Naturalizing Supersymmetry with a Two-Field Relaxion Mechanism

We present a supersymmetric version of a two-field relaxion model that naturalizes tuned versions of supersymmetry. This arises from a relaxion mechanism that does not depend on QCD dynamics and where the relaxion potential barrier height is controlled by a second axion-like field. During the cosmological evolution, the relaxion rolls with a nonzero value that breaks supersymmetry and scans the soft supersymmetric mass terms. Electroweak symmetry is broken after the soft masses become of order the supersymmetric Higgs mass term and causes the relaxion to stop rolling for superpartner masses up to $\sim 10^9$ GeV. This can explain the tuning in supersymmetric models, including split-SUSY models, while preserving the QCD axion solution to the strong CP problem. Besides predicting two very weakly-coupled axion-like particles, the supersymmetric spectrum may contain an extra Goldstino, which could be a viable dark matter candidate.Comment: 33 pages, 3 figures; v2: bounds and figures correcte

Neuropilins 1 and 2 mediate neointimal hyperplasia and re-endothelialization following arterial injury

AIMS: Neuropilins 1 and 2 (NRP1 and NRP2) play crucial roles in endothelial cell migration contributing to angiogenesis and vascular development. Both NRPs are also expressed by cultured vascular smooth muscle cells (VSMCs) and are implicated in VSMC migration stimulated by PDGF-BB, but it is unknown whether NRPs are relevant for VSMC function in vivo. We investigated the role of NRPs in the rat carotid balloon injury model, in which endothelial denudation and arterial stretch induce neointimal hyperplasia involving VSMC migration and proliferation. METHODS AND RESULTS: NRP1 and NRP2 mRNAs and proteins increased significantly following arterial injury, and immunofluorescent staining revealed neointimal NRP expression. Down-regulation of NRP1 and NRP2 using shRNA significantly reduced neointimal hyperplasia following injury. Furthermore, inhibition of NRP1 by adenovirally overexpressing a loss-of-function NRP1 mutant lacking the cytoplasmic domain (ΔC) reduced neointimal hyperplasia, whereas wild-type (WT) NRP1 had no effect. NRP-targeted shRNAs impaired, while overexpression of NRP1 WT and NRP1 ΔC enhanced, arterial re-endothelialization 14 days after injury. Knockdown of either NRP1 or NRP2 inhibited PDGF-BB-induced rat VSMC migration, whereas knockdown of NRP2, but not NRP1, reduced proliferation of cultured rat VSMC and neointimal VSMC in vivo. NRP knockdown also reduced the phosphorylation of PDGFα and PDGFβ receptors in rat VSMC, which mediate VSMC migration and proliferation. CONCLUSION: NRP1 and NRP2 play important roles in the regulation of neointimal hyperplasia in vivo by modulating VSMC migration (via NRP1 and NRP2) and proliferation (via NRP2), independently of the role of NRPs in re-endothelialization

VEGF (Vascular Endothelial Growth Factor) Induces NRP1 (Neuropilin-1) Cleavage via ADAMs (a Disintegrin and Metalloproteinase) 9 and 10 to Generate Novel Carboxy- Terminal NRP1 Fragments That Regulate Angiogenic Signaling

OBJECTIVE: NRP1(neuropilin-1) acts as a coreceptor for VEGF (vascular endothelial growth factor) with an essential role in angiogenesis. Recent findings suggest that posttranslational proteolytic cleavage of VEGF receptors may be an important mechanism for regulating angiogenesis, but the role of NRP1 proteolysis and the NRP1 species generated by cleavage in endothelial cells is not known. To characterize NRP1 proteolytic cleavage in endothelial cells, determine the mechanism, and investigate the role of NRP1 cleavage in regulation of endothelial cell function. APPROACH AND RESULTS: NRP1 species comprising the carboxy (C)-terminal and transmembrane NRP1 domains but lacking the ligand-binding A and B regions are constitutively expressed in endothelial cells. Generation of these C-terminal domain NRP1 proteins is upregulated by phorbol ester and Ca2+ ionophore, and reduced by pharmacological inhibition of metalloproteinases, by small interfering RNA-mediated knockdown of 2 members of ADAM (a disintegrin and metalloproteinase) family, ADAMs 9 and 10, and by a specific ADAM10 inhibitor. Furthermore, VEGF upregulates expression of these NRP1 species in an ADAM9/10-dependent manner. Transduction of endothelial cells with adenoviral constructs expressing NRP1 C-terminal domain fragments inhibited VEGF-induced phosphorylation of VEGFR2 (VEGF receptor tyrosine kinase)/KDR and decreased VEGF-stimulated endothelial cell motility and angiogenesis in coculture and aortic ring sprouting assays. CONCLUSIONS: These findings identify novel NRP1 species in endothelial cells and demonstrate that regulation of NRP1 proteolysis via ADAMs 9 and 10 is a new regulatory pathway able to modulate VEGF angiogenic signaling

Accurate and precise viral quantification for rapid vaccine development in- process production monitoring using Radiance® Laser Force Cytology\u3csup\u3eTM

The biopharmaceutical world is evolving rapidly, bringing with it the need for technologies to support this fast-paced and changing environment. Trends in biomanufacturing are moving towards shortened development cycles as companies balance increased productivity requirements with the goal of reducing costs while at the same time ensuring production consistencies are met and batch out of specification (OOS) and failure events are minimized. LumaCyte’s Radiance® instrument using Laser Force Cytology™ (LFC), a combination of advanced optics and microfluidics to rapidly analyze single cells based upon their intrinsic biochemical and biophysical cellular properties and without the need for antibodies or labels. Subtle cellular changes can be precisely captured with Radiance’s automated workflow enabling new capabilities for measuring real-time product quality attributes to support R&D, process development and manufacturing needs across the biopharmaceutical industry. In this poster, LumaCyte demonstrates how tedious infectivity assays such as plaque and TCID50 can be replaced by Radiance’s rapid viral infectivity quantification assay to provide significant shorter time to result (TTR), reduced labor, and improved data quality and consistency. In addition, the bioproduction of vaccines, viral vectors or VLPs can be monitored in real-time, enabling rapid optimization of key processes and increasing process knowledge. As a result, product yield can be increased using the same inputs and the likelihood of OOS events can be reduced. Radiance applications in oncolytic virus research and neutralization assays are presented as well. Overall, LFC delivers faster TTR and improved data quality for vaccine analytics from R&D to manufacturing

Asymmetric quantum error correction via code conversion

In many physical systems it is expected that environmental decoherence will exhibit an asymmetry between dephasing and relaxation that may result in qubits experiencing discrete phase errors more frequently than discrete bit errors. In the presence of such an error asymmetry, an appropriately asymmetric quantum code - that is, a code that can correct more phase errors than bit errors - will be more efficient than a traditional, symmetric quantum code. Here we construct fault tolerant circuits to convert between an asymmetric subsystem code and a symmetric subsystem code. We show that, for a moderate error asymmetry, the failure rate of a logical circuit can be reduced by using a combined symmetric asymmetric system and that doing so does not preclude universality.Comment: 5 pages, 8 figures, presentation revised, figures and references adde

Laser force cytology for rapid quantification of viral infectivity

The quantification of viral infectivity is an integral step at multiple stages in the process of virally producing recombinant protein, studying the mechanism of viral infection, and developing vaccines. Accurate measurements of infectivity allow for consistent infection and expansion, maximum yield, and assurance that time or environmental conditions have not degraded product quality. Traditional methods to assess infectivity, including the end-point dilution assay (TCID50) and viral plaque assay, are slow, labor intensive, and can vary depending upon the skill and experience of the user. Application of Laser Force Cytology (LFC) for the rapid detection and quantification of viral infection will be presented and discussed for several viral systems in the context of improving the development and production of vaccines. LumaCyte’s Radiance™ instrument is an automated cell analyzer and sorter that measures the optical force, size, shape, and deformability and captures images of single cells. By measuring the intrinsic properties of single cells, cellular changes due to viral infection can be rapidly and objectively quantitated. LFC is very sensitive to agents that perturb cellular structures or change biochemical composition. High quality viral infectivity measurements can be made in a fraction of the time, labor, and cost of traditional assays such as plaque or endpoint dilution. For in-process automated bioreactor monitoring, infectivity can be measured by Radiance in near real-time throughout the process, allowing critical feedback control and optimization. The measurement speed and data quality of LFC / Radiance serve to enhance vaccine development, process optimization/scale-up, and manufacturing to ultimately improve the delivery of vaccines to patients

Line graphs, link partitions, and overlapping communities.

Accepted versio

Bcar1/p130Cas is essential for ventricular development and neural crest cell remodelling of the cardiac outflow tract.

AIM: The adapter protein p130Cas, encoded by the Bcar1 gene, is a key regulator of cell movement, adhesion, and cell cycle control in diverse cell types. Bcar1 constitutive knockout mice are embryonic lethal by embryonic days (E) 11.5-12.5, but the role of Bcar1 in embryonic development remains unclear. Here, we investigated the role of Bcar1 specifically in cardiovascular development and defined the cellular and molecular mechanisms disrupted following targeted Bcar1 deletions. METHODS AND RESULTS: We crossed Bcar1 floxed mice with Cre transgenic lines allowing for cell-specific knockout either in smooth muscle and early cardiac tissues (SM22-Cre), mature smooth muscle cells (smMHC-Cre), endothelial cells (Tie2-Cre), second heart field cells (Mef2c-Cre), or neural crest cells (NCC) (Pax3-Cre) and characterised these conditional knock outs using a combination of histological and molecular biology techniques.Conditional knockout of Bcar1 in SM22-expressing smooth muscle cells and cardiac tissues (Bcar1SM22KO) was embryonically lethal from E14.5-15.5 due to severe cardiovascular defects, including abnormal ventricular development and failure of outflow tract (OFT) septation leading to a single outflow vessel reminiscent of persistent truncus arteriosus. SM22-restricted loss of Bcar1 was associated with failure of OFT cushion cells to undergo differentiation to septal mesenchymal cells positive for SMC-specific α-actin, and disrupted expression of proteins and transcription factors involved in epithelial-to-mesenchymal transformation (EMT). Furthermore, knockout of Bcar1 specifically in NCC (Bcar1PAX3KO) recapitulated part of the OFT septation and aortic sac defects seen in the Bcar1SM22KO mutants, indicating a cell-specific requirement for Bcar1 in NCC essential for OFT septation. In contrast, conditional knockouts of Bcar1 in differentiated smooth muscle, endothelial cells, and second heart field cells survived to term and were phenotypically normal at birth and post-natally. CONCLUSIONS: Our work reveals a cell-specific requirement for Bcar1 in NCC, early myogenic and cardiac cells, essential for OFT septation, myocardialisation and EMT/cell cycle regulation and differentiation to myogenic lineages. TRANSLATIONAL PERSPECTIVE: The molecular pathways coordinating cardiogenesis and the remodelling of the OFT are complex, and dysregulation of these pathways causes human heart defects. Our findings highlight a specific requirement for Bcar1 essential for cardiogenesis. Furthermore, the failure of OFT septation in Bcar1SM22KO mice resembles persistent truncus arteriosus (PTA), a feature of several human congenital heart diseases, including DiGeorge Syndrome. Our findings have implications for the mechanisms underlying the pathogenesis of congenital heart disease, and suggest that mice with conditional Bcar1 deletions may be useful models for dissecting mechanisms involved in the pathogenesis of human heart defects

Accuracy threshold for concatenated error detection in one dimension

Estimates of the quantum accuracy threshold often tacitly assume that it is possible to interact arbitrary pairs of qubits in a quantum computer with a failure rate that is independent of the distance between them. None of the many physical systems that are candidates for quantum computing possess this property. Here we study the performance of a concatenated error-detection code in a system that permits only nearest-neighbor interactions in one dimension. We make use of a new message-passing scheme that maximizes the number of errors that can be reliably corrected by the code. Our numerical results indicate that arbitrarily accurate universal quantum computation is possible if the probability of failure of each elementary physical operation is below approximately 10^{-5}. This threshold is three orders of magnitude lower than the highest known.Comment: 7 pages, 4 figures, now with error bar