Immunogene therapy with fusogenic nanoparticles modulates macrophage response to Staphylococcus aureus.

The incidence of adverse effects and pathogen resistance encountered with small molecule antibiotics is increasing. As such, there is mounting focus on immunogene therapy to augment the immune system's response to infection and accelerate healing. A major obstacle to in vivo gene delivery is that the primary uptake pathway, cellular endocytosis, results in extracellular excretion and lysosomal degradation of genetic material. Here we show a nanosystem that bypasses endocytosis and achieves potent gene knockdown efficacy. Porous silicon nanoparticles containing an outer sheath of homing peptides and fusogenic liposome selectively target macrophages and directly introduce an oligonucleotide payload into the cytosol. Highly effective knockdown of the proinflammatory macrophage marker IRF5 enhances the clearance capability of macrophages and improves survival in a mouse model of Staphyloccocus aureus pneumonia

New Developments in Treacherous Points of Light-Front Dynamics

Light-front dynamics(LFD) plays an important role in hadron phenomenology. Last few years, however, it has been emphasized that treacherous points such as zero-mode contributions should be taken into account for successful LFD applications to hadron phenomenology. We discuss examples of treacherous points and present new progresses made last few years to handle them correctly.Comment: 5 pages, espcrc1.sty. proceedings of FB XVIII (August 2006, Brazil), to be published in Nucl. Phys.

Insight into highly conserved H1 subtype-specific epitopes in influenza virus hemagglutinin

Influenza viruses continuously undergo antigenic changes with gradual accumulation of mutations in hemagglutinin (HA) that is a major determinant in subtype specificity. The identification of conserved epitopes within specific HA subtypes gives an important clue for developing new vaccines and diagnostics. We produced and characterized nine monoclonal antibodies that showed significant neutralizing activities against H1 subtype influenza viruses, and determined the complex structure of HA derived from a 2009 pandemic virus A/Korea/01/2009 (KR01) and the Fab fragment from H1-specific monoclonal antibody GC0587. The overall structure of the complex was essentially identical to the previously determined KR01 HA-Fab0757 complex structure. Both Fab0587 and Fab0757 recognize readily accessible head regions of HA, revealing broadly shared and conserved antigenic determinants among H1 subtypes. The beta-strands constituted by Ser110-Glu115 and Lys169-Lys170 form H1 epitopes with distinct conformations from those of H1 and H3 HA sites. In particular, Glu112, Glu115, Lys169, and Lys171 that are highly conserved among H1 subtype HAs have close contacts with HCDR3 and LCDR3. The differences between Fab0587 and Fab0757 complexes reside mainly in HCDR3 and LCDR3, providing distinct antigenic determinants specific for 1918 pdm influenza strain. Our results demonstrate a potential key neutralizing epitope important for H1 subtype specificity in influenza virus

Pluripotent Transcription Factors Possess Distinct Roles in Normal versus Transformed Human Stem Cells

Cancer and normal stem cells (SCs) share proliferative properties of self-renewal and expression of key transcription factors (TFs). Despite similar TF identities, the functional role of specific TFs responsible for retaining SC state has yet to be examined in cancer.Here, we compare the role of Oct4 and Nanog, two-core pluripotent TFs, in transformed (t-hPSCs), and normal human pluripotent stem cells (hPSCs). Unlike normal SCs, self-renewal and survival of t-hPSCs were found to be independent of Oct4. In contrast, t-hPSCs exhibit hypersensitivity to reduction in Nanog and demonstrate complete loss of self-renewal coupled with apoptosis. Dual and sequential knockdown of Oct4 and Nanog revealed that sensitivity of t-hPSCs to Nanog was Oct4 dependent.Our study indicates a bifurcation for the role of two-core SC and cancer related TFs in self-renewal and survival processes. We suggest that the divergent roles of these TFs establish a paradigm to develop novel therapeutics towards selective destruction of aggressive tumors harboring cancer stem cells (CSCs) with similar molecular signatures

Bedside prediction of right subclavian venous catheter insertion length

AbstractBackground and objectiveThe present study aimed to evaluate whether right subclavian vein (SCV) catheter insertion depth can be predicted reliably by the distances from the SCV insertion site to the ipsilateral clavicular notch directly (denoted as I-IC), via the top of the SCV arch, or via the clavicle (denoted as I-T-IC and I-C-IC, respectively).MethodIn total, 70 SCV catheterizations were studied. The I-IC, I-T-IC, and I-C-IC distances in each case were measured after ultrasound-guided SCV catheter insertion. The actual length of the catheter between the insertion site and the ipsilateral clavicular notch, denoted as L, was calculated by using chest X-ray.ResultsL differed from the I-T-IC, I-C-IC, and I-IC distances by 0.14±0.53, 2.19±1.17, and −0.45±0.68cm, respectively. The mean I-T-IC distance was the most similar to the mean L (intraclass correlation coefficient=0.89). The mean I-IC was significantly shorter than L, while the mean I-C-IC was significantly longer. Linear regression analysis provided the following formula: Predicted SCV catheter insertion length (cm)=−0.037+0.036×Height (cm)+0.903×I-T-IC (cm) (adjusted r2=0.64).ConclusionThe I-T-IC distance may be a reliable bedside predictor of the optimal insertion length for a right SCV cannulation

Fracture of a Polyethylene Tibial Post in a Scorpio Posterior-Stabilized Knee Prosthesis

We report the case of a polyethylene tibial post fracture in a 72-year-old woman 14 months after a Scorpio posterior-stabilized (PS) total knee arthroplasty. The polyethylene wear was found around the fracture site of the post, especially over the anterior aspect of the post base. The failure mechanism of the post fracture in the present case was anterior impingement with excessive wear over the base of the anterior aspect of the tibial post, which became a stress-riser of post and cam articulation. This is the first report of a polyethylene tibial post fracture of a Scorpio PS prosthesis

DETC2005-84974 STRESS ANALYSIS AND LIFE ASSESSMENT OF ROTOR AND RETAINING RING OF GENERATOR FOR FOSSIL POWER PLANT

Increased rating of the generator capacity can be achieved by either increasing length or diameter of generator rotor body. Increasing the length of the rotor diameter should ensure the dynamic stability. On the other hand, increasing rotor diameter should satisfy the strength limit of current rotor material. ABSTRACT In addition to the higher centrifugal forces during normal operation in 3600 rpm, a generator rotor body is subjected to the contact pressures from shrink-fit between generator rotor and retaining ring. To obtain the structural reliability and life assessment of the generator, the finite element models were developed and structural analyses were carried out. The stress distributions and the critical locations of the rotor body were identified. Further, the fatigue life is performed to estimate the remaining life of generator. The critical crack size and probability of failure are also evaluated based on the analysis results. The critical sizes of a crack of generator are predicted using linear elastic fracture mechanics. These results will be applied to the development of a larger 1000MW capacity generator. This paper presents both stress analysis and life assessment results of the new 1000MW generator rotor assembly. The baseline design of the 800MW generator rotor was also evaluated for verifying the reliability of the analysis results. Two load cases, the contact pressures from shrink-fit between rotor and retaining ring and the centrifugal forces during normal operation in 3600 rpm, were considered. To obtain the structural reliability and life assessment of the generator, the finite element models were developed and structural analyses were carried out. The stress distributions and the critical locations of the rotor body were identified. Further, the fatigue life is performed to estimate the remaining life of generator. The critical crack size and probability of failure are also evaluated based on the analysis results INTRODUCTION In rapid technology advancement of the fossil power plant, it is inevitable that the output of a given turbine generator frame size will be increased from time to time. This has required redesign of the generator to keep pace with the increased rating. For turbine generators, increased rating presents challenges for designer. The designers to ensure that the new design can be satisfied the performance capabilities and electrical rating requirements, while maintaining mechanical, thermal and magnetic limits. These challenges come out largely as a result of increasing stresses, vibrational instability, fatigue and stress corrosion crack. To obtain the structural reliability and life assessment of the new generator, stress analyses, fatigue life assessment, and critical crack evaluation are required and the finite element analysis for the generator rotor assembly is used for this purpose