Limited Liability Multilateralism: The American Military, Armed Intervention, and IOs

Under what conditions and for what reasons do American leaders seek the endorsement of relevant international organizations (IOs) such as the UN or NATO for prospective military interventions? My central hypothesis is that U.S. government efforts to obtain IO approval for prospective interventions are frequently the result of significant bureaucratic deliberations and bargaining between hawkish policy leaders who emphasize the likely positive payoffs of a prompt use of force, on the one side, and skeptical officials--with the top military brass and war veterans in senior policy positions at the forefront--who highlight its potential downsides and long-term costs, on the other. The military leaders--the chairman and vice chairman of the Joint Chiefs of Staff (JCS), the regional combatant commanders, and senior planners on the Joint Staff in Washington--are generally skeptical of humanitarian and other "idealist" interventions that aim to change the domestic politics of foreign countries; they naturally tend to consider all the potential downsides of intervention, given their operational focus; and they usually worry more than activist civilian policy officials about public and congressional support for protracted engagements. Assuming that the military leaders are not merely stooges of the civilian leadership, they are at first likely to altogether resist a prospective intervention, when they believe that no vital American interests are at stake and fear an open-ended deployment of U.S. troops. Given the military's professional expertise and their standing in American society, they come close to holding a de facto veto over prospective interventions they clearly oppose. I hypothesize that confronted with such great initial reluctance or opposition on the part of the military brass, civilian advocates of intervention from other government agencies will seek inter alia to obtain an advance endorsement from relevant IOs, so as to lock in international support and thereby reassure the military and their bureaucratic allies that the long-term costs to the United States in terms of postwar peacekeeping and stabilization will be limited. That, in turn, can be expected to help forge a winning bureaucratic coalition in Washington and persuade the president to authorize military action. United States multilateralism for military interventions is thus often a genuine policy resultant--the outcome of sustained bureaucratic deliberations and bargaining--and it may not actually reflect the initial preferences of any particular government agency or senior official

Stochasticity of Cosmic Rays from Supernova Remnants and the Ionization Rates in Molecular Clouds

Cosmic rays are the only agent able to penetrate into the interior of dense molecular clouds. Depositing (part of) their energy through ionisation, cosmic rays play an essential role in determining the physical and chemical evolution of star-forming regions. To a first approximation their effect can be quantified by the cosmic-ray induced ionization rate. Interestingly, theoretical estimates of the ionization rate assuming the cosmic-ray spectra observed in the local interstellar medium result in an ionization rate that is one to two orders of magnitude below the values inferred from observations. However, due to the discrete nature of sources, the local spectra of MeV cosmic rays are in general not representative for the spectra elsewhere in the Galaxy. Such stochasticity effects have the potential of reconciling modelled ionization rates with measured ones. Here, we model the distribution of low-energy cosmic-ray spectra expected from a statistical population of supernova remnants in the Milky Way. The corresponding distribution for the ionization rate is derived and confronted with data. We find that the stochastic uncertainty helps with explaining the surprisingly high ionization rates observed in many molecular clouds.Comment: 14 pages, 5 figure

Prevalence and time course of post-stroke pain: A multicenter prospective hospital-based study

OBJECTIVE: Pain prevalence data for patients at various stages after stroke. DESIGN: Repeated cross-sectional, observational epidemiological study. SETTING: Hospital-based multicenter study. SUBJECTS: Four hundred forty-three prospectively enrolled stroke survivors. METHODS: All patients underwent bedside clinical examination. The different types of post-stroke pain (central post-stroke pain, musculoskeletal pains, shoulder pain, spasticity-related pain, and headache) were diagnosed with widely accepted criteria during the acute, subacute, and chronic stroke stages. Differences among the three stages were analyzed with χ(2)-tests. RESULTS: The mean overall prevalence of pain was 29.56% (14.06% in the acute, 42.73% in the subacute, and 31.90% in the chronic post-stroke stage). Time course differed significantly according to the various pain types (P < 0.001). The prevalence of musculoskeletal and shoulder pain was higher in the subacute and chronic than in the acute stages after stroke; the prevalence of spasticity-related pain peaked in the chronic stage. Conversely, headache manifested in the acute post-stroke stage. The prevalence of central post-stroke pain was higher in the subacute and chronic than in the acute post-stroke stage. Fewer than 25% of the patients with central post-stroke pain received drug treatment. CONCLUSIONS: Pain after stroke is more frequent in the subacute and chronic phase than in the acute phase, but it is still largely undertreated

CRISPR/Cas9-Mediated In Situ Correction of LAMB3 Gene in Keratinocytes Derived from a Junctional Epidermolysis Bullosa Patient

Deficiency of basement membrane heterotrimeric laminin 332 component, coded by LAMA3, LAMB3, and LAMC2 genes, causes junctional epidermolysis bullosa (JEB), a severe skin adhesion defect. Herein, we report the first application of CRISPR/Cas9-mediated homology direct repair (HDR) to in situ restore LAMB3 expression in JEB keratinocytes in vitro and in immunodeficient mice transplanted with genetically corrected skin equivalents. We packaged an adenovector carrying Cas9/guide RNA (gRNA) tailored to the intron 2 of LAMB3 gene and an integration defective lentiviral vector bearing a promoterless quasi-complete LAMB3 cDNA downstream a splice acceptor site and flanked by homology arms. Upon genuine HDR, we exploited the in vitro adhesion advantage of laminin 332 production to positively select LAMB3-expressing keratinocytes. HDR and restored laminin 332 expression were evaluated at single-cell level. Notably, monoallelic-targeted integration of LAMB3 cDNA was sufficient to in vitro recapitulate the adhesive property, the colony formation typical of normal keratinocytes, as well as their cell growth. Grafting of genetically corrected skin equivalents onto immunodeficient mice showed a completely restored dermal-epidermal junction. This study provides evidence for efficient CRISPR/Cas9-mediated in situ restoration of LAMB3 expression, paving the way for ex vivo clinical application of this strategy to laminin 332 deficiency

Flow cytometric immunobead assay for detection of BCR-ABL1 fusion proteins in chronic myleoid leukemia: Comparison with FISH and PCR techniques

Chronic Myeloid Leukemia (CML) is characterized by a balanced translocation juxtaposing the Abelson (ABL) and breakpoint cluster region (BCR) genes. The resulting BCR-ABL1 oncogene leads to increased proliferation and survival of leukemic cells. Successful treatment of CML has been accompanied by steady improvements in our capacity to accurately and sensitively monitor therapy response. Currently, measurement of BCR-ABL1 mRNA transcript levels by real-time quantitative PCR (RQ-PCR) defines critical response endpoints. An antibody-based technique for BCR-ABL1 protein recognition could be an attractive alternative to RQ-PCR. To date, there have been no studies evaluating whether flow-cytometry based assays could be of clinical utility in evaluating residual disease in CML patients. Here we describe a flow-cytometry assay that detects the presence of BCR-ABL1 fusion proteins in CML lysates to determine the applicability, reliability, and specificity of this method for both diagnosis and monitoring of CML patients for initial response to therapy. We show that: i) CML can be properly diagnosed at onset, (ii) follow-up assessments show detectable fusion protein (i.e. relative mean fluorescent intensity, rMFI%&gt;1) when BCR-ABL1IS transcripts are between 1-10%, and (iii) rMFI% levels predict CCyR as defined by FISH analysis. Overall, the FCBA assay is a rapid technique, fully translatable to the routine management of CML patients

A LYSO Calorimeter for the SuperB Factory

The SuperB project is an asymmetric e+e? accelerator of 1036cm?2s?1 luminosity, capable of collecting a data sample of 50?75 ab?1 in five years of running. The SuperB electromagnetic calorimeter (EMC), that will be described in this paper, provides energy and direction measurement of photons and electrons, and is used for identification of electrons versus other charged particles. In particular we will present its design, geometry study and related simulations, as well as R&D on LYSO crystals, a project for the mechanical structure and development on readout and electronics. A matrix of 6 crystals has been tested this year June 2010 at the Beam Test Facility of Frascati (BTF) at energies between 200 MeV and 500 MeV, and a beam test with the complete prototype of 25 crystals is foreseen at CERN in October 2010 to cover the energy range between 500 MeV and 7 GeV

Biocompatible cellulose nanocrystal-based Trojan horse enables targeted delivery of nano-Au radiosensitizers to triple negative breast cancer cells

: A hybrid cellulose-based programmable nanoplatform for applications in precision radiation oncology is described. Here, sugar heads work as tumor targeting moieties and steer the precise delivery of radiosensitizers, i.e. gold nanoparticles (AuNPs) into triple negative breast cancer (TNBC) cells. This "Trojan horse" approach promotes a specific and massive accumulation of radiosensitizers in TNBC cells, thus avoiding the fast turnover of small-sized AuNPs and the need for high doses of AuNPs for treatment. Application of X-rays resulted in a significant increase of the therapeutic effect while delivering the same dose, showing the possibility to use roughly half dose of X-rays to obtain the same radiotoxicity effect. These data suggest that this hybrid nanoplatform acts as a promising tool for applications in enhancing cancer radiotherapy effects with lower doses of X-rays

Conformational switch and multiple supramolecular structures of a newly identified self-assembling protein-mimetic peptide from Pseudomonas aeruginosa YeaZ protein

Protein-mimetic peptides (PMPs) are shorter sequences of self-assembling proteins, that represent remarkable building blocks for the generation of bioinspired functional supramolecular structures with multiple applications. The identification of novel aminoacidic sequences that permit the access to valuable biocompatible materials is an attractive area of research. In this work, in silico analysis of the Pseudomonas aeruginosa YeaZ protein (PaYeaZ) led to the identification of a tetradecapeptide that represents the shortest sequence responsible for the YeaZ-YeaZ dimer formation. Based on its sequence, an innovative 20-meric peptide, called PMP-2, was designed, synthesized, and characterized in terms of secondary structure and self-assembly properties. PMP-2 conserves a helical character and self-assembles into helical nanofibers in non-polar solvents (DMSO and trifluoroethanol), as well as in dilute (0.5 mM) aqueous solutions. In contrast, at higher concentrations (&gt;2 mM) in water, a conformational transition from α-helix to β-sheet occurs, which is accompanied by the Protein-mimetic peptide aggregation into 2D-sheets and formation supramolecular gel in aqueous environment. Our findings reveal a newly identified Protein-mimetic peptide that could turn as a promising candidate for future material applications

Microenvironmental regulation of the IL-23R/IL-23 axis overrides chronic lymphocytic leukemia indolence

Although the progression of chronic lymphocytic leukemia (CLL) requires the cooperation of the microenvironment, the exact cellular and molecular mechanisms involved are still unclear. We investigated the interleukin (IL)-23 receptor (IL-23R)/IL-23 axis and found that circulating cells from early-stage CLL patients with shorter time-to-treatment, but not of those with a more benign course, expressed a defective form of the IL-23R complex lacking the IL-12R beta 1 chain. However, cells from both patient groups expressed the complete IL-23R complex in tissue infiltrates and could be induced to express the IL-12R. 1 chain when cocultured with activated T cells or CD40L(+) cells. CLL cells activated in vitro in this context produced IL-23, a finding that, together with the presence of IL-23 in CLL lymphoid tissues, suggests the existence of an autocrine/paracrine loop inducing CLL cell proliferation. Interference with the IL-23R/IL-23 axis using an anti-IL-23p19 antibody proved effective in controlling disease onset and expansion in xenografted mice, suggesting potential therapeutic strategies