One of the defining characteristics of a pre-metastatic niche, a fundamental requirement for primary tumor metastasis, is infiltration of immunosuppressive macrophages. How these macrophages acquire ...their phenotype remains largely unexplored. Here, we demonstrate that tumor-derived exosomes (TDEs) polarize macrophages toward an immunosuppressive phenotype characterized by increased PD-L1 expression through NF-kB-dependent, glycolytic-dominant metabolic reprogramming. TDE signaling through TLR2 and NF-κB leads to increased glucose uptake. TDEs also stimulate elevated NOS2, which inhibits mitochondrial oxidative phosphorylation resulting in increased conversion of pyruvate to lactate. Lactate feeds back on NF-κB, further increasing PD-L1. Analysis of metastasis-negative lymph nodes of non-small-cell lung cancer patients revealed that macrophage PD-L1 positively correlates with levels of GLUT-1 and vesicle release gene YKT6 from primary tumors. Collectively, our study provides a novel mechanism by which macrophages within a pre-metastatic niche acquire their immunosuppressive phenotype and identifies an important link among exosomes, metabolism, and metastasis.
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•TDEs stimulate de novo synthesis of PD-L1 in macrophages•TDEs activate NF-κB, which augments glycolysis, leading to increased lactate production•Lactate drives PD-L1 expression through the NF-κB pathway•Macrophage PD-L1 in the dLNs correlates with YKT6 expression levels in primary NSCLC
Morrissey et al. report that tumor-derived exosomes stimulate pre-metastatic niche macrophages toward an immunosuppressive phenotype through NF-kB-dependent, glycolytic-dominant metabolic reprogramming, thus promoting tumor metastasis. These pro-metastatic macrophages are characterized by increased de novo synthesis of PD-L1 and increased lactate production.
Silicon is more than the dominant material in the conventional microelectronics industry: it also has potential as a host material for emerging quantum information technologies. Standard fabrication ...techniques already allow the isolation of single electron spins in silicon transistor-like devices. Although this is also possible in other materials, silicon-based systems have the advantage of interacting more weakly with nuclear spins. Reducing such interactions is important for the control of spin quantum bits because nuclear fluctuations limit quantum phase coherence, as seen in recent experiments in GaAs-based quantum dots. Advances in reducing nuclear decoherence effects by means of complex control still result in coherence times much shorter than those seen in experiments on large ensembles of impurity-bound electrons in bulk silicon crystals. Here we report coherent control of electron spins in two coupled quantum dots in an undoped Si/SiGe heterostructure and show that this system has a nuclei-induced dephasing time of 360 nanoseconds, which is an increase by nearly two orders of magnitude over similar measurements in GaAs-based quantum dots. The degree of phase coherence observed, combined with fast, gated electrical initialization, read-out and control, should motivate future development of silicon-based quantum information processors.
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Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We present the final results from a high sampling rate, multi-month, spectrophotometric reverberation mapping campaign undertaken to obtain either new or improved H{beta} reverberation lag ...measurements for several relatively low-luminosity active galactic nuclei (AGNs). We have reliably measured the time delay between variations in the continuum and H{beta} emission line in six local Seyfert 1 galaxies. These measurements are used to calculate the mass of the supermassive black hole at the center of each of these AGNs. We place our results in context to the most current calibration of the broad-line region (BLR) R{sub BLR}-L relationship, where our results remove outliers and reduce the scatter at the low-luminosity end of this relationship. We also present velocity-resolved H{beta} time-delay measurements for our complete sample, though the clearest velocity-resolved kinematic signatures have already been published.
The early-life microbiome appears to be affected by mode of delivery, but this effect may depend on intrapartum antibiotic exposure. Here, we assess the effect of delivery mode on gut microbiota, ...independent of intrapartum antibiotics, by postponing routine antibiotic administration to mothers until after cord clamping in 74 vaginally delivered and 46 caesarean section born infants. The microbiota differs between caesarean section born and vaginally delivered infants over the first year of life, showing enrichment of Bifidobacterium spp., and reduction of Enterococcus and Klebsiella spp. in vaginally delivered infants. The microbiota composition at one week of life is associated with the number of respiratory infections over the first year. The taxa driving this association are more abundant in caesarean section born children, providing a possible link between mode of delivery and susceptibility to infectious outcomes.
Recent trials have shown that avoiding peanuts during infancy increases the risk of peanut allergy; however, these studies did not address maternal peanut consumption.
We sought to investigate the ...relationship between maternal peanut consumption while breast-feeding, timing of direct peanut introduction, and peanut sensitization at age 7 years.
Secondary analysis of a nested cohort within the 1995 Canadian Asthma Primary Prevention Study intervention study was performed. Breast-feeding and maternal and infant peanut consumption were captured by repeated questionnaires during infancy. Skin prick testing for peanut sensitization was performed at age 7 years.
Overall, 58.2% of mothers consumed peanuts while breast-feeding and 22.5% directly introduced peanuts to their infant by 12 months. At 7 years, 9.4% of children were sensitized to peanuts. The lowest incidence (1.7%) was observed among children whose mothers consumed peanuts while breast-feeding and directly introduced peanuts before 12 months. Incidence was significantly higher (P < .05) if mothers consumed peanuts while breast-feeding but delayed introducing peanuts to their infant beyond 12 months (15.1%), or if mothers avoided peanuts themselves but directly introduced peanuts by 12 months (17.6%). Interaction analyses controlling for study group and maternal atopy confirmed that maternal peanut consumption while breast-feeding and infant peanut consumption by 12 months were protective in combination, whereas either exposure in isolation was associated with an increased risk of sensitization (P interaction = .003).
In this secondary analysis, maternal peanut consumption while breast-feeding paired with direct introduction of peanuts in the first year of life was associated with the lowest risk of peanut sensitization, compared with all other combinations of maternal and infant peanut consumption.
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Asthma often starts before six years of age. However, there remains uncertainty as to when and how a preschool-age child with symptoms suggestive of asthma can be diagnosed with this condition. This ...delays treatment and contributes to both short- and long-term morbidity. Members of the Canadian Thoracic Society Asthma Clinical Assembly partnered with the Canadian Paediatric Society to develop a joint working group with the mandate to develop a position paper on the diagnosis and management of asthma in preschoolers. In the absence of lung function tests, the diagnosis of asthma should be considered in children one to five years of age with frequent (≥ 8 days/month) asthma-like symptoms or recurrent (≥ 2) exacerbations (episodes with asthma-like signs). The diagnosis requires the objective document of signs or convincing parent-reported symptoms of airflow obstruction (improvement in these signs or symptoms with asthma therapy), and no clinical suspicion of an alternative diagnosis. The characteristic feature of airflow obstruction is wheezing, commonly accompanied by difficulty breathing and cough. Reversibility with asthma medications is defined as direct observation of improvement with short-acting ß2-agonists (SABA) (with or without oral corticosteroids) by a trained health care practitioner during an acute exacerbation (preferred method). However, in children with no wheezing (or other signs of airflow obstruction) on presentation, reversibility may be determined by convincing parental report of a symptomatic response to a three-month therapeutic trial of a medium dose of inhaled corticosteroids with as-needed SABA (alternative method), or as-needed SABA alone (weaker alternative method). The authors provide key messages regarding in whom to consider the diagnosis, terms to be abandoned, when to refer to an asthma specialist and the initial management strategy. Finally, dissemination plans and priority areas for research are identified.
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