Vaccination against Tick-Borne Encephalitis (TBE) in Italy: Still a Long Way to Go

Tick-borne encephalitis (TBE) is endemic in several European countries, and its incidence has recently increased. Various factors may explain this phenomenon: social factors (changes in human behavior, duration and type of leisure activities and increased tourism in European high-risk areas), ecological factors (e.g., effects of climate change on the tick population and reservoir animals), and technological factors (improved diagnostics, increased medical awareness). Furthermore, the real burden of TBE is not completely known, as the performance of surveillance systems is suboptimal and cases of disease are under-reported in several areas. Given the potentially severe clinical course of the disease, the absence of any antiviral therapy, and the impossibility of interrupting the transmission of the virus in nature, vaccination is the mainstay of prevention and control. TBE vaccines are effective (protective effect of approximately 95% after completion of the basic vaccination\u2014three doses) and well tolerated. However, their uptake in endemic areas is suboptimal. In the main endemic countries where vaccination is included in the national/regional immunization program (with reimbursed vaccination programs), this decision was driven by a cost-effectiveness assessment (CEA), which is a helpful tool in the decision-making process. All CEA studies conducted have demonstrated the cost-effectiveness of TBE vaccination. Unfortunately, CEA is still lacking in many endemic countries, including Italy. In the future, it will be necessary to fill this gap in order to introduce an effective vaccination strategy in endemic areas. Finally, raising awareness of TBE, its consequences and the benefit of vaccination is critical in order to increase vaccination coverage and reduce the burden of the disease

On the Deployment of IoT Systems: An Industrial Survey

Internet of Things (IoT) systems are complex and multifaceted, and the design of their architectures needs to consider many aspects at a time. Design decisions concern, for instance, the modeling of software components and their interconnections, as well as where to deploy the components within the available hardware infrastructure in the Edge-Cloud continuum. A relevant and challenging task, in this context, is to identify optimal deployment models due to all the different aspects involved, such as extra-functional requirements of the system, heterogeneity of the hardware resources concerning their processing and storage capabilities, and constraints like legal issues and operational cost limits. To gain insights about the deployment decisions concerning IoT systems in practice, and the factors that influence those decisions, we report about an industrial survey we conducted with 66 IoT architects from 18 countries across the world. Each participant filled in a questionnaire that comprises 15 questions. By analyzing the collected data, we have two main findings: (i) architects rely on the Cloud more than the Edge for deploying the software components of IoT systems, in the majority of the IoT application domains; and (ii) the main factors driving deployment decisions are four: reliability, performance, security, and cost

Controlling TcT_c of Iridium films using interfacial proximity effects

High precision calorimetry using superconducting transition edge sensors requires the use of superconducting films with a suitable $T_c$, depending on the application. To advance high-precision macrocalorimetry, we require low-$T_c$ films that are easy to fabricate. A simple and effective way to suppress $T_c$ of superconducting Iridium through the proximity effect is demonstrated by using Ir/Pt bilayers as well as Au/Ir/Au trilayers. While Ir/Au films fabricated by applying heat to the substrate during Ir deposition have been used in the past for superconducting sensors, we present results of $T_c$ suppression on Iridium by deposition at room temperature in Au/Ir/Au trilayers and Ir/Pt bilayers in the range of $\sim$20-100~mK. Measurements of the relative impedance between the Ir/Pt bilayers and Au/Ir/Au trilayers fabricated show factor of $\sim$10 higher values in the Ir/Pt case. These new films could play a key role in the development of scalable superconducting transition edge sensors that require low-$T_c$ films to minimize heat capacity and maximize energy resolution, while keeping high-yield fabrication methods.Comment: 5 journal pages, 4 figure

Cancer cells adapt FAM134B/BiP mediated ER-phagy to survive hypoxic stress

In the tumor microenvironment, cancer cells experience hypoxia resulting in the accumulation of misfolded/unfolded proteins largely in the endoplasmic reticulum (ER). Consequently, ER proteotoxicity elicits unfolded protein response (UPR) as an adaptive mechanism to resolve ER stress. In addition to canonical UPR, proteotoxicity also stimulates the selective, autophagy-dependent, removal of discrete ER domains loaded with misfolded proteins to further alleviate ER stress. These mechanisms can favor cancer cell growth, metastasis, and long-term survival. Our investigations reveal that during hypoxia-induced ER stress, the ER-phagy receptor FAM134B targets damaged portions of ER into autophagosomes to restore ER homeostasis in cancer cells. Loss of FAM134B in breast cancer cells results in increased ER stress and reduced cell proliferation. Mechanistically, upon sensing hypoxia-induced proteotoxic stress, the ER chaperone BiP forms a complex with FAM134B and promotes ER-phagy. To prove the translational implication of our mechanistic findings, we identified vitexin as a pharmacological agent that disrupts FAM134B-BiP complex, inhibits ER-phagy, and potently suppresses breast cancer progression in vivo

Crucial Positively Charged Residues for Ligand Activation of the GPR35 Receptor

GPR35 is a G protein-coupled receptor expressed in the immune, gastrointestinal, and nervous systems in gastric carcinomas and is implicated in heart failure and pain perception. We investigated residues in GPR35 responsible for ligand activation and the receptor structure in the active state. GPR35 contains numerous positively charged amino acids that face into the binding pocket that cluster in two distinct receptor regions, TMH3-4-5-6 and TMH1-2-7. Computer modeling implicated TMH3-4-5-6 for activation by the GPR35 agonists zaprinast and pamoic acid. Mutation results for the TMH1-2-7 region of GPR35 showed no change in ligand efficacies at the K1.32A, R2.65A, R7.33A, and K7.40A mutants. However, mutation of arginine residues in the TMH3-4-5-6 region (R4.60, R6.58, R3.36, R(164), and R(167) in the EC2 loop) had effects on signaling for one or both agonists tested. R4.60A resulted in a total ablation of agonist-induced activation in both the β-arrestin trafficking and ERK1/2 activation assays. R6.58A increased the potency of zaprinast 30-fold in the pERK assay. The R(167)A mutant decreased the potency of pamoic acid in the β-arrestin trafficking assay. The R(164)A and R(164)L mutants decreased potencies of both agonists. Similar trends for R6.58A and R(167)A were observed in calcium responses. Computer modeling showed that the R6.58A mutant has additional interactions with zaprinast. R3.36A did not express on the cell surface but was trapped in the cytoplasm. The lack of surface expression of R3.36A was rescued by a GPR35 antagonist, CID2745687. These results clearly show that R4.60, R(164), R(167), and R6.58 play crucial roles in the agonist initiated activation of GPR35

Janus effect of glucocorticoids on differentiation of muscle fibro/adipogenic progenitors

Muscle resident fibro-adipogenic progenitors (FAPs), support muscle regeneration by releasing cytokines that stimulate the differentiation of myogenic stem cells. However, in non-physiological contexts (myopathies, atrophy, aging) FAPs cause fibrotic and fat infiltrations that impair muscle function. We set out to perform a fluorescence microscopy-based screening to identify compounds that perturb the differentiation trajectories of these multipotent stem cells. From a primary screen of 1,120 FDA/EMA approved drugs, we identified 34 compounds as potential inhibitors of adipogenic differentiation of FAPs isolated from the murine model (mdx) of Duchenne muscular dystrophy (DMD). The hit list from this screen was surprisingly enriched with compounds from the glucocorticoid (GCs) chemical class, drugs that are known to promote adipogenesis in vitro and in vivo. To shed light on these data, three GCs identified in our screening efforts were characterized by different approaches. We found that like dexamethasone, budesonide inhibits adipogenesis induced by insulin in sub-confluent FAPs. However, both drugs have a pro-adipogenic impact when the adipogenic mix contains factors that increase the concentration of cAMP. Gene expression analysis demonstrated that treatment with glucocorticoids induces the transcription of Gilz/Tsc22d3, an inhibitor of the adipogenic master regulator PPARγ, only in anti-adipogenic conditions. Additionally, alongside their anti-adipogenic effect, GCs are shown to promote terminal differentiation of satellite cells. Both the anti-adipogenic and pro-myogenic effects are mediated by the glucocorticoid receptor and are not observed in the presence of receptor inhibitors. Steroid administration currently represents the standard treatment for DMD patients, the rationale being based on their anti-inflammatory effects. The findings presented here offer new insights on additional glucocorticoid effects on muscle stem cells that may affect muscle homeostasis and physiology

Trafficking

In cities the world over we are able to determine stability in daily existence, to identify with our social spaces, because modes of transport have become essential components of subjective autonomy. But would it not be just as accurate to say that in transit modern life puts the self in abeyance? I argue that the ways we allow ourselves to be moved around in ‘traffic space’ creates a passivity that renders almost invisible the complex mechanics of movement, which we only become alert to at the moment of breakdown, precisely when they become a threat to autonomy. Our trafficking, I conclude, has an almost narcotic effect, rendering us immobile against the continual movements that constitute urban life, one that also magnifies out of all proportion the accidents or aberrations that sometimes disturb our traffic space, making it seem as if we may easily descend into an uncontrollable chaos

Controlling TcT_c of Iridium Films Using the Proximity Effect

A superconducting Transition-Edge Sensor (TES) with low-$T_c$ is essential in a high resolution calorimetric detection. With a motivation of developing sensitive calorimeters for applications in cryogenic neutrinoless double beta decay searches, we have been investigating methods to reduce the $T_c$ of an Ir film down to 20 mK. Utilizing the proximity effect between a superconductor and a normal metal, we found two room temperature fabrication recipes of making Ir-based low-$T_c$ films. In the first approach, an Ir film sandwiched between two Au films, a Au/Ir/Au trilayer, has a tunable $T_c$ in the range of 20-100 mK depending on the relative thicknesses. In the second approach, a paramagnetic Pt thin film is used to create Ir/Pt bilayer with a tunable $T_c$ in the same range. We present detailed study of fabrication and characterization of Ir-based low-$T_c$ films, and compare the experimental results to theoretical models. We show that Ir-based films with predictable and reproducible critical temperature can be consistently fabricated for use in large scale detector applications.Comment: 5 figures, accepted in the Journal of Applied Physic