Tissue compartmentalization enables; Salmonella; persistence during chemotherapy

Antimicrobial chemotherapy can fail to eradicate the pathogen, even in the absence of antimicrobial resistance. Persisting pathogens can subsequently cause relapsing diseases. In vitro studies suggest various mechanisms of antibiotic persistence, but their in vivo relevance remains unclear because of the difficulty of studying scarce pathogen survivors in complex host tissues. Here, we localized and characterized rare surviving; Salmonella; in mouse spleen using high-resolution whole-organ tomography. Chemotherapy cleared >99.5% of the; Salmonella; but was inefficient against a small; Salmonella; subset in the white pulp. Previous models could not explain these findings: drug exposure was adequate,; Salmonella; continued to replicate, and host stresses induced only limited; Salmonella; drug tolerance. Instead, antimicrobial clearance required support of; Salmonella; -killing neutrophils and monocytes, and the density of such cells was lower in the white pulp than in other spleen compartments containing higher; Salmonella; loads. Neutrophil densities declined further during treatment in response to receding; Salmonella; loads, resulting in insufficient support for; Salmonella; clearance from the white pulp and eradication failure. However, adjunctive therapies sustaining inflammatory support enabled effective clearance. These results identify uneven; Salmonella; tissue colonization and spatiotemporal inflammation dynamics as main causes of; Salmonella; persistence and establish a powerful approach to investigate scarce but impactful pathogen subsets in complex host environments

Myeloperoxidase targets oxidative host attacks to Salmonella and prevents collateral tissue damage

Host control of infections crucially depends on the capability to kill pathogens with reactive oxygen species (ROS). However, these toxic molecules can also readily damage host components and cause severe immunopathology. Here, we show that neutrophils use their most abundant granule protein, myeloperoxidase, to target ROS specifically to pathogens while minimizing collateral tissue damage. A computational model predicted that myeloperoxidase efficiently scavenges diffusible H2O2 at the surface of phagosomal Salmonella and converts it into highly reactive HOCl (bleach), which rapidly damages biomolecules within a radius of less than 0.1 μm. Myeloperoxidase-deficient neutrophils were predicted to accumulate large quantities of H2O2 that still effectively kill Salmonella, but most H2O2 would leak from the phagosome. Salmonella stimulation of neutrophils from normal and myeloperoxidase-deficient human donors experimentally confirmed an inverse relationship between myeloperoxidase activity and extracellular H2O2 release. Myeloperoxidase-deficient mice infected with Salmonella had elevated hydrogen peroxide tissue levels and exacerbated oxidative damage of host lipids and DNA, despite almost normal Salmonella control. These data show that myeloperoxidase has a major function in mitigating collateral tissue damage during antimicrobial oxidative bursts, by converting diffusible long-lived H2O2 into highly reactive, microbicidal and locally confined HOCl at pathogen surfaces

Dissecting cytokine networks in the inflammatory responses in epidermal barrier-defective skin

Le mécanisme qui sous-tend la réponse inflammatoire en cas de défaut de la barrière épidermique reste à élucider. Dans cette étude, nous montrons qu’en cas de rupture de la barrière formée par le stractum corneum épidermal, une réponse inflammatoire mixte de type 17 et 2 est induite. Nous décrivons ici une régulation réciproque entre les axes cytokiniques IL-23/IL-17/IL-22 et TSLP/IL-4 qui conditionne l’apparition du phénotype inflammatoire au niveau cutané. Par ailleurs, nous démontrons également que la flore bactérienne présente à la surface de la peau est engagée dans l’induction de l’IL-23 et de la réponse de type 17 alors que le PAR2 stimule, quant à lui, l’expression de TSLP et à la réponse de type 2. Nos résultats montrent donc la complexité et l’hétérogénéité des réponses inflammatoires en conditions de rupture de la barrière cutanée et ont des implications au niveau des thérapies pour les maladies inflammatoires de la peau.Dysfunction of the epidermal barrier has been recognized as a critical factor in the development of skin inflammation; yet, the mechanism underlying the inflammatory responses triggered by epidermal defects remains still elusive. Here, by employing mice with corneodesmosin (CDSN) gene ablated in keratinocytes, we show that upon the breakdown of the epidermal barrier, type 17 and type 2 inflammatory responses are co-induced in the skin. Furthermore, we delineate a counter-regulation between IL-23/IL-17/IL-22 and TSLP/IL-4 cytokine axes, which shapes the outcome of the inflammatory phenotype in skin. Moreover, we show that the bacteria skin flora are engaged in the induction of IL-23 and the type 17 response, whereas the protease activation receptor PAR2 mediates TSLP expression and the type 2 response. Our results shed light on the complexity and heterogeneity of inflammatory responses in barrier-defective skin, and have implications for treating skin inflammatory diseases

Dissecting cytokine networks in the inflammatory responses in epidermal barrier-defective skin

Le mécanisme qui sous-tend la réponse inflammatoire en cas de défaut de la barrière épidermique reste à élucider. Dans cette étude, nous montrons qu’en cas de rupture de la barrière formée par le stractum corneum épidermal, une réponse inflammatoire mixte de type 17 et 2 est induite. Nous décrivons ici une régulation réciproque entre les axes cytokiniques IL-23/IL-17/IL-22 et TSLP/IL-4 qui conditionne l’apparition du phénotype inflammatoire au niveau cutané. Par ailleurs, nous démontrons également que la flore bactérienne présente à la surface de la peau est engagée dans l’induction de l’IL-23 et de la réponse de type 17 alors que le PAR2 stimule, quant à lui, l’expression de TSLP et à la réponse de type 2. Nos résultats montrent donc la complexité et l’hétérogénéité des réponses inflammatoires en conditions de rupture de la barrière cutanée et ont des implications au niveau des thérapies pour les maladies inflammatoires de la peau.Dysfunction of the epidermal barrier has been recognized as a critical factor in the development of skin inflammation; yet, the mechanism underlying the inflammatory responses triggered by epidermal defects remains still elusive. Here, by employing mice with corneodesmosin (CDSN) gene ablated in keratinocytes, we show that upon the breakdown of the epidermal barrier, type 17 and type 2 inflammatory responses are co-induced in the skin. Furthermore, we delineate a counter-regulation between IL-23/IL-17/IL-22 and TSLP/IL-4 cytokine axes, which shapes the outcome of the inflammatory phenotype in skin. Moreover, we show that the bacteria skin flora are engaged in the induction of IL-23 and the type 17 response, whereas the protease activation receptor PAR2 mediates TSLP expression and the type 2 response. Our results shed light on the complexity and heterogeneity of inflammatory responses in barrier-defective skin, and have implications for treating skin inflammatory diseases

Patent Propensity in Small Technology-based Firms: Evidence from Zhongguancun Science Park

Using a survey administered in Zhongguancun Science Park in Beijing, China, this paper investigates the impact of R&D personnel-related intellectual property management practices on the patent propensity of small technology-based firms. It is found that R&D personnel-related management practices, including training and reward mechanisms, are effective in enhancing a firm's willingness to patent. In particular, we find that reward mechanisms can negatively moderate the effect of size on a firm's willingness to patent. One implication that emerged from the analysis is that a small firm can counteract its size disadvantage in patenting by introducing a well-developed reward mechanism. Copyright (c) 2010 The Authors Journal compilation (c) 2010 Institute of World Economics and Politics, Chinese Academy of Social Sciences.

Experimental investigation on the dynamic behaviour of metal foam: From yield to densification

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On the impact shear tests using Hopkinson bar

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Effects of visual working memory on brain information processing of irrelevant auditory stimuli.

Selective attention has traditionally been viewed as a sensory processing modulator that promotes cognitive processing efficiency by favoring relevant stimuli while inhibiting irrelevant stimuli. However, the cross-modal processing of irrelevant information during working memory (WM) has been rarely investigated. In this study, the modulation of irrelevant auditory information by the brain during a visual WM task was investigated. The N100 auditory evoked potential (N100-AEP) following an auditory click was used to evaluate the selective attention to auditory stimulus during WM processing and at rest. N100-AEP amplitudes were found to be significantly affected in the left-prefrontal, mid-prefrontal, right-prefrontal, left-frontal, and mid-frontal regions while performing a high WM load task. In contrast, no significant differences were found between N100-AEP amplitudes in WM states and rest states under a low WM load task in all recorded brain regions. Furthermore, no differences were found between the time latencies of N100-AEP troughs in WM states and rest states while performing either the high or low WM load task. These findings suggested that the prefrontal cortex (PFC) may integrate information from different sensory channels to protect perceptual integrity during cognitive processing

Treatment of MCPT8 DTR mice with high- or low-dose diphtheria toxin leads to differential depletion of basophils and granulocyte-macrophage progenitors

International audienceBasophils have been recently recognized to play important roles in type 2 immune responses during allergies and parasitic infection, largely due to the development of novel tools for the in vivo study of these cells. As such, the genetically-engineered MCPT8DTR mouse line has been used to specifically deplete basophils following treatment with diphtheria toxin (DT). In this study, we showed that DT-injected MCPT8DTR mice exhibited a striking decrease of eosinophils and neutrophils in skin when subjected to a hapten fluorescein isothiocyanate (FITC)-induced allergic contact dermatitis (ACD) experimental protocol. Unexpectedly, we found that loss of skin eosinophils and neutrophils was not due to a lack of basophil-mediated recruitment, as DT injection caused a systemic reduction of eosinophils and neutrophils in MCPT8DTR mice in a time-dependent manner. Furthermore, we found that hematopoietic stem-cell-derived granulocyte-macrophage progenitors (GMPs) expressed MCPT8 gene, and that these cells were depleted upon DT injection. Finally, we optimized a protocol in which a low-dose DT achieved a better specificity for depleting basophils, but not GMPs, in MCPT8DTR mice, and demonstrate that basophils do not play a major role in recruiting eosinophils and neutrophils to ACD skin. These data provide new and valuable information about functional studies of basophils

Fabrication of Al/AlOx/Al junctions with high uniformity and stability on sapphire substrates

Tantalum and aluminum on sapphire are widely used platforms for qubits of long coherent time. As quantum chips scale up, the number of Josephson junctions on Sapphire increases. Thus, both the uniformity and stability of the junctions are crucial to quantum devices, such as scalable superconducting quantum computer circuit, and quantum-limited amplifiers. By optimizing the fabrication process, especially, the conductive layer during the electron beam lithography process, Al/AlOx/Al junctions of sizes ranging from 0.0169 to 0.04 {\mu}m2 on sapphire substrates were prepared. The relative standard deviation of room temperature resistances (RN) of these junctions is better than 1.7% on 15 mmx15 mm chips, and better than 2.66% on 2 inch wafers, which is the highest uniformity on sapphire substrates has been reported. The junctions are robust and stable in resistances as temperature changes. The resistances increase by the ratio of 9.73% relative to RN as the temperature ramp down to 4K, and restore their initial values in the reverse process as the temperature ramps back to RT. After being stored in a nitrogen cabinet for 100 days, the resistance of the junctions changed by1.16% in average. The demonstration of uniform and stable Josephson junctions in large area paves the way for the fabrication of superconducting chip of hundreds of qubits on sapphire substrates