Multi-fluxon steps in long Josephson junctions and their application to oscillators

Journal ArticleStudies of long NbN Josephson junctions of the overlap type in the presence of an external magnetic field show constant voltage steps, of the Fiske type, and large voltage steps. The latter are attributed to multifluxon resonances within the cavity of the junction. The multifluxon steps correspond to bunches of fluxons introduced in the junction because the junction electrode thicknesses are comparable to the penetration depth. These steps are very sharp and they have large current amplitudes. When biased at such constant voltage steps the device can be a resonant mode oscillator. The power and frequency will be determined by the mode of fluxon motion inside the junction

Large steps in long Josephson junctions

Journal ArticleLarge constant voltage current-steps were observed in the IV-characteristics of long NbN-MgO-NbN Josephson junctions in the presence of external magnetic fields of a few Gauss. The steps are separated by a voltage AV corresponding roughly to 3 to 5 times the voltage spacing expected between adjacent Fiske-steps. Models discussing the origin of such steps are presented. Simultaneous nucleation of fluxons at several sites along the junction with thin electrodes, favored by the large London penetration depth of NbN, would introduce a large amount of magnetic flux into the junction at once which would lead to large steps. A new model is presented here; involves pinning of fluxons in the junction. Due to the granularity of NbN and its very small coherence length there will be pinning sites in the junction preventing single fluxons to move at low bias currents. At particular junction parameter values the steps become very regular and sharp. Such characteristics are well suited for a voltage standard and oscillators

Hemorrhage-activated NRF2 in tumor-associated macrophages drives cancer growth, invasion, and immunotherapy resistance

Microscopic hemorrhage is a common aspect of cancers, yet its potential role as an independent factor influencing both cancer progression and therapeutic response is largely ignored. Recognizing the essential function of macrophages in red blood cell disposal, we explored a pathway that connects intratumoral hemorrhage with the formation of cancer-promoting tumor-associated macrophages (TAMs). Using spatial transcriptomics, we found that NRF2-activated myeloid cells possessing characteristics of procancerous TAMs tend to cluster in peri-necrotic hemorrhagic tumor regions. These cells resembled anti-inflammatory erythrophagocytic macrophages. We identified heme, a red blood cell metabolite, as a pivotal microenvironmental factor steering macrophages toward protumorigenic activities. Single-cell RNA-seq and functional assays of TAMs in 3D cell culture spheroids revealed how elevated intracellular heme signals via the transcription factor NRF2 to induce cancer-promoting TAMs. These TAMs stabilized epithelial-mesenchymal transition, enhancing cancer invasiveness and metastatic potential. Additionally, NRF2-activated macrophages exhibited resistance to reprogramming by IFNγ and anti-CD40 antibodies, reducing their tumoricidal capacity. Furthermore, MC38 colon adenocarcinoma-bearing mice with NRF2 constitutively activated in leukocytes were resistant to anti-CD40 immunotherapy. Overall, our findings emphasize hemorrhage-activated NRF2 in TAMs as a driver of cancer progression, suggesting that targeting this pathway could offer new strategies to enhance cancer immunity and overcome therapy resistance

3D modeling of underground objects with the use of SLAM technology on the example of historical mine in Ciechanowice (Ołowiane Range, The Sudetes)

Terrestrial Laser Scanning is a currently one of the most popular methods for producing representations of 3D objects. This paper presents the potential of applying the mobile laser scanning method to inventory underground objects. The examined location was a historic crystalline limestone mine situated in the vicinity of Ciechanowice village (Kaczawa Mts., SW Poland). The authors present a methodology for performing measurements and for processing the obtained results, whose accuracy is additionally verified

Magnetron sputter deposition of Ta2O5-SiO2 quantized nanolaminates

Quantized nanolaminates are a type of optical metamaterials, which were discovered only recently. Their feasibility was demonstrated by atomic layer deposition and ion beam sputtering so far. In this paper, we will report on the successful magnetron sputter deposition of quantized nanolaminates based on Ta2O5-SiO2. We will describe the deposition process, show results and material characterization of films deposited in a very wide parameter range. Furthermore, we will show how quantized nanolaminates deposited by magnetron sputtering were used in optical interference coatings such as antireflection and mirror coatings

MyD88-TLR4-dependent choroid plexus activation precedes perilesional inflammation and secondary brain edema in a mouse model of intracerebral hemorrhage

Background: The functional neurological outcome of patients with intracerebral hemorrhage (ICH) strongly relates to the degree of secondary brain injury (ICH-SBI) evolving within days after the initial bleeding. Different mechanisms including the incitement of inflammatory pathways, dysfunction of the blood–brain barrier (BBB), activation of resident microglia, and an influx of blood-borne immune cells, have been hypothesized to contribute to ICH-SBI. Yet, the spatiotemporal interplay of specific inflammatory processes within different brain compartments has not been sufficiently characterized, limiting potential therapeutic interventions to prevent and treat ICH-SBI. Methods: We used a whole-blood injection model in mice, to systematically characterized the spatial and temporal dynamics of inflammatory processes after ICH using 7-Tesla magnetic resonance imaging (MRI), spatial RNA sequencing (spRNAseq), functional BBB assessment, and immunofluorescence average-intensity-mapping. Results: We identified a pronounced early response of the choroid plexus (CP) peaking at 12–24 h that was characterized by inflammatory cytokine expression, epithelial and endothelial expression of leukocyte adhesion molecules, and the accumulation of leukocytes. In contrast, we observed a delayed secondary reaction pattern at the injection site (striatum) peaking at 96 h, defined by gene expression corresponding to perilesional leukocyte infiltration and correlating to the delayed signal alteration seen on MRI. Pathway analysis revealed a dependence of the early inflammatory reaction in the CP on toll-like receptor 4 (TLR4) signaling via myeloid differentiation factor 88 (MyD88). TLR4 and MyD88 knockout mice corroborated this observation, lacking the early upregulation of adhesion molecules and leukocyte infiltration within the CP 24 h after whole-blood injection. Conclusions: We report a biphasic brain reaction pattern after ICH with a MyD88-TLR4-dependent early inflammatory response of the CP, preceding inflammation, edema and leukocyte infiltration at the lesion site. Pharmacological targeting of the early CP activation might harbor the potential to modulate the development of ICH-SBI

Antibody-induced erythrophagocyte reprogramming of Kupffer cells prevents anti-CD40 cancer immunotherapy-associated liver toxicity

BackgroundAgonistic anti-CD40 monoclonal antibodies (mAbs) have emerged as promising immunotherapeutic compounds with impressive antitumor effects in mouse models. However, preclinical and clinical studies faced dose-limiting toxicities mediated by necroinflammatory liver disease. An effective prophylactic treatment for liver immune-related adverse events that does not suppress specific antitumor immunity remains to be found.MethodsWe used different mouse models and time-resolved single-cell RNA-sequencing to characterize the pathogenesis of anti-CD40 mAb induced liver toxicity. Subsequently, we developed an antibody-based treatment protocol to selectively target red blood cells (RBCs) for erythrophagocytosis in the liver, inducing an anti-inflammatory liver macrophage reprogramming.ResultsWe discovered that CD40 signaling in Clec4f$^{+}$Kupffer cells is the non-redundant trigger of anti-CD40 mAb-induced liver toxicity. Taking advantage of the highly specific functionality of liver macrophages to clear antibody-tagged RBCs from the blood, we hypothesized that controlled erythrophagocytosis and the linked anti-inflammatory signaling by the endogenous metabolite heme could be exploited to reprogram liver macrophages selectively. Repeated low-dose administration of a recombinant murine Ter119 antibody directed RBCs for selective phagocytosis in the liver and skewed the phenotype of liver macrophages into a Hmox$^{high}$/Marco$^{high}$/MHCII$^{low}$anti-inflammatory phenotype. This unique mode of action prevented necroinflammatory liver disease following high-dose administration of anti-CD40 mAbs. In contrast, extrahepatic inflammation, antigen-specific immunity, and antitumor activity remained unaffected in Ter119 treated animals.ConclusionsOur study offers a targeted approach to uncouple CD40-augmented antitumor immunity in peripheral tissues from harmful inflammatoxicity in the liver

Inequality and growth: A review on a great open debate in economics

What is the relationship between inequality and growth? This question has occupied and fascinated social scientists for more than a century. This article critically reviews the recent empirical and theoretical literature on the complex interplay between inequality and economic growth. Inequality might come in many forms: (top) incomes, wages, wealth, land, or opportunities. At the same time, growth performance could be measured as average growth rates, variability of growth, or the potential for growth to 'take off'. We consider causality running from inequality to growth; hence, the Kuznets hypothesis is only touched on in passing. The empirical literature estimating the effect of inequality on growth has produced a wide range of results, precluding clear-cut conclusions on the inequality-growth relationship. Consequently, it remains central to understand the underlying economic causes and channels through which (different aspects of) inequality can promote or hamper economic growth. This review aims to provide a broad overview of the contemporary results and an outline for prospective empirical and theoretical work

Shades of grey; Assessing the contribution of the magno- and parvocellular systems to neural processing of the retinal input in the human visual system from the influence of neural population size and its discharge activity on the VEP

Introduction: Retinal input processing in the human visual system involves a phasic and tonic neural response. We investigated the role of the magno- and parvocellular systems by comparing the influence of the active neural population size and its discharge activity on the amplitude and latency of four VEP components. Method: We recorded the scalp electric potential of 20 human volunteers viewing a series of dartboard images presented as a pattern reversing and pattern on-/offset stimulus. These patterns were designed to vary both neural population size coding the temporal- and spatial luminance contrast property and the discharge activity of the population involved in a systematic manner. Results: When the VEP amplitude reflected the size of the neural population coding the temporal luminance contrast property of the image, the influence of luminance contrast followed the contrast response function of the parvocellular system. When the VEP amplitude reflected the size of the neural population responding to the spatial luminance contrast property the image, the influence of luminance contrast followed the contrast response function of the magnocellular system. The latencies of the VEP components examined exhibited the same behavior across our stimulus series. Conclusions: This investigation demonstrates the complex interplay of the magno- and parvocellular systems on the neural response as captured by the VEP. It also demonstrates a linear relationship between stimulus property, neural response, and the VEP and reveals the importance of feedback projections in modulating the ongoing neural response. In doing so, it corroborates the conclusions of our previous study