Roger Koenker, Jiaying Gu.

Source: Statistical Science, Volume 34, Number 2, 209--213.

Abstract:
Efron’s elegant approach to $g$-modeling for empirical Bayes problems is contrasted with an implementation of the Kiefer–Wolfowitz nonparametric maximum likelihood estimator for mixture models for several examples. The latter approach has the advantage that it is free of tuning parameters and consequently provides a relatively simple complementary method.

The detection and segmentation of meaningful figures from their background is one of the primary functions of vision. While work in nonhuman primates has implicated early visual mechanisms in this figure–ground modulation, neuroimaging in humans has instead largely ascribed the processing of figures and objects to higher stages of the visual hierarchy. Here, we used high-field fMRI at 7 Tesla to measure BOLD responses to task-irrelevant orientation-defined figures in human early visual cortex (N = 6, four females). We used a novel population receptive field mapping-based approach to resolve the spatial profiles of two constituent mechanisms of figure–ground modulation: a local boundary response, and a further enhancement spanning the full extent of the figure region that is driven by global differences in features. Reconstructing the distinct spatial profiles of these effects reveals that figure enhancement modulates responses in human early visual cortex in a manner consistent with a mechanism of automatic, contextually driven feedback from higher visual areas.

SIGNIFICANCE STATEMENT A core function of the visual system is to parse complex 2D input into meaningful figures. We do so constantly and seamlessly, both by processing information about visible edges and by analyzing large-scale differences between figure and background. While influential neurophysiology work has characterized an intriguing mechanism that enhances V1 responses to perceptual figures, we have a poor understanding of how the early visual system contributes to figure–ground processing in humans. Here, we use advanced computational analysis methods and high-field human fMRI data to resolve the distinct spatial profiles of local edge and global figure enhancement in the early visual system (V1 and LGN); the latter is distinct and consistent with a mechanism of automatic, stimulus-driven feedback from higher-level visual areas.

Endogenous neuropeptide Y (NPY) and corticotrophin-releasing factor (CRF) modulate the responses of the basolateral amygdala (BLA) to stress and are associated with the development of stress resilience and vulnerability, respectively. We characterized persistent effects of repeated NPY and CRF treatment on the structure and function of BLA principal neurons in a novel organotypic slice culture (OTC) model of male rat BLA, and examined the contributions of specific NPY receptor subtypes to these neural and behavioral effects. In BLA principal neurons within the OTCs, repeated NPY treatment caused persistent attenuation of excitatory input and induced dendritic hypotrophy via Y₅ receptor activation; conversely, CRF increased excitatory input and induced hypertrophy of BLA principal neurons. Repeated treatment of OTCs with NPY followed by an identical treatment with CRF, or vice versa, inhibited or reversed all structural changes in OTCs. These structural responses to NPY or CRF required calcineurin or CaMKII, respectively. Finally, repeated intra-BLA injections of NPY or a Y₅ receptor agonist increased social interaction, a validated behavior for anxiety, and recapitulated structural changes in BLA neurons seen in OTCs, while a Y₅ receptor antagonist prevented NPY's effects both on behavior and on structure. These results implicate the Y₅ receptor in the long-term, anxiolytic-like effects of NPY in the BLA, consistent with an intrinsic role in stress buffering, and highlight a remarkable mechanism by which BLA neurons may adapt to different levels of stress. Moreover, BLA OTCs offer a robust model to study mechanisms associated with resilience and vulnerability to stress in BLA.

SIGNIFICANCE STATEMENT Within the basolateral amygdala (BLA), neuropeptide Y (NPY) is associated with buffering the neural stress response induced by corticotropin releasing factor, and promoting stress resilience. We used a novel organotypic slice culture model of BLA, complemented with in vivo studies, to examine the cellular mechanisms associated with the actions of NPY. In organotypic slice cultures, repeated NPY treatment reduces the complexity of the dendritic extent of anxiogenic BLA principal neurons, making them less excitable. NPY, via activation of Y5 receptors, additionally inhibits and reverses the increases in dendritic extent and excitability induced by the stress hormone, corticotropin releasing factor. This NPY-mediated neuroplasticity indicates that resilience or vulnerability to stress may thus involve neuropeptide-mediated dendritic remodeling in BLA principal neurons.

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The number of nurse practitioner graduates in the United States has nearly doubled over the past 2 decades. However, the number of pediatric nurse practitioner (PNP) graduates has remained relatively flat, although the demand for PNPs is expected to increase.

This study estimates the best-case shortage of PNPs over the next 25 years. We propose possible policy interventions to address key areas of the PNP workforce system and we compute their impact on the forecasted PNP shortage. (Read the full article)

  Introduction Character modeling is the process of creating a character within the 3D space of computer programs. The techniques for character modeling are essential for third - and first - person e...

Verification is the top challenge in mixed-signal design. Bringing analog and digital domains together into unified verification planning, simulating, and debugging is a challenging task for rapidly increasing size and complexity of mixed-signal designs. To more completely verify functionality and performance of a mixed-signal SoC and its AMS IP blocks used to build it, verification teams use simulations at transistor, analog behavioral and real-number model (RNM) and RTL levels, and combination of these.

In recent years, RNM and simulation is being adopted for functional verification by many, due to advantages it offers including simpler modeling requirements and much faster simulation speed (compared to a traditional analog behavioral models like Verilog-A or VHDL-AMS). Verilog-AMS with its wreal continue to be popular choice. Standardization of real number extensions in SystemVerilog (SV) made SV-RNM an even more attractive choice for MS SoC verification.

Verilog-AMS/wreal is scalar real type. SV-RNM offers a powerful ability to define complex data types, providing a user-defined structure (record) to describe the net value. In a typical design, most analog nodes can be modeled using a single value for passing a voltage (or current) from one module to another. The ability to pass multiple values over a net can be very powerful when, for example, the impedance load impact on an analog signal needs to be modeled. Here is an example of a user-defined net (UDN) structure that holds voltage, current, and resistance values:

When there are multiple drives on a single net, the simulator will need a resolution function to determine the final net value. When the net is just defined as a single real value, common resolution functions such as min, max, average, and sum are built into the simulator.  But definition of more complex structures for the net also requires the user to provide appropriate resolution functions for them. Here is an example of a net with three drivers modeled using the above defined structural elements (a voltage source with series resistance, a resistive load, and a current source):

To properly solve for the resulting output voltage, the resolution function for this net needs to perform Norton conversion of the elements, sum their currents and conductances, and then calculate the resolved output voltage as the sum of currents divided by sum of conductances.

With some basic understanding of circuit theory, engineers can use SV-RNM UDN capability to model electrical behavior of many different circuits. While it is primarily defined to describe source/load impedance interactions, its use can be extended to include systems including capacitors, switching circuits, RC interconnect, charge pumps, power regulators, and others. Although this approach extends the scope of functional verification, it is not a replacement for transistor-level simulation when accuracy, performance verification, or silicon correlation are required:  It simply provides an efficient solution for discretely modeling small analog networks (one to several nodes).  Mixed-signal simulation with an analog solver is still the best solution when large nonlinear networks must be evaluated.

Cadence provides a tutorial on EEnet usage as well as the package (EEnet.pkg) with UDN definitions and resolution functions and modeling examples. To learn more, please login to your Cadence account to access the tutorial.

ABSTRACT

Host-associated microbial communities are shaped by extrinsic and intrinsic factors to the holobiont organism. Environmental factors and microbe-microbe interactions act simultaneously on the microbial community structure, making the microbiome dynamics challenging to predict. The coral microbiome is essential to the health of coral reefs and sensitive to environmental changes. Here, we develop a dynamic model to determine the microbial community structure associated with the surface mucus layer (SML) of corals using temperature as an extrinsic factor and microbial network as an intrinsic factor. The model was validated by comparing the predicted relative abundances of microbial taxa to the relative abundances of microbial taxa from the sample data. The SML microbiome from Pseudodiploria strigosa was collected across reef zones in Bermuda, where inner and outer reefs are exposed to distinct thermal profiles. A shotgun metagenomics approach was used to describe the taxonomic composition and the microbial network of the coral SML microbiome. By simulating the annual temperature fluctuations at each reef zone, the model output is statistically identical to the observed data. The model was further applied to six scenarios that combined different profiles of temperature and microbial network to investigate the influence of each of these two factors on the model accuracy. The SML microbiome was best predicted by model scenarios with the temperature profile that was closest to the local thermal environment, regardless of the microbial network profile. Our model shows that the SML microbiome of P. strigosa in Bermuda is primarily structured by seasonal fluctuations in temperature at a reef scale, while the microbial network is a secondary driver.

IMPORTANCE Coral microbiome dysbiosis (i.e., shifts in the microbial community structure or complete loss of microbial symbionts) caused by environmental changes is a key player in the decline of coral health worldwide. Multiple factors in the water column and the surrounding biological community influence the dynamics of the coral microbiome. However, by including only temperature as an external factor, our model proved to be successful in describing the microbial community associated with the surface mucus layer (SML) of the coral P. strigosa. The dynamic model developed and validated in this study is a potential tool to predict the coral microbiome under different temperature conditions.

ABSTRACT

A microfluidic system coupled with fluorescence microscopy is a powerful approach for quantitative analysis of bacterial growth. Here, we measure parameters of growth and dynamic localization of the cell division initiation protein FtsZ in Bacillus subtilis. Consistent with previous reports, we found that after division, FtsZ rings remain at the cell poles, and polar FtsZ ring disassembly coincides with rapid Z-ring accumulation at the midcell. In cells mutated for minD, however, the polar FtsZ rings persist indefinitely, suggesting that the primary function of the Min system is in Z-ring disassembly. The inability to recycle FtsZ monomers in the minD mutant results in the simultaneous maintenance of multiple Z-rings that are restricted by competition for newly synthesized FtsZ. Although the parameters of FtsZ dynamics change in the minD mutant, the overall cell division time remains the same, albeit with elongated cells necessary to accumulate a critical threshold amount of FtsZ for promoting medial division. Finally, the minD mutant characteristically produces minicells composed of polar peptidoglycan shown to be inert for remodeling in the wild type. Polar peptidoglycan, however, loses its inert character in the minD mutant, suggesting that the Min system not only is important for recycling FtsZ but also may have a secondary role in the spatiotemporal regulation of peptidoglycan remodeling.

IMPORTANCE Many bacteria grow and divide by binary fission in which a mother cell divides into two identical daughter cells. To produce two equally sized daughters, the division machinery, guided by FtsZ, must dynamically localize to the midcell each cell cycle. Here, we quantitatively analyzed FtsZ dynamics during growth and found that the Min system of Bacillus subtilis is essential to disassemble FtsZ rings after division. Moreover, a failure to efficiently recycle FtsZ results in an increase in cell size. Finally, we show that the Min system has an additional role in inhibiting cell wall turnover and contributes to the "inert" property of cell walls at the poles.

ABSTRACT

In Gram-negative bacteria, the permeability of the outer membrane governs rates of antibiotic uptake and thus the efficacy of antimicrobial treatment. Hydrophilic drugs like β-lactam antibiotics depend on diffusion through pore-forming outer membrane proteins to reach their intracellular targets. In this study, we investigated the distribution of porin genes in more than 2,700 Klebsiella isolates and found a widespread loss of OmpK35 functionality, particularly in those strains isolated from clinical environments. Using a defined set of outer-membrane-remodeled mutants, the major porin OmpK35 was shown to be largely responsible for β-lactam permeation. Sequence similarity network analysis characterized the porin protein subfamilies and led to discovery of a new porin family member, OmpK38. Structure-based comparisons of OmpK35, OmpK36, OmpK37, OmpK38, and PhoE showed near-identical pore frameworks but defining differences in the sequence characteristics of the extracellular loops. Antibiotic sensitivity profiles of isogenic Klebsiella pneumoniae strains, each expressing a different porin as its dominant pore, revealed striking differences in the antibiotic permeability characteristics of each channel in a physiological context. Since K. pneumoniae is a nosocomial pathogen with high rates of antimicrobial resistance and concurrent mortality, these experiments elucidate the role of porins in conferring specific drug-resistant phenotypes in a global context, informing future research to combat antimicrobial resistance in K. pneumoniae.

IMPORTANCE Klebsiella pneumoniae is a pathogen of humans with high rates of mortality and a recognized global rise in incidence of carbapenem-resistant K. pneumoniae (CRKP). The outer membrane of K. pneumoniae forms a permeability barrier that modulates the ability of antibiotics to reach their intracellular target. OmpK35, OmpK36, OmpK37, OmpK38, PhoE, and OmpK26 are porins in the outer membrane of K. pneumoniae, demonstrated here to have a causative relationship to drug resistance phenotypes in a physiological context. The data highlight that currently trialed combination treatments with a carbapenem and β-lactamase inhibitors could be effective on porin-deficient K. pneumoniae. Together with structural data, the results reveal the role of outer membrane proteome remodeling in antimicrobial resistance of K. pneumoniae and point to the role of extracellular loops, not channel parameters, in drug permeation. This significant finding warrants care in the development of phage therapies for K. pneumoniae infections, given the way porin expression will be modulated to confer phage-resistant—and collateral drug-resistant—phenotypes in K. pneumoniae.

The extracellular matrix (ECM) initiates mechanical cues that activate intracellular signaling through matrix–cell interactions. In blood vessels, additional mechanical cues derived from the pulsatile blood flow and pressure play a pivotal role in homeostasis and disease development. Currently, the nature of the cues from the ECM and their interaction with...

The apparent detection of an exoplanet orbiting Fomalhaut was announced in 2008. However, subsequent observations of Fomalhaut b raised questions about its status: Unlike other exoplanets, it is bright in the optical and nondetected in the infrared, and its orbit appears to cross the debris ring around the star without...

Protease-activated receptor 2 (PAR-2) is activated by secreted proteases from immune cells or fungi. PAR-2 is normally expressed basolaterally in differentiated nasal ciliated cells. We hypothesized that epithelial remodeling during diseases characterized by cilial loss and squamous metaplasia may alter PAR-2 polarization. Here, using a fluorescent arrestin assay, we confirmed that the common fungal airway pathogen Aspergillus fumigatus activates heterologously-expressed PAR-2. Endogenous PAR-2 activation in submerged airway RPMI 2650 or NCI–H520 squamous cells increased intracellular calcium levels and granulocyte macrophage–colony-stimulating factor, tumor necrosis factor α, and interleukin (IL)-6 secretion. RPMI 2650 cells cultured at an air–liquid interface (ALI) responded to apically or basolaterally applied PAR-2 agonists. However, well-differentiated primary nasal epithelial ALIs responded only to basolateral PAR-2 stimulation, indicated by calcium elevation, increased cilia beat frequency, and increased fluid and cytokine secretion. We exposed primary cells to disease-related modifiers that alter epithelial morphology, including IL-13, cigarette smoke condensate, and retinoic acid deficiency, at concentrations and times that altered epithelial morphology without causing breakdown of the epithelial barrier to model early disease states. These altered primary cultures responded to both apical and basolateral PAR-2 stimulation. Imaging nasal polyps and control middle turbinate explants, we found that nasal polyps, but not turbinates, exhibit apical calcium responses to PAR-2 stimulation. However, isolated ciliated cells from both polyps and turbinates maintained basolateral PAR-2 polarization, suggesting that the calcium responses originated from nonciliated cells. Altered PAR-2 polarization in disease-remodeled epithelia may enhance apical responses and increase sensitivity to inhaled proteases.

In vitro approaches for predicting drug-drug interactions (DDIs) caused by alterations in transporter protein regulation are not well established. However, reports of transporter regulation via nuclear receptor (NR) modulation by drugs are increasing. This study examined alterations in transporter protein levels in sandwich-cultured human hepatocytes (SCHH; n = 3 donors) measured by liquid chromatography–tandem mass spectrometry–based proteomic analysis after treatment with N-[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl]-N-(2,2,2-trifluoroethyl)benzenesulfonamide (T0901317), the first described synthetic liver X receptor agonist. T0901317 treatment (10 μM, 48 hours) decreased the levels of organic cation transporter (OCT) 1 (0.22-, 0.43-, and 0.71-fold of control) and organic anion transporter (OAT) 2 (0.38-, 0.38-, and 0.53-fold of control) and increased multidrug resistance protein (MDR) 1 (1.37-, 1.48-, and 1.59-fold of control). The induction of NR downstream gene expression supports the hypothesis that T0901317 off-target effects on farnesoid X receptor and pregnane X receptor activation are responsible for the unexpected changes in OCT1, OAT2, and MDR1. Uptake of the OCT1 substrate metformin in SCHH was decreased by T0901317 treatment. Effects of decreased OCT1 levels on metformin were simulated using a physiologically-based pharmacokinetic (PBPK) model. Simulations showed a clear decrease in metformin hepatic exposure resulting in a decreased pharmacodynamic effect. This DDI would not be predicted by the modest changes in simulated metformin plasma concentrations. Altogether, the current study demonstrated that an approach combining SCHH, proteomic analysis, and PBPK modeling is useful for revealing tissue concentration–based DDIs caused by unexpected regulation of hepatic transporters by NR modulators.

PF06821497 has been identified as an orally available small-molecule enhancer of zeste homolog 2 inhibitor. The objectives of the present study were to characterize pharmacokinetic-pharmacodynamic-disease relationships of PF06821497 in xenograft mouse models with diffuse large B-cell lymphoma (Karpas422). An indirect-response model reasonably fit dose-dependent pharmacodynamic responses [histone H3 on lysine 27 (H3K27) me3 inhibition] with an unbound EC₅₀ of 76 nM, whereas a signal-transduction model sufficiently fit dose-dependent disease responses (tumor growth inhibition) with an unbound tumor stasis concentration (T_sc) of 168 nM. Thus, effective concentration for 70% of maximal effect (EC₇₀) for H3K27me3 inhibition was roughly comparable to T_sc, suggesting that 70% H3K27me3 inhibition could be required for tumor stasis. Consistently, an integrated pharmacokinetic-pharmacodynamic-disease model adequately describing tumor growth inhibition also suggested that ~70% H3K27me3 inhibition was associated with tumor stasis. Based on these results, we would propose that an EC₇₀ estimate for H3K27me3 inhibition corresponding to tumor stasis could be considered a minimum target efficacious concentration of PF06821497 in cancer patients.

Dalton Buysse, Anna-Katharina Pfitzner, Matt West, Aurelien Roux, and Greg Odorizzi

The ESCRT-III protein complex executes reverse-topology membrane scission. The scission mechanism is unclear but is linked to remodeling of ESCRT-III complexes at the membrane surface. At endosomes, ESCRT-III mediates the budding of intralumenal vesicles (ILVs). In Saccharomyces cerevisiae, ESCRT-III activity at endosomes is regulated through an unknown mechanism by Doa4, an ubiquitin hydrolase that deubiquitylates transmembrane proteins sorted into ILVs. We report that the non-catalytic N-terminus of Doa4 binds Snf7, the predominant ESCRT-III subunit. Through this interaction, Doa4 overexpression alters Snf7 assembly status and inhibits ILV membrane scission. In vitro, the Doa4 N-terminus inhibits association of Snf7 with Vps2, which functions with Vps24 to arrest Snf7 polymerization and remodel Snf7 polymer structure. In vivo, Doa4 overexpression inhibits Snf7 interaction with Vps2 and also with the ATPase Vps4, which is recruited by Vps2 and Vps24 to remodel ESCRT-III complexes by catalyzing subunit turnover. Our data suggest a mechanism by which the deubiquitylation machinery regulates ILV biogenesis by interfering with ESCRT-III remodeling.

The requisites for protein translation in T cells are poorly understood and how translation shapes the antitumor efficacy of T cells is unknown. Here we demonstrated that IL15-conditioned T cells were primed by the metabolic energy sensor AMP-activated protein kinase to undergo diminished translation relative to effector T cells. However, we showed that IL15-conditioned T cells exhibited a remarkable capacity to enhance their protein translation in tumors, which effector T cells were unable to duplicate. Studying the modulation of translation for applications in cancer immunotherapy revealed that direct ex vivo pharmacologic inhibition of translation elongation primed robust T-cell antitumor immunity. Our work elucidates that altering protein translation in CD8⁺ T cells can shape their antitumor capability.

BACKGROUND AND PURPOSE:

Brain metastases are a common finding on brain MRI. However, the factors that dictate their size and distribution are incompletely understood. Our aim was to discover a statistical model that can account for the size distribution of parenchymal metastases in the brain as measured on contrast-enhanced MR imaging.

See the new ad that has fans cheering for the baby girl!

Lipids are essential building blocks of cell membranes, which control the exchange of substances and energy between a cell and its environment. Developed at the Moscow Institute of Physics and Technology, a new open-source software tool PCAlipids aims to analyze lipid behavior.

Apr 11, 2020

A simplified nuclear exchange model demonstrates that China’s ability to launch a successful nuclear retaliatory strike in response to an adversary’s nuclear first strike has been and remains far from assured. This study suggests that China’s criterion for effective nuclear deterrence is very low.

Apr 11, 2020

A simplified nuclear exchange model demonstrates that China’s ability to launch a successful nuclear retaliatory strike in response to an adversary’s nuclear first strike has been and remains far from assured. This study suggests that China’s criterion for effective nuclear deterrence is very low.

Apr 11, 2020

A simplified nuclear exchange model demonstrates that China’s ability to launch a successful nuclear retaliatory strike in response to an adversary’s nuclear first strike has been and remains far from assured. This study suggests that China’s criterion for effective nuclear deterrence is very low.

Apr 11, 2020

A simplified nuclear exchange model demonstrates that China’s ability to launch a successful nuclear retaliatory strike in response to an adversary’s nuclear first strike has been and remains far from assured. This study suggests that China’s criterion for effective nuclear deterrence is very low.

Apr 11, 2020

A simplified nuclear exchange model demonstrates that China’s ability to launch a successful nuclear retaliatory strike in response to an adversary’s nuclear first strike has been and remains far from assured. This study suggests that China’s criterion for effective nuclear deterrence is very low.

Apr 11, 2020

A simplified nuclear exchange model demonstrates that China’s ability to launch a successful nuclear retaliatory strike in response to an adversary’s nuclear first strike has been and remains far from assured. This study suggests that China’s criterion for effective nuclear deterrence is very low.

Apr 11, 2020

A simplified nuclear exchange model demonstrates that China’s ability to launch a successful nuclear retaliatory strike in response to an adversary’s nuclear first strike has been and remains far from assured. This study suggests that China’s criterion for effective nuclear deterrence is very low.

Apr 11, 2020

A simplified nuclear exchange model demonstrates that China’s ability to launch a successful nuclear retaliatory strike in response to an adversary’s nuclear first strike has been and remains far from assured. This study suggests that China’s criterion for effective nuclear deterrence is very low.

Apr 11, 2020

A simplified nuclear exchange model demonstrates that China’s ability to launch a successful nuclear retaliatory strike in response to an adversary’s nuclear first strike has been and remains far from assured. This study suggests that China’s criterion for effective nuclear deterrence is very low.

Apr 11, 2020

A simplified nuclear exchange model demonstrates that China’s ability to launch a successful nuclear retaliatory strike in response to an adversary’s nuclear first strike has been and remains far from assured. This study suggests that China’s criterion for effective nuclear deterrence is very low.

Apr 11, 2020

A simplified nuclear exchange model demonstrates that China’s ability to launch a successful nuclear retaliatory strike in response to an adversary’s nuclear first strike has been and remains far from assured. This study suggests that China’s criterion for effective nuclear deterrence is very low.

Carbon pricing is an important policy tool for reducing greenhouse gas pollution. The Stanford Energy Modeling Forum exercise 32 convened eleven modeling teams to project emissions, energy, and economic outcomes of an illustrative range of economy-wide carbon price policies. The study compared a coordinated reference scenario involving no new policies with policy scenarios that impose…

Why childhood obesity matters According to the latest data, childhood obesity affects nearly 1 in 5 children in the United States, a number which has more than tripled since the early 1970s. Children who have obesity are at a higher risk of many immediate health risks such as high blood pressure and high cholesterol, type…

Why childhood obesity matters According to the latest data, childhood obesity affects nearly 1 in 5 children in the United States, a number which has more than tripled since the early 1970s. Children who have obesity are at a higher risk of many immediate health risks such as high blood pressure and high cholesterol, type…

A link between MMP7 (tissue-remodeling enzyme) and the risk of hypertension has been identified by Indian Institute of Technology Madras (IIT-M) researchers.

And 40-year-old Kourtney can even be seen modeling SKIMS lingerie for her little sister who has made not only bras and undies but also shapewear and pajamas under the line.

The 24-year-old stunner explained how designers and casting agents were 'hard on her' about her lean, athletic body at the start of her career, until Jean Paul Gaultier gave her a chance.

Cham : Springer, c2019.

Cham : Springer, c2019.

Cham : Springer, 2019.

Cham : Springer, 2020.