Severe influenza disease strikes otherwise healthy children and remains unexplained. We report compound heterozygous null mutations in IRF7, which encodes the transcription factor interferon ...regulatory factor 7, in an otherwise healthy child who suffered life-threatening influenza during primary infection. In response to influenza virus, the patient's leukocytes and plasmacytoid dendritic cells produced very little type I and III interferons (IFNs). Moreover, the patient's dermal fibroblasts and induced pluripotent stem cell (iPSC)–derived pulmonary epithelial cells produced reduced amounts of type I IFN and displayed increased influenza virus replication. These findings suggest that IRF7-dependent amplification of type I and III IFNs is required for protection against primary infection by influenza virus in humans. They also show that severe influenza may result from single-gene inborn errors of immunity.
Previous results from our trial showed that adding oxaliplatin to radiotherapy (RT) increased survival in patients with locoregionally advanced nasopharyngeal carcinoma (NPC) at 2 years. Here, we ...present the data of long-term efficacy and late toxic effects.
Between January 2001 and January 2003, 115 Patients with nonkeratinizing/undifferentiated locoregionally advanced NPC were randomly to receive either RT alone (n = 56) or plus concurrent oxaliplatin 70 mg/m2 weekly for six cycles (n = 59).
After a median follow-up of 114 months (range 18–139 months), the 5-year overall survival (OS) and metastasis-free survival (MFS) rates in the concurrent chemoradiotherapy (CCRT) group were significantly higher than those observed in the RT-alone group (OS, 73.2% versus 60.2%, P = 0.028; MFS, 74.7% versus 63.0%, P = 0.027). However, CCRT did not improve locoregional failure-free survival significantly. Subgroup analyses showed that the superiorities of CCRT mainly existed in the T3-4N0-1 stage subgroup (OS: HR = 0.394, P = 0.034). The grade 3/4 late toxic effects were similar in the two groups.
The long-term follow-up data confirms the role of CCRT as a treatment of locoregionally advanced NPC. Oxaliplatin can be considered as an alternative optional therapeutic regimen for these patients due to its high efficiency and low toxic effect.
Lung and airway epithelial cells generated in vitro from human pluripotent stem cells (hPSCs) have applications in regenerative medicine, modeling of lung disease, drug screening and studies of human ...lung development. Here we describe a strategy for directed differentiation of hPSCs into developmental lung progenitors, and their subsequent differentiation into predominantly distal lung epithelial cells. The protocol entails four stages that recapitulate lung development, and it takes ∼50 d. First, definitive endoderm (DE) is induced in the presence of high concentrations of activin A. Subsequently, lung-biased anterior foregut endoderm (AFE) is specified by sequential inhibition of bone morphogenetic protein (BMP), transforming growth factor-β (TGF-β) and Wnt signaling. AFE is then ventralized by applying Wnt, BMP, fibroblast growth factor (FGF) and retinoic acid (RA) signaling to obtain lung and airway progenitors. Finally, these are further differentiated into more mature epithelial cells types using Wnt, FGF, cAMP and glucocorticoid agonism. This protocol is conducted in defined conditions, it does not involve genetic manipulation of the cells and it results in cultures in which the majority of the cells express markers of various lung and airway epithelial cells, with a predominance of cells identifiable as functional type II alveolar epithelial cells.
The ability to generate lung and airway epithelial cells from human pluripotent stem cells (hPSCs) would have applications in regenerative medicine, modeling of lung disease, drug screening and ...studies of human lung development. We have established, based on developmental paradigms, a highly efficient method for directed differentiation of hPSCs into lung and airway epithelial cells. Long-term differentiation of hPSCs in vivo and in vitro yielded basal, goblet, Clara, ciliated, type I and type II alveolar epithelial cells. The type II alveolar epithelial cells were capable of surfactant protein-B uptake and stimulated surfactant release, providing evidence of specific function. Inhibiting or removing retinoic acid, Wnt and BMP-agonists to signaling pathways critical for early lung development in the mouse-recapitulated defects in corresponding genetic mouse knockouts. As this protocol generates most cell types of the respiratory system, it may be useful for deriving patient-specific therapeutic cells.
Patients with severe chronic obstructive pulmonary disease (COPD) are at higher risk of developing invasive pulmonary aspergillosis (IPA). However, there are limited data for this disease. To ...evaluate risk factors and the clinical characteristics of IPA in COPD patients, we conducted a hospital-based, retrospective case-control study of 30 COPD patients with IPA and 60 COPD control patients without IPA. Patients in the case group were significantly more likely to have concurrent co-morbidities than controls. Of the IPA patients, 65.4% had worsening radiological findings vs. 11.4% in the control group (p <0.001). IPA in COPD was associated with a higher proportion of mechanical ventilation (43.3% vs. 5%; p <0.001), a longer hospital stay duration (45.8 ± 39.1 days vs. 18.4 ± 11.8 days; p <0.001), and higher mortality (43.3% vs. 11.4%; p <0.001). Systemic use of steroids in the stable phase, treatment with three or more antibiotics during hospitalization and antibiotic treatment longer than 10 days were independent risk factors associated with IPA. COPD patients with obvious dyspnoea, antibiotic-resistant lower respiratory tract infection and repeated detection of Aspergillus in sputum should be considered for the possibility of IPA.
Abstract
We report the discovery of a new unidentified extended
γ
-ray source in the Galactic plane named LHAASO J0341+5258 with a pretrial significance of 8.2 standard deviations above 25 TeV. The ...best-fit position is R.A. = 55.°34 ± 0.°11 and decl. = 52.°97 ± 0.°07. The angular size of LHAASO J0341+5258 is 0.°29 ± 0.°06
stat
± 0.°02
sys
. The flux above 25 TeV is about 20% of the flux of the Crab Nebula. Although a power-law fit of the spectrum from 10 to 200 TeV with the photon index
α
= 2.98 ± 0.19
stat
± 0.02
sys
is not excluded, the LHAASO data together with the flux upper limit at 10 GeV set by the Fermi-LAT observation, indicate a noticeable steepening of an initially hard power-law spectrum with a cutoff at ≈50 TeV. We briefly discuss the origin of ultra-high-energy gamma rays. The lack of an energetic pulsar and a young supernova remnant inside or in the vicinity of LHAASO J0341+5258 challenge, but do not exclude, both the leptonic and hadronic scenarios of gamma-ray production.
High-β_{θe} (a ratio of the electron thermal pressure to the poloidal magnetic pressure) steady-state long-pulse plasmas with steep central electron temperature gradient are achieved in the ...Experimental Advanced Superconducting Tokamak. An intrinsic current is observed to be modulated by turbulence driven by the electron temperature gradient. This turbulent current is generated in the countercurrent direction and can reach a maximum ratio of 25% of the bootstrap current. Gyrokinetic simulations and experimental observations indicate that the turbulence is the electron temperature gradient mode (ETG). The dominant mechanism for the turbulent current generation is due to the divergence of ETG-driven residual flux of current. Good agreement has been found between experiments and theory for the critical value of the electron temperature gradient triggering ETG and for the level of the turbulent current. The maximum values of turbulent current and electron temperature gradient lead to the destabilization of an m/n=1/1 kink mode, which by counteraction reduces the turbulence level (m and n are the poloidal and toroidal mode number, respectively). These observations suggest that the self-regulation system including turbulence, turbulent current, and kink mode is a contributing mechanism for sustaining the steady-state long-pulse high-β_{θe} regime.
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Interfaces have been reported to significantly strengthen and toughen metallic materials. However, there has been a long-standing question on whether interface-affected-zone (IAZ) ...exists, and how it might behave. Here we report in situ high-resolution strain mapping near interfaces in a copper–bronze heterogeneous laminate, which revealed the existence of IAZs. Defined as the zone with strain gradient, the IAZ was found to form by the dislocations emitted from the interface. The IAZ width remained largely constant with a magnitude of a few micrometers with increasing applied strain. Interfaces produced both back stress strengthening and work hardening, which led to both higher strength and higher ductility with decreasing interface spacing until adjacent IAZs started to overlap, after which a tradeoff between strength and ductility occurred, indicating the existence of an optimum interface spacing for the best mechanical properties. These findings are expected to help with designing laminates and other heterogeneous metals and alloys for superior mechanical properties.
The amyloid-β protein (Aβ) protein plays a pivotal role in the pathogenesis of Alzheimer's disease (AD). It is believed that Aβ deposited in the brain originates from the brain tissue itself. ...However, Aβ is generated in both brain and peripheral tissues. Whether circulating Aβ contributes to brain AD-type pathologies remains largely unknown. In this study, using a model of parabiosis between APPswe/PS1dE9 transgenic AD mice and their wild-type littermates, we observed that the human Aβ originated from transgenic AD model mice entered the circulation and accumulated in the brains of wild-type mice, and formed cerebral amyloid angiopathy and Aβ plaques after a 12-month period of parabiosis. AD-type pathologies related to the Aβ accumulation including tau hyperphosphorylation, neurodegeneration, neuroinflammation and microhemorrhage were found in the brains of the parabiotic wild-type mice. More importantly, hippocampal CA1 long-term potentiation was markedly impaired in parabiotic wild-type mice. To the best of our knowledge, our study is the first to reveal that blood-derived Aβ can enter the brain, form the Aβ-related pathologies and induce functional deficits of neurons. Our study provides novel insight into AD pathogenesis and provides evidence that supports the development of therapies for AD by targeting Aβ metabolism in both the brain and the periphery.
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