libraries10, 11. Many millions of distinguishable tags become available. This method should be extensible to far smaller objects, with the only requirement being a 'wash and watch' protocol12. Our focus on converting molecular science into technology concerning analog sensors13, 14, turns to digital logic devices in the present work.

'The Aftermath of the Annan Plan Referendums' Cross-Voting Moderation for Cyprus

This article examines recent developments in the Cyprus negotiations and suggests a number of changes to the proposed electoral system. Specifically, cross-voting and other electoral methods that encourage coalition-building across ethnic communities might add significantly to the functionality of the Annan Plan. Combined with other innovative mechanisms already in the plan, cross-voting could force political parties to seriously take into account the interests and concerns of the two Cypriot communities, an element that is currently missing from both the Turkish Cypriot (TC) and Greek Cypriot (GC) political systems. Special conditions on the island, as well as the way most political parties operated in the critical pre-April 2004 referendum period, suggest the need for this amendment. Although this study respects the consociational logic of the Annan Plan, it supplements consociationalism with elements that foster integration and inter-dependence between the two communities and their voters. The article also reviews the postreferendum developments in Cyprus which might have worrisome future implications, not only for its two communities, but also for EU enlargement in general. Cyprus both holds one of the keys to Turkey's entrance into the EU and is a litmus test for the Euro-Atlantic nexus and its capacity to pacify and integrate ethnically divided societies in Europe and elsewhere.

Proteomic Analysis of Recurrent Joint Inflammation in Juvenile Idiopathic Arthritis

The synovial fluid proteome in juvenile idiopathic arthritis was investigated to isolate joint-specific biomarkers that are expressed in patients displaying recurrent joint inflammation. To identify the synovial specific proteome, matched synovial fluid and plasma samples were subjected to protein separation by 2-dimension electrophoresis (2DE). Forty-three protein spots, overexpressed in the joint, were identified. Synovial fluids from children with single-event knee joint inflammation were then compared with a group with recurrent knee disease. Nine synovial specific proteins were significantly differentially expressed in the recurrent group. Proteolytic fragments of collagen X, fibrin beta-chain, and T-cell receptor alpha-region have been identified among this protein cluster. Putative biomarkers, overexpressed in the joint and differentially expressed in children with recurrent joint inflammation, have been identified. These proteins may play a significant role determining the pathological state within the chronically inflamed joint and influence disease progression in JIA. This is the first study of the synovial proteome in children.

The Tragedy of Darfur and the Limits of the Responsibility to Protect

The view that states which claim sovereign status must comply with the responsibility to protect their own citizens is gaining ground in international politics. When a state is unable or unwilling to meet this responsibility, the international community is justified in intervening militarily to end widespread human rights violations. This article argues that a diffuse responsibility to protect, as currently conceived, may have important negative consequences. By using the ongoing tragedy of Darfur as an example, the article argues that the responsibility to protect is reactive and focused on the short term, contributes to the outbreak of violence and perversely provides repressed groups with a further incentive to continue their armed struggle after war breaks out. The tragedy of Darfur shows that effective protection requires case-specific policies aimed at prevention, democratization and economic and political development.