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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]

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]

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]

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]

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]

Objective: Routine medical testing is not recommended before cataract surgery, but no consensus exists about preoperative testing before general ophthalmologic surgery. We aimed to assess the impact of preoperative testing on patients undergoing ophthalmologic surgery by analyzing their surgical outcomes and complications.Methods: We retrospectively reviewed electronic health records of patients who had preoperative evaluations before cataract or noncataract ophthalmologic surgery at a tertiary care center from January 1, 2015, through December 31, 2019.Results: The cohort consisted of 2268 patients (1270 [56.0%] women). The most frequent ophthalmologic procedure was cataract extraction (n = 1450 [63.9%]). Laboratory tests results were available for 489 patients (33.7%) in the cataract group; of these, 275 results (56.2%) had abnormal values, and 18 patients (6.5%) required preoperative interventions. Preoperative test results were available for 772 out of 818 patients (94.4%) having noncataract procedures. Of these, 384 results (49.7%) had abnormal values, and 10 patients (2.6%) required additional intervention. No significant differences were observed for the rate of surgery cancellations between the cataract and noncataract patient groups (0.6% vs 1.0%; P = .24). Of the 12 patients (0.5%) who had complications, all had undergone preoperative testing.Conclusions: No differences in outcomes and complications were observed among patients who underwent cataract or noncataract surgery. It is reasonable to consider avoiding preoperative testing in patients undergoing ophthalmologic surgery. [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]

Most studies of cohesin function consider the Stromalin Antigen (STAG/SA) proteins as core complex members given their ubiquitous interaction with the cohesin ring. Here, we provide functional data to support the notion that the SA subunit is not a mere passenger in this structure, but instead plays a key role in the localization of cohesin to diverse biological processes and promotes loading of the complex at these sites. We show that in cells acutely depleted for RAD21, SA proteins remain bound to chromatin, cluster in 3D and interact with CTCF, as well as with a wide range of RNA binding proteins involved in multiple RNA processing mechanisms. Accordingly, SA proteins interact with RNA, and R-loops, even in the absence of cohesin. Our results place SA1 on chromatin upstream of the cohesin ring and reveal a role for SA1 in cohesin loading which is independent of NIPBL, the canonical cohesin loader. We propose that SA1 takes advantage of structural R-loop platforms to link cohesin loading and chromatin structure with diverse functions. Since SA proteins are pan-cancer targets, and R-loops play an increasingly prevalent role in cancer biology, our results have important implications for the mechanistic understanding of SA proteins in cancer and disease. [ABSTRACT FROM AUTHOR]

Expression of Snail1 in epithelial cells triggers an epithelial-mesenchymal transition (EMT). Here, we demonstrate that the synthesis of Zeb2, a transcriptional repressor of E-cadherin, is up-regulated after Snail1-induced EMT. Snail1 does not affect the synthesis of Zeb2 mRNA, but prevents the processing of a large intron located in its 5'-untranslated region (UTR). This intron contains an internal ribosome entry site (IRES) necessary for the expression of Zeb2. Maintenance of 5'-UTR Zeb2 intron is dependent on the expression of a natural antisense transcript (NAT) that overlaps the 5' splice site in the intron. Ectopic overexpression of this NAT in epithelial cells prevents splicing of the Zeb2 5'-UTR, increases the levels of Zeb2 protein, and consequently down-regulates E-cadherin mRNA and protein. The relevance of these results is demonstrated by the strong association between NAT presence and conservation of the 5'-UTR intron in cells that have undergone EMT or in human tumors with low E-cadherin expression. Therefore, the results presented in this article reveal the existence of a NAT capable of activating Zeb2 expression, explain the mechanism involved in this activation, and demonstrate that this NAT regulates E-cadherin expression. [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]

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]

Background Salt consumption activates the brain reward system, inducing cravings and the search for salted food. Its excessive intake is associated with high blood pressure and obesity. The high quantity of salt in processed food is most likely a major cause of the global pandemic of hypertension (HT). Objective To review the current information on the topic of salt addiction and the health consequences this has. Method A search in PubMed, ScienceDirect, and EBSCOhost databases was conducted with the keywords "salt", "salt addiction", and "food addiction". Articles with information relative to the topic of interest were checked, as were references of those articles and historical and culturally complementary information. Results We described the historical relationship between man and salt, the physiology of salty taste perception, its role in the reward system and the health consequences of a high sodium diet. Discussion and conclusion There is physiological and behavioural evidence that some people may develop a true addiction to food. Among these people, salt addiction seems to be of great importance in the development of obesity, HT and other diseases. Sodium is present in high quantities in processed food as salt and monosodium glutamate (MSG), used as flavour enhancers and food preservatives, including in non-salty foods like bread and soft drinks. [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]