RNA interference therapeutics targeting angiotensinogen ameliorate preeclamptic phenotype in rodent models

Preeclampsia, with the hallmark features of new-onset hypertension and proteinuria after 20 weeks of gestation, is a major cause of fetal and maternal morbidity and mortality. Studies have demonstrated a role for the renin-angiotensin system (RAS) in its pathogenesis; however, small-molecule RAS blockers are contraindicated because of fetal toxicity. We evaluated whether siRNA targeting maternal hepatic angiotensinogen (Agt) could ameliorate symptoms of preeclampsia without adverse placental or fetal effects in 2 rodent models. The first model used a cross of females expressing human Agt with males expressing human renin, resulting in upregulation of the circulating and uteroplacental RAS. The second model induced ischemia/reperfusion injury and subsequent local and systemic inflammation by surgically reducing placental blood flow midgestation (reduced uterine perfusion pressure [RUPP]). These models featured hypertension, proteinuria, and fetal growth restriction, with altered biomarkers. siRNA treatment ameliorated the preeclamptic phenotype in both models, reduced blood pressure, and improved intrauterine growth restriction, with no observed deleterious effects on the fetus. Treatment also improved the angiogenic balance and proteinuria in the transgenic model, and it reduced angiotensin receptor activating antibodies in both. Thus, an RNAi therapeutic targeting Agt ameliorated the clinical sequelae and improved fetal outcomes in 2 rodent models of preeclampsia

Generation of a wave packet tailored to efficient free space excitation of a single atom

We demonstrate the generation of an optical dipole wave suitable for the process of efficiently coupling single quanta of light and matter in free space. We employ a parabolic mirror for the conversion of a transverse beam mode to a focused dipole wave and show the required spatial and temporal shaping of the mode incident onto the mirror. The results include a proof of principle correction of the parabolic mirror's aberrations. For the application of exciting an atom with a single photon pulse we demonstrate the creation of a suitable temporal pulse envelope. We infer coupling strengths of 89% and success probabilities of up to 87% for the application of exciting a single atom for the current experimental parameters.Comment: to be published in Europ. Phys. J.

Subclone eradication analysis identifies targets for enhanced cancer therapy and reveals L1 retrotransposition as a dynamic source of cancer heterogeneity

Treatment-eradicated cancer subclones have been reported in leukemia and have recently been detected in solid tumors. Here we introduce Differential Subclone Eradication and Resistance Analysis (DSER), a method developed to identify molecular targets for improved therapy by direct comparison of genomic features of eradicated and resistant subclones in pre- and post-treatment samples from a patient with BRCA2-deficient metastatic prostate cancer. FANCI and EYA4 were identified as candidate DNA repair-related targets for converting subclones from resistant to eradicable, and RNAi-mediated depletion of FANCI confirmed it as a potential target. The EYA4 alteration was associated with adjacent L1 transposon insertion during cancer evolution upon treatment, raising questions surrounding the role of therapy in L1 activation. Both carboplatin and enzalutamide turned on L1 transposon machinery in LNCaP and VCaP but not in PC-3 and 22Rv1 prostate cancer cell lines. L1 activation in LNCaP and VCaP was inhibited by the antiretroviral drug azidothymidine. L1 activation was also detected post-castration in LuCaP 77 and LuCaP 105 xenograft models and post-chemotherapy in previously published time-series transcriptomic data from SCC25 head and neck cancer cells. In conclusion DSER provides an informative intermediate step toward effective precision cancer medicine and should be tested in future studies, especially those including dramatic but temporary metastatic tumor regression. L1 transposon activation may be a modifiable source of cancer genomic heterogeneity, suggesting the potential of leveraging newly discovered triggers and blockers of L1 activity to overcome therapy resistance

Topological String Amplitudes, Complete Intersection Calabi-Yau Spaces and Threshold Corrections

We present the most complete list of mirror pairs of Calabi-Yau complete intersections in toric ambient varieties and develop the methods to solve the topological string and to calculate higher genus amplitudes on these compact Calabi-Yau spaces. These symplectic invariants are used to remove redundancies in examples. The construction of the B-model propagators leads to compatibility conditions, which constrain multi-parameter mirror maps. For K3 fibered Calabi-Yau spaces without reducible fibers we find closed formulas for all genus contributions in the fiber direction from the geometry of the fibration. If the heterotic dual to this geometry is known, the higher genus invariants can be identified with the degeneracies of BPS states contributing to gravitational threshold corrections and all genus checks on string duality in the perturbative regime are accomplished. We find, however, that the BPS degeneracies do not uniquely fix the non-perturbative completion of the heterotic string. For these geometries we can write the topological partition function in terms of the Donaldson-Thomas invariants and we perform a non-trivial check of S-duality in topological strings. We further investigate transitions via collapsing D5 del Pezzo surfaces and the occurrence of free Z2 quotients that lead to a new class of heterotic duals.Comment: 117 pages, 1 Postscript figur

Expitope: A web server for epitope expression.

MOTIVATION: Adoptive T cell therapies based on introduction of new T cell receptors (TCRs) into patient recipient T cells is a promising new treatment for various kinds of cancers. A major challenge, however, is the choice of target antigens. If an engineered TCR can cross-react with self-antigens in healthy tissue, the side-effects can be devastating. We present the first webserver for assessing epitope sharing when designing new potential lead targets. We enable the users to find all known proteins containing their peptide of interest. The web server returns not only exact matches, but also approximate ones, allowing a number of mismatches of the users choice. For the identified candidate proteins the expression values in various healthy tissues, representing all vital human organs, are extracted from RNA-Seq data as well as from some cancer tissues as control. All results are returned to the user sorted by a score, which is calculated using well established methods and tools for immunological predictions. It depends on the probability that the epitope is created by proteasomal cleavage and its affinities to the TAP transporter and the MHC class I alleles. With this framework we hope to provide a helpful tool to exclude potential cross-reactivity in the early stage of TCR selection for use in design of adoptive T cell immunotherapy. Availability: The Expitope web server can be accessed via http://webclu.bio.wzw.tum.de/expitope. CONTACT: [email protected]