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During myocardial infarction, cellular debris is released, causing a sterile inflammation via pattern recognition receptors. These reactions amplify damage and promotes secondary heart failure. The pattern recognition receptor, Toll-like receptor 9 (TLR9) detects immunogenic fragments of endogenous DNA, inducing inflammation by NFκB. The p66ShcA adaptor protein plays an important role in both ischemic myocardial damage and immune responses. We hypothesized that p66ShcA adaptor protein promotes DNA-sensing signaling via the TLR9 pathway after myocardial infarction. TLR9 protein expression increased in cardiac tissue from patients with end-stage heart failure due to ischemic heart disease. Myocardial ischemia in mice in vivo induced gene expression of key TLR9 pathway proteins (MyD88 and Unc93b1). In this model, a functional link between TLR9 and p66ShcA was revealed as; (i) ischemia-induced upregulation of TLR9 protein was abrogated in myocardium of p66ShcA knockout mice; (ii) when p66ShcA was overexpressed in NFkB reporter cells stably expressing TLR9, NFkB-activation increased during stimulation with the TLR9 agonist CpG B; (iii) in cardiac fibroblasts, p66ShcA overexpression caused TLR9 upregulation. Co-immunoprecipitation showed that ShcA proteins and TLR9 may be found in the same protein complex, which was dissipated upon TLR9 stimulation in vivo. A proximity assay confirmed the co-localization of TLR9 and ShcA proteins. The systemic immune response after myocardial ischemia was dampened in p66ShcA knockout mice as interleukin-4, -17 and −22 expression in mononuclear cells isolated from spleens was reduced. In conclusion, p66ShcA adaptor may be an interaction partner and a regulator of the TLR9 pathway post-infarction.

Since the advent of modern-day screening collections in the early 2000s, various aspects of our knowledge of good handling practices have continued to evolve. Some early practices, however, continue to prevail due to the absence of defining data that would bust the myths of tradition. The lack of defining data leads to a gap between plate-based screeners, on the one hand, and compound sample handling groups, on the other, with the latter being the default party to blame when an assay goes awry.In this paper, we highlight recommended practices that ensure sample integrity and present myth busting data that can help determine the root cause of an assay gone bad. We show how a strong and collaborative relationship between screening and sample handling groups is the better state that leads to the accomplishment of the common goal of finding breakthrough medicines.

Silicon spin qubits are among the most promising candidates for large scale quantum computers, due to their excellent coherence and compatibility with CMOS technology for upscaling. Advanced industrial CMOS process flows allow wafer-scale uniformity and high device yield, but off the shelf transistor processes cannot be directly transferred to qubit structures due to the different designs and operation conditions. To therefore leverage the know-how of the micro-electronics industry, we customize a 300mm wafer fabrication line for silicon MOS qubit integration. With careful optimization and engineering of the MOS gate stack, we report stable and uniform quantum dot operation at the Si/SiOx interface at milli-Kelvin temperature. We extract the charge noise in different devices and under various operation conditions, demonstrating a record-low average noise level of 0.61 ${\mu}$eV/${\sqrt{Hz}}$ at 1 Hz and even below 0.1 ${\mu}$eV/${\sqrt{Hz}}$ for some devices and operating conditions. By statistical analysis of the charge noise with different operation and device parameters, we show that the noise source can indeed be well described by a two-level fluctuator model. This reproducible low noise level, in combination with uniform operation of our quantum dots, marks CMOS manufactured MOS spin qubits as a mature and highly scalable platform for high fidelity qubits., Comment: 22 pages, 13 figures

Background In February 2021 the “Cortina2021” Alpine World Ski Championships took place in the mountain town of Cortina d'Ampezzo (Italy), thus gaining the definition of “first sporting event of global significance in the time of covid-19 pandemic”. Though the event took place behind closed doors and in a context of national public health restrictive measures, it counted almost 6,000 participants. Methods A rigorous “Covid-19 Prevention and Hygiene Protocol” was drawn up by the local and regional health authorities together with the organizing committee, in order to contain the risk of viral circulation within the venue. Results Overall about 20,000 rapid antigen nasal swabs were performed to screen-detect sars-cov2 cases: only 22 of these were found positive, whereas 25 people were quarantined as close contacts. Conclusions The experience of “Cortina2021” proves that mass gatherings can take place even in times of epidemic threats, if adequately planned and by providing public health recommendations tailored on the viral circulation foreseen by the time the event is due. If new epidemics should arise in the future, hopefully the public health management of “Cortina2021” may be a template for next mass gatherings to be held, as far as possible, despite the viral circulation.

Large-scale superconducting quantum computing systems entail high-fidelity control and readout of large numbers of qubits at millikelvin temperatures, resulting in a massive input-output bottleneck. Cryo-electronics, based on complementary metal-oxide-semiconductor (CMOS) technology, may offer a scalable and versatile solution to overcome this bottleneck. However, detrimental effects due to cross-coupling between the electronic and thermal noise generated during cryo-electronics operation and the qubits need to be avoided. Here we present an ultra-low power radio-frequency (RF) multiplexing cryo-electronics solution operating below 15 mK that allows for control and interfacing of superconducting qubits with minimal cross-coupling. We benchmark its performance by interfacing it with a superconducting qubit and observe that the qubit's relaxation times ($T_1$) are unaffected, while the coherence times ($T_2$) are only minimally affected in both static and dynamic operation. Using the multiplexer, single qubit gate fidelities above 99.9%, i.e., well above the threshold for surface-code based quantum error-correction, can be achieved with appropriate thermal filtering. In addition, we demonstrate the capability of time-division-multiplexed qubit control by dynamically windowing calibrated qubit control pulses. Our results show that cryo-CMOS multiplexers could be used to significantly reduce the wiring resources for large-scale qubit device characterization, large-scale quantum processor control and quantum error correction protocols., 16+6 pages, 4+1+5 figures, 1 table

Sex differences in the behavioral responses of Labrador Retriever dogs in the Strange Situation Test were explored. Behaviors expressed by dogs during seven 3-min episodes were analyzed through a Principal Component Analysis (PCA). The scores of factors obtained were analyzed with a Generalized Linear Mixed Model to reveal the effects of the dog’s sex and age and the owner’s sex. In Episode 1 (dog and owner) and 5 (dog alone), the PCA identified three and two factors, respectively, which overall explained 68.7% and 59.8% of the variance, with no effect of sex. In Episodes 2 (dog, owner, and stranger), 3 and 6 (dog and stranger), and 4 and 7 (dog and owner), the PCA identified four factors, which overall explained 51.0% of the variance. Effects of sex were found on: Factor 1 (distress), with lower scores obtained by females in Episode 2 and higher in Episode 3; Factor 2 (sociability), which was overall higher in females; Factor 3 (separation-distress), with females, but not males, obtaining higher scores when left with the stranger than when with the owner. Therefore, females were overall more social but seemed more affected than males by the owner’s absence. Parallels can be traced between our results and sex differences found in adult human romantic attachment, suggesting that the dog-owner bond has characteristics that are not found in the infant-mother relationship.

We present a novel mean-field theory for balanced neuronal networks with arbitrary levels of symmetry in the synaptic connectivity. The theory determines the fixed point of the network dynamics and the conditions for its stability. The fixed point becomes unstable by increasing the synaptic gain beyond a critical value that depends on the level of symmetry. Beyond this critical gain, for positive levels of symmetry, we find a previously unreported phase. In this phase, the dynamical landscape is dominated by a large number of marginally-stable fixed points. As a result, the network dynamics exhibit non-exponential relaxation and ergodicity is broken. We discuss the relevance of such a glassy phase for understanding dynamical and computational aspects of cortical operation.

In un mondo in cui l'attività economica si è globalizzata e la dimensione transfrontaliera del crimine di impresa è esponenzialmente cresciuta, il tema dell'estensione spaziale delle leggi penali nazionali assume rilievo centrale. La parcellizzazione della produzione in gruppi societari, joint venture e catene di approvvigionamento globali, oltre a fomentare reati e violazioni di diritti umani da parte delle imprese multinazionali o transnazionali, erode la capacità di enforcement degli Stati. Il saggio si concentra, così, sulle nuove forme di giurisdizione extraterritoriale - sia autentiche che "mimetizzate" sotto una nozione di territorialità dilatata all'estremo - da una duplice prospettiva: efficacia della risposta punitiva e tutela dei diritti fondamentali dei soggetti (individui e società) sottoposti a procedimento penale da parte di molteplici autorità nazionali, nell'ottica di un equilibrio ragionevole.

Introduction Although standard doublet chemotherapy represents the upfront gold standard to increase survival and improve quality of life of gastric cancer patients, overall improvements in long-term outcomes are modest and novel treatments are urgently needed. Among these, immunotherapy is an increasingly attractive option. Areas covered A number of clinical trials have shown that checkpoint inhibitors may be of value, but many unclear issues remain controversial and should be promptly untangled. In our short review, we offer the current available data regarding immunotherapies in gastric cancers, discuss potential limits of the reported trials, compare outcomes of checkpoints inhibitor to those of standard chemotherapy or other novel treatments, and present basic principles of immune surveillance and immune escape that may be embraced in the near future with novel drug combinations. Expert opinion Gastric cancer patients may benefit from immunotherapy, both given alone in advanced lines or upfront in combination with chemotherapy. We believe that appropriate patients' and tumor's. selection are crucial issues to maximize its potential efficacy. In addition, we think that assay standardization, biomarker agreement, and translational studies will improve the benefit-to-risk ratio of these agents in the clinical practice.