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Atmospheric regime transitions are highly impactful as drivers of extreme weather events, but pose two formidable modeling challenges: predicting the next event (weather forecasting) and characterizing the statistics of events of a given severity (the risk climatology). Each event has a different duration and spatial structure, making it hard to define an objective "average event." We argue here that transition path theory (TPT), a stochastic process framework, is an appropriate tool for the task. We demonstrate TPT's capacities on a wave–mean flow model of sudden stratospheric warmings (SSWs) developed by Holton and Mass, which is idealized enough for transparent TPT analysis but complex enough to demonstrate computational scalability. Whereas a recent article (Finkel et al. 2021) studied near-term SSW predictability, the present article uses TPT to link predictability to long-term SSW frequency. This requires not only forecasting forward in time from an initial condition, but also backward in time to assess the probability of the initial conditions themselves. TPT enables one to condition the dynamics on the regime transition occurring, and thus visualize its physical drivers with a vector field called the reactive current. The reactive current shows that before an SSW, dissipation and stochastic forcing drive a slow decay of vortex strength at lower altitudes. The response of upper-level winds is late and sudden, occurring only after the transition is almost complete from a probabilistic point of view. This case study demonstrates that TPT quantities, visualized in a space of physically meaningful variables, can help one understand the dynamics of regime transitions. [ABSTRACT FROM AUTHOR]

Traditional numerical methods for calculating matrix eigenvalues are prohibitively expensive for high-dimensional problems. Iterative random sparsification methods allow for the estimation of a single dominant eigenvalue at reduced cost by leveraging repeated random sampling and averaging. We present a general approach to extending such methods for the estimation of multiple eigenvalues and demonstrate its performance for several benchmark problems in quantum chemistry. [ABSTRACT FROM AUTHOR]

Rare events arising in nonlinear atmospheric dynamics remain hard to predict and attribute. We address the problem of forecasting rare events in a prototypical example, sudden stratospheric warmings (SSWs). Approximately once every other winter, the boreal stratospheric polar vortex rapidly breaks down, shifting midlatitude surface weather patterns for months. We focus on two key quantities of interest: the probability of an SSW occurring, and the expected lead time if it does occur, as functions of initial condition. These optimal forecasts concretely measure the event's progress. Direct numerical simulation can estimate them in principle but is prohibitively expensive in practice: each rare event requires a long integration to observe, and the cost of each integration grows with model complexity. We describe an alternative approach using integrations that are short compared to the time scale of the warming event. We compute the probability and lead time efficiently by solving equations involving the transition operator, which encodes all information about the dynamics. We relate these optimal forecasts to a small number of interpretable physical variables, suggesting optimal measurements for forecasting. We illustrate the methodology on a prototype SSW model developed by Holton and Mass and modified by stochastic forcing. While highly idealized, this model captures the essential nonlinear dynamics of SSWs and exhibits the key forecasting challenge: the dramatic separation in time scales between a single event and the return time between successive events. Our methodology is designed to fully exploit high-dimensional data from models and observations, and has the potential to identify detailed predictors of many complex rare events in meteorology. [ABSTRACT FROM AUTHOR]

Extreme mesoscale weather, including tropical cyclones, squall lines, and floods, can be enormously damaging and yet challenging to simulate; hence, there is a pressing need for more efficient simulation strategies. Here, we present a new rare event sampling algorithm called quantile diffusion Monte Carlo (quantile DMC). Quantile DMC is a simple-to-use algorithm that can sample extreme tail behavior for a wide class of processes. We demonstrate the advantages of quantile DMC compared to other sampling methods and discuss practical aspects of implementing quantile DMC. To test the feasibility of quantile DMC for extreme mesoscale weather, we sample extremely intense realizations of two historical tropical cyclones, 2010 Hurricane Earl and 2015 Hurricane Joaquin. Our results demonstrate quantile DMC's potential to provide low-variance extreme weather statistics while highlighting the work that is necessary for quantile DMC to attain greater efficiency in future applications. [ABSTRACT FROM AUTHOR]

Direct computer simulation of intense tropical cyclones (TCs) in weather models is limited by computational expense. Intense TCs are rare and have small‐scale structures, making it difficult to produce large ensembles of storms at high resolution. Further, models often fail to capture the process of rapid intensification, which is a distinguishing feature of many intense TCs. Understanding rapid intensification is especially important in the context of global warming, which may increase the frequency of intense TCs. To better leverage computational resources for the study of rapid intensification, we introduce an action minimization algorithm applied to the Weather Research and Forecasting and WRFPLUS models. Action minimization nudges the model into forming more intense TCs than it otherwise would; it does so via the maximum likelihood path in a stochastic formulation of the model, thereby allowing targeted study of intensification mechanisms. We apply action minimization to simulations of Hurricanes Danny (2015) and Fred (2009) at 6‐km resolution to demonstrate that the algorithm consistently intensifies TCs via physically plausible pathways. We show an approximately tenfold computational savings using action minimization to study the tail of the TC intensification distribution. Further, for Hurricanes Danny and Fred, action minimization produces perturbations that preferentially reduce low‐level shear as compared to upper‐level shear, at least above a threshold of approximately 4 m/s. We also demonstrate that asymmetric, time‐dependent patterns of heating can cause significant TC intensification beyond symmetric, azimuthally averaged heating and find a regime of nonlinear response to asymmetric heating that has not been extensively studied in previous work. Key Points: Action minimization reduces the computational cost of intense cyclone simulation as compared to an ensemble studyAction minimization perturbs climate/weather models into producing realistic and more intense tropical cyclonesTime‐dependent, asymmetric heating can contribute significantly to tropical cyclone intensification [ABSTRACT FROM AUTHOR]

The implicit trace estimation problem asks for an approximation of the trace of a square matrix, accessed via matrix-vector products (matvecs). This paper designs new randomized algorithms, XTrace and XNysTrace, for the trace estimation problem by exploiting both variance reduction and the exchangeability principle. For a fixed budget of matvecs, numerical experiments show that the new methods can achieve errors that are orders of magnitude smaller than existing algorithms, such as the Girard--Hutchinson estimator or the Hutch++ estimator. A theoretical analysis confirms the benefits by offering a precise description of the performance of these algorithms as a function of the spectrum of the input matrix. The paper also develops an exchangeable estimator, XDiag, for approximating the diagonal of a square matrix using matvecs. [ABSTRACT FROM AUTHOR]

To determine whether mitigating the harmful effects of circulating microvesicle-associated inducible nitric oxide (MV-A iNOS) in vivo increases the survival of challenged mice in three different mouse models of sepsis, the ability of anti-MV-A iNOS monoclonal antibodies (mAbs) to rescue challenged mice was assessed using three different mouse models of sepsis. The vivarium of a research laboratory Balb/c mice were challenged with an LD80 dose of either lipopolysaccharide (LPS/endotoxin), TNFα, or MV-A iNOS and then treated at various times after the challenge with saline as control or with an anti-MV-A iNOS mAb as a potential immunotherapeutic to treat sepsis. Each group of mice was checked daily for survivors, and Kaplan–Meier survival curves were constructed. Five different murine anti-MV-A iNOS mAbs from our panel of 24 murine anti-MV-A iNOS mAbs were found to rescue some of the challenged mice. All five murine mAbs were used to genetically engineer humanized anti-MV-A iNOS mAbs by inserting the murine complementarity-determining regions (CDRs) into a human IgG1,kappa scaffold and expressing the humanized mAbs in CHO cells. Three humanized anti-MV-A iNOS mAbs were effective at rescuing mice from sepsis in three different animal models of sepsis. The effectiveness of the treatment was both time- and dose-dependent. Humanized anti-MV-A iNOS rHJ mAb could rescue up to 80% of the challenged animals if administered early and at a high dose. Our conclusions are that MV-A iNOS is a novel therapeutic target to treat sepsis; anti-MV-A iNOS mAbs can mitigate the harmful effects of MV-A iNOS; the neutralizing mAb's efficacy is both time- and dose-dependent; and a specifically targeted immunotherapeutic for MV-A iNOS could potentially save tens of thousands of lives annually and could result in improved antibiotic stewardship. [ABSTRACT FROM AUTHOR]

Background: Use of numerical and spatial language, also known as math talk, is critical to the development of foundational number and spatial skills in early childhood. However, caregivers and children of low socioeconomic status (SES) tend to use less math talk than their higher-SES peers. Objective: The current efficacy study tested the hypothesis that quantity of math talk among low-SES caregivers and children is increased via a caregiver education curriculum aimed at improving caregivers' language input to children. Methods: Caregiver-child dyads (n = 37; children aged 17 to 36 months) participated in either the language input or a control intervention. Math talk (operationalized as number and spatial word tokens) was coded from video recordings of each dyad engaging in free play at three time points: baseline, post-intervention, and follow-up. Results: The language input curriculum significantly increased caregivers' amount of spatial talk and cildren's amount of number and spatial talk for up to 4 months after the intervention. Conclusions: A caregiver education intervention increased caregivers' use of math talk, which resulted in higher math talk usage by their children. Further verification is needed through an adequately powered longitudinal randomized controlled trial. [ABSTRACT FROM AUTHOR]

We report on High Temperature Superconductor (HTS) DC current leads developed for the specific purpose of delivering small currents (<100 mA) to cryocooled electronic devices operating at 4 K, with significantly reduced heat leak. Multi-stage cryocoolers can provide a suitable platform for niobium-based superconducting electronics at 4 K; the necessary multiple parallel biasing of the circuitry can result in total currents of several amps, which can produce substantial thermal loading of the cryocooler when conventional resistive leads are used. Our approach has been to adapt the comparatively mature technology of high-current second-generation (2G) YBCO-coated conductor tape to low current needs by splitting the tape into electrically isolated narrow lines by ion milling. Performance issues discussed are: obtained critical currents, thermal conductance of the composite conductors, line-to-line electrical isolation, resistance of the joints and robustness. Operation as a current lead between the first and second stage of a Gifford-McMahon cryocooler is reported. [ABSTRACT FROM AUTHOR]

We report on the performance of a 1-V dc programmable Josephson voltage standard (PJVS) operating on a commercially available Gifford-McMahon cryocooler at 4 K. The NIST-fabricated niobium superconductor-normal metal-superconductor junction chip has been shown to operate successfully as integrated with this cryopackage, generating 1.229 V at the maximum operating frequency of 19.364 GHz with Shapiro steps at constant voltage that are flat to within less than 100 nV. Because of the large operating margin (greater than 1 mA), these steps were highly stable and immune from noise. Differences in behavior of the PJVS in liquid helium and on the cryocooler are discussed. This demonstration paves the way towards automated warming and cooling of the Josephson device and a fully automated voltage standard system. [ABSTRACT FROM AUTHOR]

Packaging of a superconducting electronic system on a compact multistage cryocooler requires careful management of thermal loads from input and output leads, in order not to exceed the heat lift capacity of the various stages of the cooler. In particular, RSFQ systems typically require a large total bias current Ib ∼ 1 A or greater. A general analysis of resistive wires shows that the tradeoff between heat flow and Joule heating yields a minimum heat load Qmin from optimized bias leads on a Iow-T stage, given by Qmin [0.3 mW/(A - K)]ThotIb, where Thot is the thermalization temperature of the leads on the previous (hotter) stage. This is independent of the material, number, and geometry of the leads, as long as the total lead resistance is optimized. A similar tradeoff between heat flow and signal attenuation can be applied to the optimization of high-frequency input/output lines. Superconducting leads are not subject to these limitations, and can result in further reduction in heat load. Design examples are presented for an RSFQ-based radio receiver on either a two-stage or a four-stage cooler. [ABSTRACT FROM AUTHOR]

Complex RSFQ circuits are typically dc-biased with one or more current bias trees, with current returning through a superconducting ground plane. As the bias currents become larger in mere complex circuits, it is increasingly critical to pay attention to the distribution of these return currents, and the effects of the resulting magnetic fields on the performance of the RSFQ circuits. We have modeled the current and field distributions, and found that magnetic field and flux are indeed significant. This has been confirmed by direct measurement using a distribution of SQUIDs. Furthermore, we have measured the performance of several RSFQ circuits, and have found that currents in the ground plane can significantly affect performance margins. Approaches to circuit and. system designs that can reduce these problems are discussed. [ABSTRACT FROM AUTHOR]

NIST and HYPRES, Inc. have been collaborating to develop a 1 Volt DC programmable Josephson voltage standard (PJVS) that operates on a closed-cycle refrigerator. The goal of this work is to construct a platform that will allow the chip to work at 4 K without liquid helium, thereby making the system more convenient and eliminating the need for users to handle liquid cryogens. In our existing PJVS systems, the Josephson chip temperature is the only parameter that is not computer controlled. The addition of a cryocooler will allow automated warming and cooling of the Josephson device and enable an intrinsic voltage standard system in which every control function is automated, and the only required user input is the desired output voltage. The cryocooler package is designed to allow PJVS chips to be easily interchanged between the cryocooler and liquid helium cryoprobes. [ABSTRACT FROM AUTHOR]

A total of 427 women (aged 18-45 years) who delivered a singleton neonate without serious medical complications were randomized to watch either an educational intervention (n = 225) or the sudden infant death syndrome (n = 202) video. Linear mixed models showed that the intervention women significantly gained knowledge over time. Knowledge gain was largest among high-socioeconomic status (high-SES) and middle-SES English-speaking, smaller among low-SES Spanish-speaking, and nonsignificant among low-SES English-speaking women. Analysis of deviance revealed that the intervention women of all SES learned strategies fostering secure attachment and language acquisition. Participants considered watching an educational video alongside the universal newborn hearing screening (UNHS) conveniently timed. The intervention women were more likely than the control women to recognize the importance of timely UNHS follow-up. [ABSTRACT FROM AUTHOR]

Pemphigus vulgaris (PV) is a life-long, potentially fatal IgG autoantibody-mediated blistering disease targeting mucocutaneous keratinocytes (KCs). PV patients develop pathogenic anti-desmoglein (Dsg) 3 ± 1 and antimitochondrial antibodies (AMA), but it remained unknown whether and how AMA enter KCs and why other cell types are not affected in PV. Therefore, we sought to elucidate mechanisms of cell entry, trafficking, and pathogenic action of AMA in PV. We found that PVIgGs associated with neonatal Fc receptor (FcRn) on the cell membrane, and the PVIgG-FcRn complexes entered KCs and reached mitochondria where they dissociated. The liberated AMA altered mitochondrial membrane potential, respiration, and ATP production and induced cytochrome c release, although the lack or inactivation of FcRn abolished the ability of PVIgG to reach and damage mitochondria and to cause detachment of KCs. The assays of mitochondrial functions and keratinocyte adhesion demonstrated that although the pathobiological effects ofAMA on KCs are reversible, they become irreversible, leading to epidermal blistering (acantholysis), when AMA synergize with anti-Dsg antibodies. Thus, it appears that AMA enter a keratinocyte in a complex with FcRn, become liberated from the endosome in the cytosol, and are trafficked to the mitochondria, wherein they trigger pro-apoptotic events leading to shrinkage of basal KCs uniquely expressing FcRn in epidermis. During recovery, KCs extend their cytoplasmic aprons toward neighboring cells, but anti-Dsg antibodies prevent assembly of nascent desmosomes due to steric hindrance, thus rendering acantholysis irreversible. In conclusion, FcRn is a common acceptor protein for internalization of AMA and, perhaps, for PV autoantibodies to other intracellular antigens, and PV is a novel disease paradigm for investigating and elucidating the role of FcRn in this autoimmune disease and possibly other autoimmune diseases. [ABSTRACT FROM AUTHOR]

A custom-designed laboratory prototype of a four-stage Stirling-type pulse tube cryocooler was recently developed by Lockheed Martin for niobium integrated circuits (ICs) operating close to 4 K. Basic system performance has been verified by integration with a Nb IC test chip, with cells that include a high-speed rapid single flux quantum (RSFQ) binary counter. For 650 W total compressor power, extended stable operation of the counter at T = 4.5 K was demonstrated with a clock frequency up to 46 GHz, with 25 mW of excess cooling capacity on the coldest stage. The thermodynamic, electromagnetic, and mechanical performance are promising for the development of an improved compact cryocooler for practical superconducting electronic applications in fields such as wireless communications. [ABSTRACT FROM AUTHOR]

A novel paradigm of keratinocyte (KC) regulation via nicotinic acetylcholine receptors (nAChR) has been discovered in studies of SLURP (secreted mammalian Ly-6/urokinase-type plasminogen activator receptor-related protein)-1 in Mal de Meleda. We cloned human SLURP-1 and produced recombinant protein and the monoclonal antibody 336H12-1A3 that visualized native SLURP-1. SLURP-1 ligated the conventional ligand-binding site of KC nAChR, showing a higher affinity to the [3H]nicotine-, compared with the [3H]epibatidine-sensitive nAChR. SLURP-1 significantly (p<0.05) increased the activities of caspases 3 and 8, and the number of terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling-positive cells. The pro-apoptotic activity of SLURP-1 exceeded that of tumor necrosis factor-α, suggesting the involvement of separate pathways. In a series of real-time PCR and in-cell western experiments, SLURP-1 significantly (p<0.05) upregulated expression of transglutaminase type I cytokeratin 10, p21, and caspase-3. In the presence of the agonist carbachol, the effects of SLURP-1 on gene expression were augmented, which is in keeping with the notion that SLURP-1 acts as an allosteric agonist at the KC nAChR. Thus, the changes in the cell state induced by SLURP-1 could result from nAChR-mediated effects on the KC gene expression. These results suggest that the biological role of SLURP-1 in the epidermis is to provide fine tuning of the physiologic regulation of KC functions through the cholinergic pathways. [ABSTRACT FROM AUTHOR]

HYPRES is developing a prototype digital system comprising a Nb RSFQ analog-to-digital converter (ADC) and SiGe amplifiers on a commercial two-stage cryocooler. This involves the detailed thermal, electrical, and mechanical design of the ADC chip mount, input/output (I/O) cables, and electromagnetic shielding. Our objective is to minimize the heat load on the second (4 K) stage of the cryocooler, in order to ensure stable ADC operation. The design incorporates thermal radiation shields and magnetic shielding for the RSFQ circuit. For the I/O cables, the thermal design must be balanced against the acceptable attenuation of rf lines and resistance of dc bias lines. SiGe heterojunction bipolar transistor (HBT) signal conditioning circuits, placed on the first (60 K) stage of the cryocooler, will amplify the mV-level ADC outputs to V-level (e.g., ECL) outputs for seamless transition to room-temperature electronics. Cooling these HBT circuits lowers noise and improves their high-frequency performance. Demonstration of this prototype should lead the way to commercialization of high-speed digital superconducting systems, for such applications as wireless communication, radars, and switching networks. [ABSTRACT FROM AUTHOR]

Superconductor digital receiver systems of increasing functionality, modularity and user-friendliness have been developed. The modular design methodology ensures that within its input-output and heat load capacity, the system can be reconfigured to perform a different function by changing the chip module and by reprogramming FPGA-based digital signal processors. One of the systems (ADR-004), originally equipped with a 10\times 10\ mm^2 channelizing receiver chip for signals intelligence application, was reconfigured with a 5\times 5\ mm^2 1.1-GHz bandpass ADC chip to perform world's first multi-net Link-16 demonstration at a U.S. Navy facility. Substantial improvements in system integration have been obtained in each successive generation of digital-RF receiver systems. The latest (third) generation system (ADR-005), hosting a 5\times 5\ mm^2 7.5-GHz bandpass ADC chip and an FPGA channelizer, successfully repeated the over-the-air SATCOM demonstration performed previously using a 1-cm^2 single-chip bandpass digital receiver with an on-chip superconductor channelizer. This system ran error-free for over 12 hours with and without a low-noise amplifier. To our knowledge, this is the first time an X-band SATCOM receiver has been operated without analog amplification and down-conversion in a military application. [ABSTRACT FROM AUTHOR]

HYPRES is developing a class of digital receivers featuring direct digitization at radio frequency. The complete system, consisting of a cryopackaged Nb superconductor All-Digital Receiver (ADR) chip followed by room-temperature interface electronics and a field-programmable gate array (FPGA) based post-processing module, has been developed. Depending on the targeted application the ADR chip comprised either a low-pass delta with phase modulation-demodulation architecture or X-band band-pass sigma-delta modulators together with digital in-phase and quadrature mixer and a pair of digital decimation filters. The chips were fabricated using a 4.5-kA/cm2 HYPRES process and were cryopackaged using a commercial-off-the-shelf cryocooler. Recently, with significant improvements in chip cryopackage, room-temperature electronics and FPGA programming we were able to achieve stable operation of a low-pass ADR at 28.16 GHz and X-band ADR at 30.72 GHz clock frequencies. Experimental results are presented and discussed. [ABSTRACT FROM AUTHOR]

The biologic role of novel cholinergic toxin-like signaling peptides termed SLURP (secreted mammalian Ly-6/uPAR-related protein) in the mucocutaneous epithelium is a subject of intense research. Previous studies demonstrated that SLURP-1 activates the α7 subtype of keratinocyte nicotinic acetylcholine receptors (nAChRs) and facilitates keratinization and programmed cell death, and that the level of SLURP-2 was found to be upregulated several fold in the hyperproliferative skin of patients with psoriasis. In this study, we demonstrated for the first time that human epidermal and oral keratinocytes secrete SLURP-2. We cloned human SLURP-2 and produced the mouse monoclonal antibody 341F10-1F12 that visualized SLURP-2 in the cytoplasm of normal human epidermal and oral keratinocytes grown in culture. In epidermis, SLURP-2 was found predominantly in the suprabasal compartment, whereas in the attached gingiva—in the lowermost epithelial layers. Recombinant SLURP-2 (rSLURP-2) competed with nicotinic radioligands for binding to keratinocytes, showing a higher affinity to the [3H]epibatidine- than [3H]nicotine-labeled sites. Treatment with rSLURP-2 significantly (P < 0.05) increased the number of keratinocytes in culture and their resistance to apoptosis, which could be abolished by mecamylamine more efficiently than α-bungarotoxin. By real-time PCR and in-cell western, rSLURP-2 significantly (P < 0.05) downregulated gene expression of the differentiation markers loricrin, filaggrin, and cytokeratins 1 and 10, and pro-apoptotic Bax, Bad, and caspase 3 which were elevated by high extracellular calcium, and rSLURP-2 also abolished activation of caspases 3 and 8 caused by camptothecin. These results indicated that SLURP-2 competes with acetylcholine predominantly at the α3 nAChR, and that receptor ligation with SLURP-2 delays keratinocyte differentiation and prevents apoptosis. Thus, the different effects observed for SLURP-1 and -2 can be explained by their differential binding to the nAChR subtypes expressed in keratinocytes. These findings present a novel paradigm of the physiologic regulation of mucocutaneous epithelial cells by locally produced small hormone-like peptide molecules, and open novel directions toward better understanding and treating of skin and mucosal diseases. J. Cell. Physiol. © 2006 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Acetylcholine mediates cell‐to‐cell communications in the skin. Human epidermal keratinocytes respond to acetylcholine via two classes of cell‐surface receptors, the nicotinic and the muscarinic cholinergic receptors. High affinity muscarinic acetylcholine receptors (mAChR) have been found on keratinocyte cell surfaces at high density. These receptors mediate effects of muscarinic drugs on keratinocyte viability, proliferation, adhesion, lateral migration, and differentiation. In this study, we investigated the molecular structure of keratinocyte mAChR and their location in human epidermis. Polymerase chain reaction amplification of cDNA sequences uniquely present within the third cytoplasmic loop of each subtype demonstrated the expression of the m1, m3, m4, and m5 mAChR subtypes. To visualize these mAChR, we raised rabbit anti‐sera to synthetic peptide analogs of the carboxyl terminal regions of each subtype. The antibodies selectively bound to keratinocyte mAChR subtypes in immunoblotting membranes and epidermis, both of which could be abolished by preincubating the anti‐serum with the peptide used for immunization. The immunofluorescent staining patterns produced by each antibody in the epidermis suggested that the profile of keratinocyte mAChR changes during epidermal turnover. The semiquantitative analysis of fluorescence revealed that basal cells predominantly expressed m3, prickle cells had equally high levels of m4 and m5, and granular cells mostly possessed m1. Thus, the results of this study demonstrate for the first time the presence of m1, m3, m4, and m5 mAChR in epidermal keratinocytes. Because keratinocytes express a unique combination of mAChR subtypes at each stage of their development in the epidermis, each receptor may regulate a specific cell function. Hence, a single cytotransmitter, acetylcholine, and muscarinic drugs may exert different biologic effects on keratinocytes at different stages of their maturation. [ABSTRACT FROM AUTHOR]