Nanoscale phase-engineering of thermal transport with a Josephson heat modulator

Macroscopic quantum phase coherence has one of its pivotal expressions in the Josephson effect [1], which manifests itself both in charge [2] and energy transport [3-5]. The ability to master the amount of heat transferred through two tunnel-coupled superconductors by tuning their phase difference is the core of coherent caloritronics [4-6], and is expected to be a key tool in a number of nanoscience fields, including solid state cooling [7], thermal isolation [8, 9], radiation detection [7], quantum information [10, 11] and thermal logic [12]. Here we show the realization of the first balanced Josephson heat modulator [13] designed to offer full control at the nanoscale over the phase-coherent component of thermal currents. Our device provides magnetic-flux-dependent temperature modulations up to 40 mK in amplitude with a maximum of the flux-to-temperature transfer coefficient reaching 200 mK per flux quantum at a bath temperature of 25 mK. Foremost, it demonstrates the exact correspondence in the phase-engineering of charge and heat currents, breaking ground for advanced caloritronic nanodevices such as thermal splitters [14], heat pumps [15] and time-dependent electronic engines [16-19].Comment: 6+ pages, 4 color figure

Measurement of the Charge Collection Efficiency after Heavy Non-Uniform Irradiation in BaBar Silicon Detectors

We have investigated the depletion voltage changes, the leakage current increase and the charge collection efficiency of a silicon microstrip detector identical to those used in the inner layers of the BaBar Silicon Vertex Tracker (SVT) after heavy non-uniform irradiation. A full SVT module with the front-end electronics connected has been irradiated with a 0.9 GeV electron beam up to a peak fluence of 3.5 x 10^14 e^-/cm^2, well beyond the level causing substrate type inversion. We irradiated one of the two sensors composing the module with a non-uniform profile with sigma=1.4 mm that simulates the conditions encountered in the BaBar experiment by the modules intersecting the horizontal machine plane. The position dependence of the charge collection properties and the depletion voltage have been investigated in detail using a 1060 nm LED and an innovative measuring technique based only on the digital output of the chip.Comment: 7 pages, 13 figures. Presented at the 2004 IEEE Nuclear Science Symposium, October 18-21, Rome, Italy. Accepted for publication by IEEE Transactions on Nuclear Scienc

Human metapneumovirus establishes persistent infection in lung microvascular endothelial cells and primes a th2-skewed immune response

Human metapneumovirus (HMPV) is a major cause of lower respiratory tract infections. HMPV infection has been hypothesized to alter dendritic cell (DC) immune response; however, many questions regarding HMPV pathogenesis within the infected lung remain unanswered. Here, we show that HMPV productively infects human lung microvascular endothelial cells (L-HMVECs). The release of infectious virus occurs for up to more than 30 days of culture without producing overt cytopathic effects and medium derived from persistently HMPV-infected L-HMVECs (secretome) induced monocyte-derived DCs to prime naïve CD4 T-cells toward a Th2 phenotype. Moreover, we demonstrated that infected secretomes trigger DCs to up-regulate OX40L expression and OX40L neutralization abolished the pro-Th2 effect that is induced by HMPV-secretome. We clarified secretome from HMPV by size exclusion and ultracentrifugation with the aim to characterize the role of viral particles in the observed pro-Th2 effect. In both cases, the percentage of IL-4-producing cells and expression of OX40L returned at basal levels. Finally, we showed that HMPV, per se, could reproduce the ability of secretome to prime pro-Th2 DCs. These results suggest that HMPV, persistently released by L-HMVECs, might take part in the development of a skewed, pro-Th2 lung microenvironment

The RIG-I agonist M8 triggers cell death and natural killer cell activation in human papillomavirus-associated cancer and potentiates cisplatin cytotoxicity

Although the activation of innate immunity to treat a wide variety of cancers is gaining increasing attention, it has been poorly investigated in human papillomavirus (HPV)-associated malignancies. Because these tumors harbor a severely impaired cGAS-STING axis, but they still retain a largely functional RIG-I pathway, another critical mediator of adaptive and innate immune responses, we asked whether RIG-I activation by the 5'ppp-RNA RIG-I agonist M8 would represent a therapeutically viable option to treat HPV+ cancers. Here, we show that M8 transfection of two cervical carcinoma-derived cell lines, CaSki and HeLa, both expressing a functional RIG-I, triggers intrinsic apoptotic cell death, which is significantly reduced in RIG-I KO cells. We also demonstrate that M8 stimulation potentiates cisplatin-mediated cell killing of HPV+ cells in a RIG-I dependent manner. This combination treatment is equally effective in reducing tumor growth in a syngeneic pre-clinical mouse model of HPV16-driven cancer, where enhanced expression of lymphocyte-recruiting chemokines and cytokines correlated with an increased number of activated natural killer (NK) cells in the tumor microenvironment. Consistent with a role of RIG-I signaling in immunogenic cell killing, stimulation of NK cells with conditioned medium from M8-transfected CaSki boosted NK cell proliferation, activation, and migration in a RIG-I-dependent tumor cell-intrinsic manner. Given the highly conserved molecular mechanisms of carcinogenesis and genomic features of HPV-driven cancers and the remarkably improved prognosis for HPV+ oropharyngeal cancer, targeting RIG-I may represent an effective immunotherapeutic strategy in this setting, favoring the development of de-escalating strategies