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We present electrical characterization data of sputtered Nb/a-Si/Nb Josephson junctions (JJs) for high-speed and high-density superconducting circuits. Junctions were studied with critical current densities ( J c ) ranging from 0.01 to 3 mA/μm2 at 4 K. For junctions deposited at room temperature and processed to a maximum temperature of 150 °C, the dependence of J c on barrier thickness d is exponential, J c ∝ exp (− d / d 0) , with d 0 constant over the entire range of J c values studied. Junctions were annealed at temperatures up to 300 °C to study changes in their electrical properties and possible compatibility with high temperature fabrication processes. Current–voltage characteristics, critical current uniformity, critical current modulation with in-plane magnetic field, and sub-gap resistance behavior of these junctions were measured at 4 K and demonstrate that the junction properties do not degrade with annealing. These data indicate that Nb/a-Si/Nb JJs are a potential candidate for higher speed and higher density superconducting circuits. [ABSTRACT FROM AUTHOR]

Introduction: The transparency of data on the value chain of medicines is crucial for the study and monitoring of the pharmaceutical system. These data may impact medicine pricing negotiations, contribute to patient access to pharmaceutical products, and strengthen health systems. Objective: This study analyzed the national strategies to ensure the transparency of data from medicine cost development to marketing in Argentina, Brazil, and Colombia. Method: A descriptive study was carried out by searching databases, reports, documents, and scientific articles published between January and August 2022 related to rules on transparency and databases, including 1) marketing authorization; 2) pricing; 3) intellectual property; 4) clinical trials; 5) research and development (R&D); and 6) health technology assessment (HTA) of selected biopharmaceuticals. Results: Transparency data, rules, and information are not uniform. The infostructures (organizational capacity for collecting and distributing information) regarding the pharmaceutical value chain in these three countries face limitations in appropriate measures to publicly share data and evidence, including pre-clinical data, clinical data, and costs. None of the countries require transparency about data on research and development costs. All three countries present similar publicization of data on marketing authorization and intellectual property, with some differences. The significant limitations in Argentina include the absence of formal price regulation and data on the volume of medicine purchased and respective amounts paid. Among the three countries, Brazil showed a higher degree of information transparency, perhaps due to the legal regulation that guarantees citizens access to information of public interest. Brazil also stands out in terms of the public availability of HTA reports and pricing, in addition to the highest volume of information. In contrast, Colombia has in place a decree that allows 5 years of trial data exclusivity for new medicines, an act contrary to data transparency. Despite the different stages of transparency, no country has evidenced a robust use of these data in public policy decision-making. Conclusion: The results reinforce the presence of information asymmetry between stakeholders, data fragmentation, data gaps and overlap, and difficulty in comparing available data across the three countries and the use of these data nationally to produce evidence. [ABSTRACT FROM AUTHOR]

Superconducting optoelectronic hardware has been proposed for large-scale neural computing. In this work, we expand upon the circuit and network designs previously introduced. We investigate circuits using superconducting single-photon detectors and Josephson junctions to perform signal reception, synaptic weighting, and integration. Designs are presented for synapses and neurons that perform integration of rate-coded signals as well as detect coincidence events for temporal coding. A neuron with a single integration loop can receive input from thousands of synaptic connections, and many such loops can be employed for dendritic processing. We show that a synaptic weight can be modified via a superconducting flux-storage loop inductively coupled to the current bias of the synapse. Synapses with hundreds of stable states are designed. Spike-timing-dependent plasticity can be implemented using two photons to strengthen and two photons to weaken the synaptic weight via Hebbian-type learning rules. In addition to the synaptic receiver and plasticity circuits, we describe an amplifier chain that converts the current pulse generated when a neuron reaches threshold to a voltage pulse sufficient to produce light from a semiconductor diode. This light is the signal used to communicate between neurons in the network. We analyze the performance of the elements in the amplifier chain to calculate the energy consumption per photon created. The speed of the amplification sequence allows neuronal firing up to at least 20 MHz, independent of connectivity. We consider these neurons in network configurations to investigate near-term technological potential and long-term physical limitations. By modeling the physical size of superconducting optoelectronic neurons, we calculate the area of these networks. A system with 8100 neurons and 330 430 total synapses will fit on a 1 × 1 cm 2 die. Systems of millions of neurons with hundreds of millions of synapses will fit on a 300 mm wafer. For multiwafer assemblies, communication at light speed enables a neuronal pool the size of a large data center (10 5 m 2) comprised of trillions of neurons with coherent oscillations at 1 MHz. [ABSTRACT FROM AUTHOR]

We are developing a new instrument, the RF Josephson arbitrary waveform synthesizer (RF-JAWS), for communications metrology and quantum information applications. An important aspect of the RF-JAWS design is the accurate and traceable characterization of its superconducting devices. In this article, we present a procedure for characterizing microwave superconducting devices in a cryogenic RF probe station via a vector network analyzer (VNA) calibrated with a custom cryogenic calibration kit colocated with the superconducting device under test (DUT) in the cryogenic environment. By de-embedding lossy and dispersive RF interconnects linking the superconducting DUT to the measurement apparatus at room temperature, we characterize the DUT exactly at the cryogenic on-wafer reference plane. More importantly, we operate our VNA with an external modulated source and our procedure features metrology-grade multiline thru-reflect-line calibration and absolute power and phase corrections, as opposed to the more common relative scattering-parameter correction. In addition, we apply an X-parameter model to account for impedance mismatch in cryogenic Josephson microwave sources. Our techniques are also suitable for cryogenic characterization of microwave superconducting devices for solid-state quantum computers and could help to optimize the quantum-classical interfaces in these systems. [ABSTRACT FROM AUTHOR]

We designed, simulated, and experimentally demonstrated components for a microwave-frequency digital-to-analog converter based on single flux quantum (SFQ) circuits and an amplifier based on superconducting-quantum-interference-device (SQUID) stacks. These are key components for a self-calibrated programmable waveform reference for communications metrology capable of synthesizing high-frequency signals with quantum-based output accuracy. The amplifier is an SFQ voltage multiplier circuit that consists of a network of SFQ-splitters and SQUID transformers that provides output signals consisting of quantized pulses. The circuits were fabricated using our Nb/Nbx Si1-x/Nb Josephson-junction (JJ) fabrication process, which produces self-shunted JJs with Nb-doped silicon barriers. In order to demonstrate quantum-based reproducibility, stability and performance at 4 K, we synthesized single-tone and multitone waveforms at gigahertz frequencies and demonstrated their operation over a range of synthesizer output and experimental bias parameters. We also propose circuit designs for achieving higher synthesis frequencies and higher output power with improved power accuracy and spectral purity, and discuss the potential limitations of these circuits. [ABSTRACT FROM AUTHOR]

Circular RNAs (circRNAs) are expressed and are regulated in many biological processes but little is known about their ability to directly control mRNA homeostasis. We show that circRNA zinc finger protein 609 (circZNF609) interacts with several mRNAs increasing the final protein levels, which in the case of the cytoskeleton-associated protein 5 (CKAP5) leads to a stabilized microtubule cytoskeleton and an enhanced tumor cell proliferation. [ABSTRACT FROM AUTHOR]

Crystal-storing histiocytosis (CSH) is an uncommon condition in which histiocytes accumulate a crystalline matter within their cytoplasm. Generally, those crystals are composed of either monoclonal or polyclonal immunoglobulin chains, which have a strong association with an underlying lymphoproliferative or plasma cell disorder (LP-PCD). Rarely, CSH has been reported as local or generalized manifestation of a variety of benign disorders. These cases are associated with crystals composed of nonimmunoglobulin substances. We are reporting an exceptional case of a local colonic CSH with Charcot–Leyden crystals. This patient underwent a screening colonoscopy that detected some polyps. The biopsy reported tubular adenomas, with a markedly dense, transmural inflammatory infiltrates, which were predominantly composed of eosinophils and crystal-storing histiocytes containing Charcot–Leyden crystals. The patient had a negative workup for LP-PCD and autoimmune conditions, including a normal skeletal survey and bone marrow aspirate/biopsy. The only positive laboratory workup was an elevated absolute eosinophil count and a positive IgG anti-Strongyloides antibody. Giving those findings, this parasitic infection is the most likely etiology of the CSH in our patient. Although there was an initial negative evaluation for LP-PCD, close monitoring of patients with either immunoglobulin or nonimmunoglobulin CSH is recommended. [ABSTRACT FROM AUTHOR]

We describe our process for fabricating single-flux-quantum circuits for applications in communications metrology, advanced computing, and quantum information. The process flow includes four superconducting metal layers, one junction layer, one palladium-gold bias resistor layer, and a contact pad layer. Planarization using chemical–mechanical polishing is performed on the two lower insulating layers. This process is based on Josephson junctions with niobium superconducting electrodes and self-shunted, amorphous niobium-doped silicon barriers on the insulating side near the metal-insulator transition. The barrier material is deposited by cosputtering silicon and niobium, with the junction properties controlled by the relative sputtering powers and the duration of the barrier deposition step. The profiles of the deposition rates across 3-in (76.2 mm) wafers give a corresponding radial profile of the critical current density $\boldsymbol{J_\mathrm{c}}$ that increases by $\boldsymbol{\sim }\text{46}$ % from the center to the edge of the wafer. To characterize our process, we have measured and show data for niobium metal quality and its magnetic penetration depth, as well as for wire and via inductances, and for via critical currents. The uniformity of the junction critical current $\boldsymbol{I_\mathrm{c}}$ across a wafer was measured on test chips with 2.7- ${\mu }$ m-diameter junctions. Within a 5 mm $\boldsymbol{\times }$ 5 mm area, the standard deviation of $\boldsymbol{I_\mathrm{c}}$ was $\boldsymbol{\sim }\text{2}$ % for chips near the center of the wafer and up to $\boldsymbol{\sim }\text{7}$ % for chips near the edge. We also describe process improvements and innovations under development aimed at increasing circuit density and high-speed performance. [ABSTRACT FROM AUTHOR]

The initiation and the regulation of the Zeb2 or Sip1 expression during the process of snail-1 induced epithelial-mesenchymal transition (EMT) are discussed. The activation of the Zeb2 expression is shown to be highly dependent on the presence of a natural antisense transcript (NAT) in the pathway.

Cutaneous involvement by precursor T-cell lymphoblastic leukemia/lymphoma (T-ALL/LBL) is rare, and almost all cases are seen in association with bone marrow, blood, and/or lymph node involvement. Presentation with isolated skin involvement is very rare. Literature review revealed only one case report of primary cutaneous T-cell LBL. We discuss here another patient diagnosed with primary cutaneous T-cell LBL at our institute. This patient was initially misdiagnosed as having peripheral T-cell lymphoma NOS. Cytogenetic analysis showed the CDKN2A deletion (−9p21×2) in addition to three intact copies of ABL1 (+9q34). Although she failed multiple lines of intensive chemotherapy, her disease remained confined to the skin. We believe that this presentation of T-LBL is underreported, and many patients are likely misdiagnosed as having high-grade cutaneous T-cell lymphomas. With this case and literature review, we would like to highlight the importance of keeping lymphoblastic lymphoma on the differential diagnosis of cutaneous T-cell lymphoma-like lesions to avoid delay in diagnosis and inappropriate treatment of this aggressive disease. [ABSTRACT FROM AUTHOR]

This research is focused on analyzing the environmental pollution potential of biomass bottom ashes as individual materials, as mixtures manufactured with biomass bottom ashes and granular construction aggregates, and these mixtures treated with cement. For the environmental assessment of all of the samples and materials mentioned, the following leaching procedures have been performed: the compliance batch test of UNE-EN 12457-3:2003 for aggregates and bottom ashes; the column test according to NEN 7343:1994 for the mixtures prepared in the laboratory; and the tank test by EA NEN 7375:2004 for analyzing the behavior of mixtures after their solidification/stabilization with 5% cement. After the discussion of the data, the reduction of the pollution load of the most hazardous biomass bottom ashes after their combination with different aggregates can be confirmed, which implies their possible application in civil infrastructures, such as filler embankments and road construction layers, without negatively impacting the environment. In addition, the positive effect of the stabilization/solidification of the cement-treated mixtures with a reduction of the heavy metals that were released at the highest levels, namely As, Hg Cr, Ni, Cu, Se and Mo, was proven. [ABSTRACT FROM AUTHOR]

Transcriptome analyses have revealed the existence of a large variety of non-coding RNAs (ncRNAs) that, although specifically expressed, are largely unknown in function. The best-studied role of ncRNAs is the regulation of gene expression, mostly participating in transcription. We report here the role of an antisense ncRNA that represses transcription of LEF1 by recruiting Polycomb repressive complex 2 (PRC2), which trimethylates H3K27. This antisense LEF1 transcript undergoes splicing losing its inhibitory function. We also discuss the possible general relevance of this finding. [ABSTRACT FROM PUBLISHER]

Polycomb repressive complex 2 (PRC2) methylates histone H3 lysine 27 (H3K27me3) to maintain gene repression and is essential for cell differentiation. In low-grade endometrial stromal sarcoma (LG-ESS), the PRC2 subunit SUZ12 is often fused with the NuA4/TIP60 subunit JAZF1. We show that JAZF1-SUZ12 dysregulates PRC2 composition, genome occupancy, histone modification, gene expression, and cell differentiation. Loss of the SUZ12 N terminus in the fusion protein abrogates interaction with specific PRC2 accessory factors, reduces occupancy at PRC2 target genes, and diminishes H3K27me3. Fusion to JAZF1 increases H4Kac at PRC2 target genes and triggers recruitment to JAZF1 binding sites during cell differentiation. In human endometrial stromal cells, JAZF1-SUZ12 upregulated PRC2 target genes normally activated during decidualization while repressing genes associated with immune clearance, and JAZF1-SUZ12-induced genes were also overexpressed in LG-ESS. These results reveal defects in chromatin regulation, gene expression, and cell differentiation caused by JAZF1-SUZ12 that may underlie its role in oncogenesis. [Display omitted] • JAZF1-SUZ12 fails to bind PRC2 subunits due to loss of the SUZ12 N terminus • JAZF1-SUZ12 switches to a JAZF1-like binding profile during cell differentiation • JAZF1-SUZ12 reduces H3K27me3 and increases H4Kac at polycomb target genes • JAZF1-SUZ12 activates polycomb target genes and dysregulates hEnSC decidualization Fusion of JAZF to SUZ12 often occurs in endometrial stromal sarcoma, but the effects of JAZF1-SUZ12 on chromatin and cell differentiation are not understood. Tavares et al. demonstrate that JAZF1-SUZ12 alters PRC2 composition and genome occupancy, reduces H3K27me3 and increases H4Kac, and dysregulates gene expression and endometrial stromal cell decidualization. [ABSTRACT FROM AUTHOR]

Circular RNAs (circRNAs) are widely expressed in eukaryotes and are regulated in many biological processes. Although several studies indicate their activity as microRNA (miRNA) and protein sponges, little is known about their ability to directly control mRNA homeostasis. We show that the widely expressed circZNF609 directly interacts with several mRNAs and increases their stability and/or translation by favoring the recruitment of the RNA-binding protein ELAVL1. Particularly, the interaction with CKAP5 mRNA, which interestingly overlaps the back-splicing junction, enhances CKAP5 translation, regulating microtubule function in cancer cells and sustaining cell-cycle progression. Finally, we show that circZNF609 downregulation increases the sensitivity of several cancer cell lines to different microtubule-targeting chemotherapeutic drugs and that locked nucleic acid (LNA) protectors against the pairing region on circZNF609 phenocopy such effects. These data set an example of how the small effects tuned by circZNF609 /CKAP5 mRNA interaction might have a potent output in tumor growth and drug response. [Display omitted] • circZNF609 interacts with CKAP5 , UPF2 , and SRRM1 mRNAs in vivo • circZNF609-mRNA interaction increases ELAVL1 loading on the mRNAs • ELAVL1 loading by circZNF609 regulates stability and translation of its targets • CAKP5 regulation alters MT dynamics, sensitizing cells to chemotherapeutic drugs In this article, Rossi et al. provide an interesting mechanism in which circZNF609-mRNA interaction increases translation, and among them, CKAP5 is a key factor in microtubule dynamics stability. The authors show how the disruption of RNA-RNA interactions is able to alter microtubule dynamics, sensitizing rhabdomyosarcoma cells to chemotherapeutic drugs. [ABSTRACT FROM AUTHOR]

The transcription factor SNAIL1 is a master regulator of epithelial to mesenchymal transition. SNAIL1 is a very unstable protein, and its levels are regulated by the E3 ubiquitin ligase β-TrCP1 that interacts with SNAIL1 upon its phosphorylation by GSK-3β. Here we show that SNAIL! polyubiquitylation and degradation may occur in conditions precluding SNAIL1 phosphorylation by GSK-3β, suggesting that additional E3 ligases participate in the control of SNAIL1 protein stability. In particular, we demonstrate that the F-box E3 ubiquitin ligase FBX114 interacts with SNAIL 1 and promotes its ubiquitylation and proteasome degradation independently of phosphorylation by GSK-3β. In vivo, inhibition of FBXI14 using short hairpin RNA stabilizes both ectopically expressed and endogenous SNAIL1. Moreover, the expression of FBXI14 is potently down-regulated during hypoxia, a condition that increases the levels of SNAIL! protein but not SNAIL1 mRNA. FBX14 mRNA is decreased in tumors with a high expression of two proteins up-regulated in hypoxia, carbonic anhydrase 9 and TWIST 1. In addition, Twist1 small interfering RNA prevents hypoxia-induced Fbxl14 down-regulation and SNAIL1 stabilization in NMuMG cells. Altogether, these results demonstrate the existence of an alternative mechanism controlling SNAIL1 protein levels relevant for the induction of SNAIL1 during hypoxia. [ABSTRACT FROM AUTHOR]

We characterize the signal bandwidth and dynamic range of a recently developed type of Josephson parametric amplifier. These amplifiers consist of a series array of SQUIDs embedded in a microwave cavity. They are narrow band, only amplifying signals close to the cavity's resonance frequency, but the cavity's resonance frequency, and hence the amplified band, can be widely tuned. For a particular realization of these amplifiers we measure how the signal bandwidth depends on amplifier's gain. We find that the amplitude gain times signal bandwidth is approximately the linewidth of the cavity. In addition we measure the amplifier's dynamic range and saturation power. [ABSTRACT FROM AUTHOR]

A number of regulatory factors are recruited to chromatin by specialized RNAs. Whether RNA has a more general role in regulating the interaction of proteins with chromatin has not been determined. We used proteomics methods to measure the global impact of nascent RNA on chromatin in embryonic stem cells. Surprisingly, we found that nascent RNA primarily antagonized the interaction of chromatin modifiers and transcriptional regulators with chromatin. Transcriptional inhibition and RNA degradation induced recruitment of a set of transcriptional regulators, chromatin modifiers, nucleosome remodelers, and regulators of higher-order structure. RNA directly bound to factors, including BAF, NuRD, EHMT1, and INO80 and inhibited their interaction with nucleosomes. The transcriptional elongation factor P-TEFb directly bound pre-mRNA, and its recruitment to chromatin upon Pol II inhibition was regulated by the 7SK ribonucleoprotein complex. We postulate that by antagonizing the interaction of regulatory proteins with chromatin, nascent RNA links transcriptional output with chromatin composition. [Display omitted] • Pol II inhibition induced recruitment of a set of regulatory proteins to chromatin • Many of these changes were also observed upon RNA degradation • RNA binds a set of chromatin modifiers and inhibits interaction with nucleosomes • P-TEFb binds pre-mRNA, and 7SK regulates its interaction with RNA and chromatin Nascent RNA interacts with a wide array of regulatory proteins but its impact on chromatin composition has not been assessed. Skalska and colleagues use proteomics methods to reveal that nascent RNA antagonizes the association of a set of regulatory proteins with chromatin. [ABSTRACT FROM AUTHOR]

Introduction: The transparency of data on the value chain of medicines is crucial for the study and monitoring of the pharmaceutical system. These data may impact medicine pricing negotiations, contribute to patient access to pharmaceutical products, and strengthen health systems. Objective: This study analyzed the national strategies to ensure the transparency of data from medicine cost development to marketing in Argentina, Brazil, and Colombia. Method: A descriptive study was carried out by searching databases, reports, documents, and scientific articles published between January and August 2022 related to rules on transparency and databases, including 1) marketing authorization; 2) pricing; 3) intellectual property; 4) clinical trials; 5) research and development (R&D); and 6) health technology assessment (HTA) of selected biopharmaceuticals. Results: Transparency data, rules, and information are not uniform. The infostructures (organizational capacity for collecting and distributing information) regarding the pharmaceutical value chain in these three countries face limitations in appropriate measures to publicly share data and evidence, including pre-clinical data, clinical data, and costs. None of the countries require transparency about data on research and development costs. All three countries present similar publicization of data on marketing authorization and intellectual property, with some differences. The significant limitations in Argentina include the absence of formal price regulation and data on the volume of medicine purchased and respective amounts paid. Among the three countries, Brazil showed a higher degree of information transparency, perhaps due to the legal regulation that guarantees citizens access to information of public interest. Brazil also stands out in terms of the public availability of HTA reports and pricing, in addition to the highest volume of information. In contrast, Colombia has in place a decree that allows 5 years of trial data exclusivity for new medicines, an act contrary to data transparency. Despite the different stages of transparency, no country has evidenced a robust use of these data in public policy decision-making. Conclusion: The results reinforce the presence of information asymmetry between stakeholders, data fragmentation, data gaps and overlap, and difficulty in comparing available data across the three countries and the use of these data nationally to produce evidence., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ribeiro, Acosta, Pontes, Machado Beltran, Peixoto and Leite.)

We demonstrate Josephson arbitrary waveform synthesizers (JAWS) with increased operating temperature range for temperatures below 4 K. These JAWS synthesizers were fabricated with externally-shunted Nb/ a -Si/Nb junctions whose critical current exhibits improved temperature stability compared to the self-shunted Nb/Nb 0.15 Si 0.85 /Nb junctions typically used. Vertical stud resistors made of 230 nm of PdAu were developed to provide the milliohm shunt resistance required for junction overdamping while maintaining a small footprint suitable for high-density series arrays embedded in a coplanar waveguide. We evaluated the performance of these resistors from 3.8 K down to 20 mK. We designed, fabricated and tested a JAWS circuit with 4650 externally shunted Nb/ a -Si/Nb JJs with a critical current density ( J c ) of 0.12 mA ∕ μ m 2 and critical current ( I c ) of 3 mA. This circuit was designed to be mounted to the 3 K stage of a dilution refrigerator and used to control and calibrate a qubit mounted at the 10 mK stage. To increase the circuit density of the JAWS circuits we made arrays of two-junction vertical stacks. Current-voltage ( I - V ) curves of this JAWS circuit with stacked junctions under microwave excitation show Shapiro steps with quantum-locking ranges similar to those of JAWS circuits used for qubit control.

Polycomb repressive complex 2 (PRC2) modifies chromatin to maintain genes in a repressed state during development. PRC2 is primarily associated with CpG islands at repressed genes and also possesses RNA binding activity. However, the RNAs that bind PRC2 in cells, the subunits that mediate these interactions, and the role of RNA in PRC2 recruitment to chromatin all remain unclear. By performing iCLIP for PRC2 in comparison with other RNA binding proteins, we show here that PRC2 binds nascent RNA at essentially all active genes. Although interacting with RNA promiscuously, PRC2 binding is enriched at specific locations within RNAs, primarily exon-intron boundaries and the 3' UTR. Deletion of other PRC2 subunits reveals that SUZ12 is sufficient to establish this RNA binding profile. Contrary to prevailing models, we also demonstrate that the interaction of PRC2 with RNA or chromatin is mutually antagonistic in cells and in vitro. RNA degradation in cells triggers PRC2 recruitment to CpG islands at active genes. Correspondingly, the release of PRC2 from chromatin in cells increases RNA binding. Consistent with this, RNA and nucleosomes compete for PRC2 binding in vitro. We propose that RNA prevents PRC2 recruitment to chromatin at active genes and that mutual antagonism between RNA and chromatin underlies the pattern of PRC2 chromatin association across the genome., (© 2016 Beltran et al.; Published by Cold Spring Harbor Laboratory Press.)