High operating temperature in V-based superconducting quantum interference proximity transistors

Here we report the fabrication and characterization of fully superconducting quantum interference proximity transistors (SQUIPTs) based on the implementation of vanadium (V) in the superconducting loop. At low temperature, the devices show high flux-to-voltage (up to 0.52$\ \textrm{mV}/\Phi_0$) and flux-to-current (above 12$\ \textrm{nA}/\Phi_0$) transfer functions, with the best estimated flux sensitivity $\sim$2.6$\ \mu\Phi_0/\sqrt{\textrm{Hz}}$ reached under fixed voltage bias, where $\Phi_0$ is the flux quantum. The interferometers operate up to $T_\textrm{bath}\simeq$ 2 $\textrm{K}$, with an improvement of 70$\%$ of the maximal operating temperature with respect to early SQUIPTs design. The main features of the V-based SQUIPT are described within a simplified theoretical model. Our results open the way to the realization of SQUIPTs that take advantage of the use of higher-gap superconductors for ultra-sensitive nanoscale applications that operate at temperatures well above 1 K.Comment: Published version with Supplementary Informatio

Thermal superconducting quantum interference proximity transistor

Superconductors are known to be excellent thermal insulators at low temperature owing to the presence of the energy gap in their density of states (DOS). In this context, the superconducting \textit{proximity effect} allows to tune the local DOS of a metallic wire by controlling the phase bias ($\varphi$) imposed across it. As a result, the wire thermal conductance can be tuned over several orders of magnitude by phase manipulation. Despite strong implications in nanoscale heat management, experimental proofs of phase-driven control of thermal transport in superconducting proximitized nanostructures are still very limited. Here, we report the experimental demonstration of efficient heat current control by phase tuning the superconducting proximity effect. This is achieved by exploiting the magnetic flux-driven manipulation of the DOS of a quasi one-dimensional aluminum nanowire forming a weal-link embedded in a superconducting ring. Our thermal superconducting quantum interference transistor (T-SQUIPT) shows temperature modulations up to $\sim 16$ mK yielding a temperature-to-flux transfer function as large as $\sim 60$ mK/$\Phi_0$. Yet, phase-slip transitions occurring in the nanowire Josephson junction induce a hysteretic dependence of its local DOS on the direction of the applied magnetic field. Thus, we also prove the operation of the T-SQUIPT as a phase-tunable \textit{thermal memory}, where the information is encoded in the temperature of the metallic mesoscopic island. Besides their relevance in quantum physics, our results are pivotal for the design of innovative coherent caloritronics devices such as heat valves and temperature amplifiers suitable for thermal logic architectures.Comment: 8 pages, 4 figure

Preliminary demonstration of a persistent Josephson phase-slip memory cell with topological protection

Superconducting computing promises enhanced computational power in both classical and quantum approaches. Yet, scalable and fast superconducting memories are not implemented. Here, we propose a fully superconducting memory cell based on the hysteretic phase-slip transition existing in long aluminum nanowire Josephson junctions. Embraced by a superconducting ring, the memory cell codifies the logic state in the direction of the circulating persistent current, as commonly defined in flux-based superconducting memories. But, unlike the latter, the hysteresis here is a consequence of the phase-slip occurring in the long weak link and associated to the topological transition of its superconducting gap. This disentangles our memory scheme from the large-inductance constraint, thus enabling its miniaturization. Moreover, the strong activation energy for phase-slip nucleation provides a robust topological protection against stochastic phase-slips and magnetic-flux noise. These properties make the Josephson phase-slip memory a promising solution for advanced superconducting classical logic architectures or flux qubits

InAs nanowire superconducting tunnel junctions: spectroscopy, thermometry and nanorefrigeration

We demonstrate an original method -- based on controlled oxidation -- to create high-quality tunnel junctions between superconducting Al reservoirs and InAs semiconductor nanowires. We show clean tunnel characteristics with a current suppression by over $4$ orders of magnitude for a junction bias well below the Al gap $\Delta_0 \approx 200\,\mu {\rm eV}$. The experimental data are in close agreement with the BCS theoretical expectations of a superconducting tunnel junction. The studied devices combine small-scale tunnel contacts working as thermometers as well as larger electrodes that provide a proof-of-principle active {\em cooling} of the electron distribution in the nanowire. A peak refrigeration of about $\delta T = 10\,{\rm mK}$ is achieved at a bath temperature $T_{bath}\approx250-350\,{\rm mK}$ in our prototype devices. This method opens important perspectives for the investigation of thermoelectric effects in semiconductor nanostructures and for nanoscale refrigeration.Comment: 6 pages, 4 color figure

Preclinical evaluation of IL2-based immunocytokines supports their use in combination with dacarbazine, paclitaxel and TNF-based immunotherapy

Antibody-cytokine fusion proteins ("immunocytokines”) represent a promising class of armed antibody products, which allow the selective delivery of potent pro-inflammatory payloads at the tumor site. The antibody-based selective delivery of interleukin-2 (IL2) is particularly attractive for the treatment of metastatic melanoma, an indication for which this cytokine received marketing approval from the US Food and drug administration. We used the K1735M2 immunocompetent syngeneic model of murine melanoma to study the therapeutic activity of F8-IL2, an immunocytokine based on the F8 antibody in diabody format, fused to human IL2. F8-IL2 was shown to selectively localize at the tumor site in vivo, following intravenous administration, and to mediate tumor growth retardation, which was potentiated by the combination with paclitaxel or dacarbazine. Combination treatment led to a substantially more effective tumor growth inhibition, compared to the cytotoxic drugs used as single agents, without additional toxicity. Analysis of the immune infiltrate revealed a significant accumulation of CD4+ T cells 24h after the administration of the combination. The fusion proteins F8-IL2 and L19-IL2, specific to the alternatively spliced extra domain A and extra domain B of fibronectin respectively, were also studied in combination with tumor necrosis factor (TNF)-based immunocytokines. The combination treatment was superior to the action of the individual immunocytokines and was able to eradicate neoplastic lesions after a single intratumoral injection, a procedure that is being clinically used for the treatment of Stage IIIC melanoma. Collectively, these data reinforce the rationale for the use of IL2-based immunocytokines in combination with cytotoxic agents or TNF-based immunotherapy for the treatment of melanoma patients

Concienciación sobre el sexismo en la Educación Secundaria: análisis de discursos audiovisuales persuasivos y musicales

Los centros educativos pueden llevar a cabo iniciativas destinadas a enriquecer el proceso de enseñanza-aprendizaje y fomentar la capacidad crítica del alumnado frente a los textos audiovisuales, así como concienciar y desarrollar una acción proactiva tanto a favor de la equidad entre personas como en la prevención de la violencia de género. El objetivo de la presente investigación es analizar los resultados de una experiencia didáctica implementada en el tercer curso de la Educación Secundaria Obligatoria (ESO) para sensibilizar acerca de los estereotipos de género fomentados por la publicidad y las músicas urbanas. Para ello se empleó una metodología cualitativa inspirada en la investigación-acción, incluyendo un instrumento de análisis de los trabajos presentados. Se realizó un trabajo grupal de análisis de discursos audiovisuales para identificar rasgos relacionados con la cosificación e instrumentalización de la mujer. El alumnado participó de forma activa en todas las fases del proceso de aprendizaje. Los resultados muestran que el alumnado destaca cuestiones como la cosificación o hipersexualización, la reivindicación de las feminidades o la crítica al sistema patriarcal, siendo los trabajos que más nivel de profundidad alcanzaron aquellos en los que más rasgos sexistas se detectaron. DISCUSIÓN. Se evidencia que el alumnado es capaz en su mayoría de identificar rasgos de sumisión y cosificación femenina, mientras que otros como las agresiones o el falso empoderamiento femenino pasan más desapercibidos.Educational centers can carry out initiatives aimed at enriching the teaching-learning process and fostering students’ critical capacity in relation to audiovisual texts, as well as raising awareness and developing a proactive action both in favor of equity among people and in the prevention of gender violence. The aim of this research is to analyze the results of a didactic experience implemented in the third year of Compulsory Secondary Education (ESO) to raise awareness about gender stereotypes promoted by advertising and urban music. To approach the study of the experience, a qualitative methodology inspired by action research, was used, and including an instrument for analyzing the work presented. The proposal consisted of a group work of analysis of audiovisual discourses to identify features related to the objectification and instrumentalization of women. The students participated in all phases of the learning process, being an active part of it through self-evaluation and peer evaluation rubrics. The results show that the students highlight issues such as objectification or hypersexualization, the vindication of femininity or criticism of the patriarchal system, being the works that reached the highest level of depth those in which more sexist traits were detected. It is evident that most of the students are able to identify traits of female submission and objectification, while others, such as aggressions or false female empowerment, go unnoticed

Does multimodal analgesia with acetaminophen, nonsteroidal antiinflammatory drugs, or selective cyclooxygenase-2 inhibitors and patientcontrolled analgesia morphine offer advantages over morphine alone? Meta-analyses of randomized trials

The authors analyzed data from 52 randomized placebocontrolled trials (4,893 adults) testing acetaminophen, nonsteroidal antiinflammatory drugs, or selective cyclooxygenase-2 inhibitors given in conjunction with morphine after surgery. The median of the average 24-h morphine consumption in controls was 49 mg (range, 15-117 mg); it was significantly decreased with all regimens by 15-55%. There was evidence of a reduction in pain intensity at 24 h (1 cm on the 0-to 10-cm visual analog scale) only with nonsteroidal antiinflammatory drugs. Nonsteroidal antiinflammatory drugs also significantly reduced the incidence of nausea/vomiting from 28.8% to 22.0% (number needed to treat, 15) and of sedation from 15.4% to 12.7% (number needed to treat, 37) but increased the risk of severe bleeding from 0% to 1.7% (number needed to harm, 59). Selective cyclooxygenase-2 inhibitors increased the risk of renal failure in cardiac patients from 0% to 1.4% (number needed to harm, 73). A decrease in morphine consumption is not a good indicator of the usefulness of a supplemental analgesic. There is evidence that the combination of nonsteroidal antiinflammatory drugs with patient-controlled analgesia morphine offers some advantages over morphine alone

SARS-CoV-2 and Skin: The Pathologist's Point of View

The SARS-CoV-2 pandemic has dramatically changed our lives and habits. In just a few months, the most advanced and efficient health systems in the world have been overwhelmed by an infectious disease that has caused 3.26 million deaths and more than 156 million cases worldwide. Although the lung is the most frequently affected organ, the skin has also resulted in being a target body district, so much so as to suggest it may be a real "sentinel" of COVID-19 disease. Here we present 17 cases of skin manifestations studied and analyzed in recent months in our Department; immunohistochemical investigations were carried out on samples for the S1 spike-protein of SARS-CoV-2, as well as electron microscopy investigations showing evidence of virions within the constituent cells of the eccrine sweat glands and the endothelium of small blood vessels. Finally, we conduct a brief review of the COVID-related skin manifestations, confirmed by immunohistochemistry and/or electron microscopy, described in the literature

Safety and efficacy of ganaxolone in patients with CDKL5 deficiency disorder: results from the double-blind phase of a randomised, placebo-controlled, phase 3 trial

BACKGROUND: CDKL5 deficiency disorder (CDD) is a rare, X-linked, developmental and epileptic encephalopathy characterised by severe global developmental impairment and seizures that can begin in the first few months after birth and are often treatment refractory. Ganaxolone, an investigational neuroactive steroid, reduced seizure frequency in an open-label, phase 2 trial that included patients with CDD. We aimed to further assess the efficacy and safety of ganaxolone in patients with CDD-associated refractory epilepsy. METHODS: In the double-blind phase of this randomised, placebo-controlled, phase 3 trial, done at 39 outpatient clinics in eight countries (Australia, France, Israel, Italy, Poland, Russia, the UK, and the USA), patients were eligible if they were aged 2-21 years with a pathogenic or probably pathogenic CDKL5 variant and at least 16 major motor seizures (defined as bilateral tonic, generalised tonic-clonic, bilateral clonic, atonic, or focal to bilateral tonic-clonic) per 28 days in each 4-week period of an 8-week historical period. After a 6-week prospective baseline period, patients were randomly assigned (1:1) via an interactive web response system to receive either enteral adjunctive ganaxolone or matching enteral adjunctive placebo (maximum dose 63 mg/kg per day for patients weighing ≤28 kg or 1800 mg/day for patients weighing >28 kg) for 17 weeks. Patients, caregivers, investigators (including those analysing data), trial staff, and the sponsor (other than the investigational product manager) were masked to treatment allocation. The primary efficacy endpoint was percentage change in median 28-day major motor seizure frequency from the baseline period to the 17-week double-blind phase and was analysed (using a Wilcoxon-rank sum test) in all patients who received at least one dose of trial treatment and for whom baseline data were available. Safety (compared descriptively across groups) was analysed in all patients who received at least one dose of trial treatment. This study is registered with ClinicalTrials.gov, NCT03572933, and the open-label extension phase is ongoing. FINDINGS: Between June 25, 2018, and July 2, 2020, 114 patients were screened for eligibility, of whom 101 (median age 6 years [IQR 3 to 10]) were randomly assigned to receive either ganaxolone (n=50) or placebo (n=51). All patients received at least one dose of a study drug, but seizure frequency for one patient in the ganaxolone group was not recorded at baseline and so the primary endpoint was analysed in a population of 100 patients. There was a median percentage change in 28-day major motor seizure frequency of -30·7% (IQR -49·5 to -1·9) in the ganaxolone group and of -6·9% (-24·1 to 39·7) in the placebo group (p=0·0036). The Hodges-Lehmann estimate of median difference in responses to ganaxolone versus placebo was -27·1% (95% CI -47·9 to - 9·6). Treatment-emergent adverse events occurred in 43 (86%) of 50 patients in the ganaxolone group and in 45 (88%) of 51 patients in the placebo group. Somnolence, pyrexia, and upper respiratory tract infections occurred in at least 10% of patients in the ganaxolone group and more frequently than in the placebo group. Serious adverse events occurred in six (12%) patients in the ganaxolone group and in five (10%) patients in the placebo group. Two (4%) patients in the ganaxolone group and four (8%) patients in the placebo group discontinued the trial. There were no deaths in the double-blind phase. INTERPRETATION: Ganaxolone significantly reduced the frequency of CDD-associated seizures compared with placebo and was generally well tolerated. Results from what is, to our knowledge, the first controlled trial in CDD suggest a potential treatment benefit for ganaxolone. Long-term treatment is being assessed in the ongoing open-label extension phase of this trial. FUNDING: Marinus Pharmaceuticals

Ferritin Metabolism Reflects Multiple Myeloma Microenvironment and Predicts Patient Outcome

Multiple myeloma (MM) is a hematologic malignancy with a multistep evolutionary pattern, in which the pro-inflammatory and immunosuppressive microenvironment and genomic instability drive tumor evolution. MM microenvironment is rich in iron, released by pro-inflammatory cells from ferritin macromolecules, which contributes to ROS production and cellular damage. In this study, we showed that ferritin increases from indolent to active gammopathies and that patients with low serum ferritin had longer first line PFS (42.6 vs. 20.7 months and, p = 0.047, respectively) and OS (NR vs. 75.1 months and p = 0.029, respectively). Moreover, ferritin levels correlated with systemic inflammation markers and with the presence of a specific bone marrow cell microenvironment (including increased MM cell infiltration). Finally, we verified by bioinformatic approaches in large transcriptomic and single cell datasets that a gene expression signature associated with ferritin biosynthesis correlated with worse outcome, MM cell proliferation, and specific immune cell profiles. Overall, we provide evidence of the role of ferritin as a predictive/prognostic factor in MM, setting the stage for future translational studies investigating ferritin and iron chelation as new targets for improving MM patient outcome