Neutrophils mediate bacterial clearance through various mechanisms, including the release of mesh-like DNA structures or neutrophil extracellular traps (NETs) that capture bacteria. Although ...neutrophils are also recruited to sites of viral infection, their role in antiviral innate immunity is less clear. We show that systemic administration of virus analogs or poxvirus infection induces neutrophil recruitment to the liver microvasculature and the release of NETs that protect host cells from virus infection. After systemic intravenous poxvirus challenge, mice exhibit thrombocytopenia and the recruitment of both neutrophils and platelets to the liver vasculature. Circulating platelets interact with, roll along, and adhere to the surface of adherent neutrophils, forming large, dynamic aggregates. These interactions facilitate the release of NETs within the liver vasculature that are able to protect host cells from poxvirus infection. These findings highlight the role of NETs and early tissue-wide responses in preventing viral infection.
► Systemic virus challenge induces neutrophil and platelet recruitment to the liver ► Platelets bind adherent neutrophils, generating large dynamic aggregates ► Viral infection induces the release of NETs within the liver microvasculature ► NETs can protect host cells from viral infection in vivo
Many diseases and injuries can impair joint mobility. Normal reference values are needed to determine extent of impairment to assess and monitor joint motion. There is very little published data ...describing normal joint range of motion (ROM) for healthy men and women across a wide span of ages. We enrolled male and female subjects aged between 2 and 69 years who were free from conditions that could potentially limit joint mobility for the study. Nine licensed physical therapists used universal goniometers to determine passive joint motion bilaterally of elbow flexion, extension, supination and pronation, shoulder flexion, hip flexion and extension, knee flexion and extension, and ankle dorsiflexion and plantarflexion. Descriptive statistics were calculated for male and female subjects in four age groups: 2–8, 9–19, 20–44 and 45–69 years. Joint ROM measurements were obtained on a total of 674 (53.6% female) healthy, normal subjects aged 2–69 years. Female subjects had greater joint mobility in all age groups in nearly all joints and the gender difference was most obvious in measures of ankle plantarflexion, elbow pronation and supination. Range of motion average values for all joints decreased with advancing age for both men and women and, in most cases, were significantly different than most commonly used normative values. Our study of ROM measurements taken by trained physical therapists on a large sample of healthy individuals revealed significant gender‐ and age‐related variation that may be an important consideration in patient assessment.
A combination of nivolumab and ipilimumab produced complete responses in 26% and partial responses in 30% of patients with previously untreated brain metastases from melanoma.
This paper contributes to the steady-state analysis of the bidirectional dual active bridge (DAB) dc-dc converter by proposing a new model that produces equations for rms and average device currents, ...and rms and peak inductor/transformer currents. These equations are useful in predicting losses that occur in the devices and passive components and aid in the converter design. An analysis of zero-voltage switching (ZVS) boundaries for buck and boost modes while considering the effect of snubber capacitors on the DAB converter is also presented. The proposed model can be used to predict the converter efficiency at any desired operating point. The new model can serve as an important teaching-cum-research tool for DAB hardware design (devices and passive components selection), soft-switching-operating range estimation, and performance prediction at the design stage. The operation of the DAB dc-dc converter has been verified through extensive simulations. A DAB converter prototype was designed on the basis of the proposed model and was built for an aerospace energy storage application. Experimental results are presented to validate the new model for a 7 kW, 390/180 V, 20 kHz converter operation and the ZVS boundary operation.
Abstract
In this paper, we explore the transitions of low-frequency noise characteristics in high-k metal-gate bulk CMOS transistors induced by Total Ionizing Dose (TID). Due to the strong bias ...dependence of the noise characteristics, differentiating between noise shifts caused by the effective biasing change and the contribution of the newly generated traps becomes extremely challenging. In order to better understand the effects of irradiation, transistor noise had to be characterized at several biasing points, both in linear and saturation regions, before and after exposure to 1 Grad (SiO
2
) of TID. Correlation between shifts in time and frequency domain is presented in this work, along with possible explanations for each variation that occurs. We present examples of irradiation-generated Random Telegraph Noise (RTN) defects as well as various TID effects on noise Power Spectral Density (PSD) curves with pre-existing RTN sources.
We develop a numerical scheme for determining the optimal asset allocation strategy for time-consistent, continuous time, mean variance optimization. Any type of constraint can be applied to the ...investment policy. The optimal policies for time-consistent and pre-commitment strategies are compared. When realistic constraints are applied, the efficient frontiers for the pre-commitment and time-consistent strategies are similar, but the optimal investment strategies are quite different.
Psychological research repeatedly identifies two dimensions of political values. Recent work argues that these dimensions reflect the dual evolutionary foundations of human social and political life: ...a trade-off between cooperation and competition that generates differences in values about social inequality, and a trade-off in managing group coordination that generates differences in values about social control. Existing scales used to measure political values, however, were created prior to this framework. Here, we introduce the Dual Foundations Scale, designed to capture values about the two trade-offs. We validate the scale across two studies, showing it accurately and reliably measures both dimensions. Our results support key predictions of the dual foundations framework and pave the way for future work on the foundations of political ideology.
Small-molecule inhibitor of apoptosis (IAP) antagonists, called Smac mimetic compounds (SMCs), sensitize tumours to TNF-α-induced killing while simultaneously blocking TNF-α growth-promoting ...activities. SMCs also regulate several immunomodulatory properties within immune cells. We report that SMCs synergize with innate immune stimulants and immune checkpoint inhibitor biologics to produce durable cures in mouse models of glioblastoma in which single agent therapy is ineffective. The complementation of activities between these classes of therapeutics is dependent on cytotoxic T-cell activity and is associated with a reduction in immunosuppressive T-cells. Notably, the synergistic effect is dependent on type I IFN and TNF-α signalling. Furthermore, our results implicate an important role for TNF-α-producing cytotoxic T-cells in mediating the anti-cancer effects of immune checkpoint inhibitors when combined with SMCs. Overall, this combinatorial approach could be highly effective in clinical application as it allows for cooperative and complimentary mechanisms in the immune cell-mediated death of cancer cells.
Neurotrophins and their receptors are frequently expressed in malignant gliomas, yet their functions are largely unknown. Previously, we have shown that p75 neurotrophin receptor is required for ...glioma invasion and proliferation. However, the role of Trk receptors has not been examined. In this study, we investigated the importance of TrkB and TrkC in survival of brain tumor-initiating cells (BTICs). Here, we show that human malignant glioma tissues and also tumor-initiating cells isolated from fresh human malignant gliomas express the neurotrophin receptors TrkB and TrkC, not TrkA, and they also express neurotrophins NGF, BDNF, and neurotrophin 3 (NT3). Specific activation of TrkB and TrkC receptors by ligands BDNF and NT3 enhances tumor-initiating cell viability through activation of ERK and Akt pathways. Conversely, TrkB and TrkC knockdown or pharmacologic inhibition of Trk signaling decreases neurotrophin-dependent ERK activation and BTIC growth. Further, pharmacological inhibition of both ERK and Akt pathways blocked BDNF, and NT3 stimulated BTIC survival. Importantly, attenuation of BTIC growth by EGFR inhibitors could be overcome by activation of neurotrophin signaling, and neurotrophin signaling is sufficient for long term BTIC growth as spheres in the absence of EGF and FGF. Our results highlight a novel role for neurotrophin signaling in brain tumor and suggest that Trks could be a target for combinatorial treatment of malignant glioma.
Background: The role of Trk neurotrophin receptors in glioma is unknown.
Results: TrkB and TrkC are required for survival of brain tumor-initiating cells in the absence of EGF and FGF.
Conclusion: Trk receptors can control the survival of BTICs in the absence of EGF and FGF.
Significance: Trks may be important targets for treatment of malignant gliomas.
In the past 5 years, the field of oncolytic virus research has matured significantly and is moving past the stage of being a laboratory novelty into a new era of preclinical and clinical trials. What ...have recent anticancer trials of oncolytic viruses taught us about this exciting new line of therapeutics?
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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