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The growing interest in quantum technologies, from fundamental physics experiments to quantum computing, demands for extremely performing electronics only adding the minimum amount of noise admitted by quantum mechanics to the input signal (i.e. quantum-limited electronics). Superconducting microwave amplifiers, due to their dissipationless nature, exhibit outstanding performances in terms of noise (quantum limited), and gain. However, bandwidth and saturation power still show space for substantial improvement. Within the DARTWARS* collaboration, we are developing state-of-the-art microwave superconducting amplifiers based on Josephson junction arrays and on distributed kinetic inductance transmission lines. Here we report the realization of a setup for the characterization of the performances of Josephson Traveling-Wave Parametric Amplifiers (JTWPA) at a temperature of 300 mK. Although in the final experimental setup these amplifiers will operate at a base temperature of about 20 mK, their characterization at 300 mK allows to evidence the main aspects of their performances, but the ultimate noise level. This represents a quick and relatively inexpensive way to test these superconductive devices that can be of help to improve their design and fabrication. IEEE

Rapidly evolving influenza A viruses (IAVs) and influenza B viruses (IBVs) are major causes of recurrent lower respiratory tract infections. Current influenza vaccines elicit antibodies predominantly to the highly variable head region of haemagglutinin and their effectiveness is limited by viral drift1 and suboptimal immune responses2. Here we describe a neuraminidase-targeting monoclonal antibody, FNI9, that potently inhibits the enzymatic activity of all group 1 and group 2 IAVs, as well as Victoria/2/87-like, Yamagata/16/88-like and ancestral IBVs. FNI9 broadly neutralizes seasonal IAVs and IBVs, including the immune-evading H3N2 strains bearing an N-glycan at position 245, and shows synergistic activity when combined with anti-haemagglutinin stem-directed antibodies. Structural analysis reveals that D107 in the FNI9 heavy chain complementarity-determinant region 3 mimics the interaction of the sialic acid carboxyl group with the three highly conserved arginine residues (R118, R292 and R371) of the neuraminidase catalytic site. FNI9 demonstrates potent prophylactic activity against lethal IAV and IBV infections in mice. The unprecedented breadth and potency of the FNI9 monoclonal antibody supports its development for the prevention of influenza illness by seasonal and pandemic viruses.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has evolved variants with substitutions in the spike receptor-binding domain (RBD) that affect its affinity for angiotensin-converting enzyme 2 (ACE2) receptor and recognition by antibodies. These substitutions could also shape future evolution by modulating the effects of mutations at other sites—a phenomenon called epistasis. To investigate this possibility, we performed deep mutational scans to measure the effects on ACE2 binding of all single–amino acid mutations in the Wuhan-Hu-1, Alpha, Beta, Delta, and Eta variant RBDs. Some substitutions, most prominently Asn 501 →Tyr (N501Y), cause epistatic shifts in the effects of mutations at other sites. These epistatic shifts shape subsequent evolutionary change—for example, enabling many of the antibody-escape substitutions in the Omicron RBD. These epistatic shifts occur despite high conservation of the overall RBD structure. Our data shed light on RBD sequence-function relationships and facilitate interpretation of ongoing SARS-CoV-2 evolution.

Cryogenic single-particle detectors are devices, operated close to absolute zero, widely used in current and future generation detectors for the search for rare particle physics processes, for example neutrino-less double beta decay. Traditionally, these detectors are assembled in copper structures inside dilution refrigerators. The use of copper, however, is expected to become a limiting factor on the path towards the background reduction needed for future generation projects. Its high density and large Z make it an effective target where gamma-rays produced by radioactive contaminants can lose part of their energy undetected, and subsequently be measured as sensitivity-spoiling spurious signals in the region of interest of the energy spectrum. We present here a new method of building assemblies for kg-scale cryogenic single particle detectors based on low Z, low density additive manufacturing-compatible polymers that can in the future be doped with scintillating compounds thus making them an active component of the experimental setup. Additive manufacturing overcomes the limitations, imposed by traditional techniques, in the design of the structures. The assembly geometry can therefore be driven by the combined needs for reduction of mass and optimization of light production and collection. The experimental setup and the performance of the detectors in terms of energy resolution and temperature stability are described.

The recent developments in quantum technologies, as well as advanced detection experiments, have raised the need to detect extremely weak signals in the microwave frequency spectrum. To this aim, the Josephson travelling wave parametric amplifier, a device capable of reaching the quantum noise limit while providing a wide bandwidth, has been proposed as a suitable cryogenic front-end amplifier. This work deals with the numerical study of a Josephson travelling wave parametric amplifier, without approximations regarding the nonlinearity of the key elements. In particular, we focus on the investigation of the system of coupled nonlinear differential equations representing all the cells of the Josephson travelling wave parametric amplifier, with proper input and output signals at the boundaries. The investigation of the output signals generated by the parametric amplification process explores the phase-space and the Fourier spectral analysis of the output voltage, as a function of the parameters describing the pump and signal tones that excite the device. Beside the expected behavior, i.e., the signal amplification, we show that, depending on the system operation, unwanted effects (such as pump tone harmonics, incommensurate frequency generation, and noise rise), which are not accounted for in simple linearized approaches, can be generated in the whole nonlinear system. IEEE

Inositol-Requiring Enzyme 1 (IRE1) is an essential component of the Unfolded Protein Response. IRE1 spans the endoplasmic reticulum membrane, comprising a sensory lumenal domain, and tandem kinase and endoribonuclease (RNase) cytoplasmic domains. Excess unfolded proteins in the ER lumen induce dimerization and oligomerization of IRE1, triggering kinase trans-autophosphorylation and RNase activation. Known ATP-competitive small-molecule IRE1 kinase inhibitors either allosterically disrupt or stabilize the active dimeric unit, accordingly inhibiting or stimulating RNase activity. Previous allosteric RNase activators display poor selectivity and/or weak cellular activity. In this study, we describe a class of ATP-competitive RNase activators possessing high selectivity and strong cellular activity. This class of activators binds IRE1 in the kinase front pocket, leading to a distinct conformation of the activation loop. Our findings reveal exquisitely precise interdomain regulation within IRE1, advancing the mechanistic understanding of this important enzyme and its investigation as a potential small-molecule therapeutic target., The RNase activity of Inositol-Requiring Enzyme 1 (IRE1) can be allosterically regulated by ATP-competitive inhibitors of the IRE1 kinase domain. Here, the authors identify ATP-competitive IRE1 RNase activators with improved selectivity and cellular activity, and elucidate their mechanism of action.

SARS-CoV-2 evolution threatens vaccine- and natural infection-derived immunity as well as the efficacy of therapeutic antibodies. To improve public health preparedness, we sought to predict which existing amino acid mutations in SARS-CoV-2 might contribute to future variants of concern. We tested the predictive value of features comprising epidemiology, evolution, immunology, and neural network-based protein sequence modeling, and identified primary biological drivers of SARS-CoV-2 intra-pandemic evolution. We found evidence that ACE2-mediated transmissibility and resistance to population-level host immunity has waxed and waned as a primary driver of SARS-CoV-2 evolution over time. We retroactively identified with high accuracy (area under the receiver operator characteristic curve, AUROC=0.92-0.97) mutations that will spread, at up to four months in advance, across different phases of the pandemic. The behavior of the model was consistent with a plausible causal structure wherein epidemiological covariates combine the effects of diverse and shifting drivers of viral fitness. We applied our model to forecast mutations that will spread in the future and characterize how these mutations affect the binding of therapeutic antibodies. These findings demonstrate that it is possible to forecast the driver mutations that could appear in emerging SARS-CoV-2 variants of concern. We validate this result against Omicron, showing elevated predictive scores for its component mutations prior to emergence, and rapid score increase across daily forecasts during emergence. This modeling approach may be applied to any rapidly evolving pathogens with sufficiently dense genomic surveillance data, such as influenza, and unknown future pandemic viruses.

Parallel Flash Talk at the "XIX International Workshop on Neutrino Telescopes" on line - 18-26 February, 2021

This article aims to elucidate the effects of the Great Recession and the retrenchment of welfare on national identity in several European countries. While different authors have observed that good economic performance, redistribution, and the growth of welfare strengthen countries as political communities of solidarity, there is much less empirical evidence regarding the consequences of an economic crisis for national identity. To investigate these consequences, we focus on a set of countries where the 2008 Great Recession resulted in different impacts, namely, Germany and four countries in Southern Europe (Italy, Spain, Portugal, and Greece). We use secondary quantitative data from Eurobarometer surveys to test aggregated and individual hypotheses relating to both the size and direction of the Great Recession’s effects on national identity. Our results suggest that the roles and impacts of economic variables may be different depending on the relative economic performance of a country within its own context. It seems easier to confirm that good economic performance, in relative terms, might strengthen national identity than proving that poor economic performance will weaken national identity. Even if no definitive empirical evidence can be given at this point, our data suggest a rationalization or compensation mechanism such that citizens look for where to anchor their strong national identities after they have decided on them. If an economy is performing well, then it would become a good anchorage for holding a strong national identity, however, if an economy is not performing well, then economic factors will cease to be a fundamental element for national identity holders.

Este artículo analiza el patriotismo español entre los partidos de izquierda de ámbito estatal y sus partidos federados o ideológicamente asimilables. Se basa en el análisis de treinta entrevistas a cuadros medios de esos partidos en las comunidades autónomas de Madrid, Cataluña, Andalucía y Galicia. Los resultados confirman que, a pesar de las conceptualizaciones estrechas que han dominado el debate sobre este tema, puede afirmarse la existencia de un patriotismo de la izquierda. Es decir, las élites de izquierda entrevistadas se sienten vinculadas con España; una actitud que expresa afecto, lealtad y preocupación fundamentalmente por el grupo (con una fuerte connotación de clase), antes que por el territorio. Posiblemente, la situación de crisis en que se recogen los testimonios (entrevistados en 2012) hace que los entrevistados sometan la definición de la comunidad política a preguntas y a críticas respecto a su sentido y a las prioridades que, aparentemente, no emergen en situaciones de normalidad, a tenor de lo reseñado en la literatura sobre el tema., This article analyses Spanish patriotism among state-wide leftist parties in Spain and their federations or ideological equivalents. The investigation rests on the analysis of thirty semi-structured interviews with middle-ranking officials in Madrid, Catalonia, Andalusia and Galicia. The findings confirm that, despite the predominance of narrow understandings of the concept, the existence of Spanish patriotism among state-wide leftist parties can be affirmed. That is, those interviewed feel attached to Spain; an attitude expressed through beliefs that imply belonging, fondness, loyalty and concern mainly focused on the group (with a strong social class connotation) rather than the territory. The fact that the testimonies were recorded in 2012 during a deep economic crisis may have prompted the respondents to question and criticize the concept of political community (its meaning, priorities, etc.), which do not seem to occur in normal situations according to the literature., Aquest article analitza el patriotisme espanyol entre els partits d'esquerra d'àmbit estatal i els seus partits federats o ideològicament assimilables. Es basa en l'anàlisi de trenta entrevistes a quadres mitjans d'aquests partits en les comunitats autònomes de Madrid, Catalunya, Andalusia i Galícia. Els resultats confirmen que, malgrat les conceptualitzacions estretes que han dominat el debat sobre aquest tema, es pot afirmar l'existència d'un patriotisme de l'esquerra. És a dir, les elits d'esquerra entrevistades se senten vinculades a Espanya; una actitud que expressa afecte, lleialtat i preocupació fonamentalment pel grup (amb una forta connotació de classe), abans que pel territori. Possiblement, la situació de crisi en què es recullen els testimoniatges (entrevistats el 2012) fa que els entrevistats sotmetin la definició de la comunitat política a preguntes i a crítiques respecte al seu sentit i a les prioritats que, aparentment, no emergeixen en situacions de normalitat, segons el ressenyat en la literatura sobre el tema.

In this article we identify the discursive positions on the territorial model of intermediate strata of the state level leftist parties (PAE) in Spain. Through thirty interviews with members of local and regional political elites of the IU and the PSOE conducted in Andalusia, Madrid, Catalonia and Galicia, we analyze the discursive differences that mark the attempt to agree on a proposal for territorial reform. These differences, which on the whole support the results of other investigations, do however also hide a set of discursive coincidences that have not been properly evaluated before. It is an added value to this analysis of a hitherto unstudied political profile that the reflection occurs at a moment marked by economic crisis and a profound debate on territorial reform.

Basándose en los barómetros autonómicos del CIS, la finalidad de este trabajo es analizar cuál es la relación que existe entre la identidad nacional española y la percepción ciudadana sobre la economía y el bienestar.

Immuno-chemotherapy elicit high response rates in B-cell non-Hodgkin lymphoma but heterogeneity in response duration is observed, with some patients achieving cure and others showing refractory disease or relapse. Using a transcriptome-powered targeted proteomics screen, we discovered a gene regulatory circuit involving the nuclear factor CYCLON which characterizes aggressive disease and resistance to the anti-CD20 monoclonal antibody, Rituximab, in high-risk B-cell lymphoma. CYCLON knockdown was found to inhibit the aggressivity of MYC-overexpressing tumours in mice and to modulate gene expression programs of biological relevance to lymphoma. Furthermore, CYCLON knockdown increased the sensitivity of human lymphoma B cells to Rituximab in vitro and in vivo. Strikingly, this effect could be mimicked by in vitro treatment of lymphoma B cells with a small molecule inhibitor for BET bromodomain proteins (JQ1). In summary, this work has identified CYCLON as a new MYC cooperating factor that autonomously drives aggressive tumour growth and Rituximab resistance in lymphoma. This resistance mechanism is amenable to next-generation epigenetic therapy by BET bromodomain inhibition, thereby providing a new combination therapy rationale for high-risk lymphoma.

To assess in vivo volumetric repeatability of an automated software algorithm in pulmonary nodules detected during a lung cancer screening trial.This study was approved by an institutional review board. Written informed consent was obtained from all participants. Data were collected from the Multicentric Italian Lung Detection project, a randomized controlled lung cancer screening trial. The first 1236 consecutive baseline computed tomographic (CT) studies performed at the Istituto Nazionale Tumori of Milan were evaluated. Among the enrolled participants, those who underwent repeat low-dose CT after 3 months and had at least one indeterminate nodule with a volume of more than 60 mm(3) (diameter of 4.8 mm or greater) were considered. Nonsolid, part-solid, and pleural-based nodules were excluded from this study. A descriptive analysis was performed by calculating means and standard deviations of nodule volumes at three assessment times (at baseline and 3 and 12 months later). The volume measurement repeatability was determined by using the approach described by Bland and Altman.One hundred one subjects (70 men, 31 women; mean age, 58 years) with 233 eligible nodules (mean volume, 98.3 mm(3); range, 5-869 mm(3)) were identified. The 95% confidence interval for difference in measured volumes was in the range of +/-27%. About 70% of measurements had a relative difference in nodule volume of less than 10%. No malignant lesions were registered during the follow-up of these subjects.Semiautomatic volumetry is sufficiently accurate and repeatable and may be useful in assisting with lung nodule management in a lung cancer screening program.

International audience; Bromodomains are epigenetic readers of histone acetylation involved in chromatin remodeling and transcriptional regulation. The human proteome comprises 46 bromodomain-containing proteins with a total of 61 bromodomains, which, despite highly conserved structural features, recognize a wide array of natural peptide ligands. Over the past five years, bromodomains have attracted great interest as promising new epigenetic targets for diverse human diseases, including inflammation, cancer, and cardiovascular disease. The demonstration in 2010 that two small molecule compounds, JQ1 and I-BET762, potently inhibit proteins of the bromodomain and extra-terminal (BET) family with translational potential for cancer and inflammatory disease sparked intense efforts in academia and pharmaceutical industry to develop novel bromodomain antagonists for therapeutic applications. Several BET inhibitors are already in clinical trials for hematological malignancies, solid tumors and cardiovascular disease. Currently, the field faces the challenge of single-target selectivity, especially within the BET family, and of overcoming problems related to the development of drug resistance. At the same time, new trends in bromodomain inhibitor research are emerging, including an increased interest in non-BET bromodomains and a focus on drug synergy with established antitumor agents to improve chemotherapeutic efficacy. This review presents an updated view of the structure and function of bromodomains, traces the development of bromodomain inhibitors and their potential therapeutic applications, and surveys the current challenges and future directions of this vibrant new field in drug discovery.

Invasive fungal infections cause significant morbidity and mortality among immunocompromised individuals, posing an urgent need for new antifungal therapeutic strategies. Here we investigate a chromatin-interacting module, the bromodomain (BD) from the BET family of proteins, as a potential antifungal target in Candida albicans, a major human fungal pathogen. We show that the BET protein Bdf1 is essential in C. albicans and that mutations inactivating its two BDs result in a loss of viability in vitro and decreased virulence in mice. We report small-molecule compounds that inhibit C. albicans Bdf1 with high selectivity over human BDs. Crystal structures of the Bdf1 BDs reveal binding modes for these inhibitors that are sterically incompatible with the human BET-binding pockets. Furthermore, we report a dibenzothiazepinone compound that phenocopies the effects of a Bdf1 BD-inactivating mutation on C. albicans viability. These findings establish BET inhibition as a promising antifungal therapeutic strategy and identify Bdf1 as an antifungal drug target that can be selectively inhibited without antagonizing human BET function.

Kinetics studies of dNTP analogues having pyrophosphate-mimicking β,γ-pCXYp leaving groups with variable X and Y substitution reveal striking differences in the chemical transition-state energy for DNA polymerase β that depend on all aspects of base-pairing configurations, including whether the incoming dNTP is a purine or pyrimidine and if base-pairings are right (T•A and G•C) or wrong (T•G and G•T). Brønsted plots of the catalytic rate constant (log(kpol)) versus pKa4 for the leaving group exhibit linear free energy relationships (LFERs) with negative slopes ranging from −0.6 to −2.0, consistent with chemical rate-determining transition-states in which the active-site adjusts to charge-stabilization demand during chemistry depending on base-pair configuration. The Brønsted slopes as well as the intercepts differ dramatically and provide the first direct evidence that dNTP base recognition by the enzyme–primer–template complex triggers a conformational change in the catalytic region of the active-site that significantly modifies the rate-determining chemical step.

New luminescent dinuclear rhenium(I) tricarbonyl complex-PNA conjugates have been synthesized through a reliable solid-phase synthetic methodology. Their photophysical properties have been measured. The most luminescent Re-PNA conjugate 7 showed interesting two-photon absorption (TPA) properties, that were exploited for imaging experiments, to demonstrate its easy uptake into living cells.