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Given that randomized studies testing the long-term impact of antithymocyte globulin (ATG) dosing are scarce, we report the results of an extended follow-up from the original trial. ...In our prospective, multicenter, randomized trial, 408 leukemia patients 14–65 years of age who underwent haploidentical hematopoietic cell transplantation (haplo-HCT) under our original “Beijing Protocol” were randomly assigned one-to-one to ATG doses of 7.5 mg/kg (n = 203, ATG-7.5) or 10 mg/kg (n = 205, ATG-10.0) at four sites. Extended follow-up (median 1968 d (range: 1300–2710 d) indicated comparable 5-year probabilities of moderate-to-severe chronic graft-versus-host disease (GVHD) (hazard ratio (HR): 1.384, 95% confidence interval (CI): 0.876–2.189, P = 0.164), nonrelapse mortality (HR: 0.814, 95% CI: 0.526–1.261, P = 0.357), relapse (HR: 1.521, 95% CI: 0.919–2.518, P = 0.103), disease-free survival (HR: 1.074, 95% CI: 0.783–1.473, P = 0.658), and GVHD-free/relapse-free survival (HR: 1.186, 95% CI: 0.904–1.555, P = 0.219) between groups (ATG-7.5 vs. ATG-10.0). The 5-year rate of late effects did not differ significantly. However, the cytomegalovirus/Epstein-Barr virus-related death rate was much higher in the ATG-10.0 cohort than in the ATG-7.5 cohort (9.8% vs. 1.5%; P = 0.003). In summary, patients undergoing haplo-HCT benefit from 7.5 mg/kg ATG compared to 10.0 mg/kg ATG based on a balance between GVHD and infection control. ATG (7.5 mg/kg) is potentially regarded as the standard regimen in the platform. These results support the optimization of ATG use in the “Beijing Protocol”, especially considering the potential economic advantage in developing countries.
•A new CNN-based model enhancement method for bearing fault diagnosis: CA-MCNN.•A new multi-scale extraction method based on pooling layers.•Adaptive parallel feature fusion mechanism based on 1-D ...convolution.
In recent years, deep learning has achieved great success in bearing fault diagnosis due to its robust feature learning capabilities. However, in the actual industry, the diagnostic accuracy would be degraded under varying operation conditions or in noisy environments. To enhance the diagnostic performance in industrial applications, a Multi-scale Convolutional Neural Network with Channel Attention (CA-MCNN) is proposed in this paper. In CA-MCNN, the maximum pooling and average pooling layers are used to extract the multi-scale information of the bearing signals, which increases the dimensions of input. The channel attention mechanism is introduced to increase the convolutional layer feature learning ability by adaptively scoring and assigning weights to the learned features. Moreover, the feature parallel fusion mechanism based on 1-D convolution is applied to capture complementary multi-scale information and reduce network complexity. The performance of CA-MCNN is compared with other fault diagnosis models, and experimental results verify that the CA-MCNN achieves the highest diagnosis accuracy under noisy environments and varying working speeds.
Cancer-related bone erosion occurs frequently in bone metastasis and is associated with severe complications such as chronic bone pain, fractures, and lower survival rates. In recognition of the fact ...that the darkness hormone melatonin is capable of regulating bone homeostasis, we explored its therapeutic potential in bone metastasis. We found that melatonin directly reduces osteoclast differentiation, bone resorption activity and promotes apoptosis of mature osteoclasts. We also observed that melatonin inhibits RANKL production in lung and prostate cancer cells by downregulating the p38 MAPK pathway, which in turn prevents cancer-associated osteoclast differentiation. In lung and prostate bone metastasis models, twice-weekly melatonin treatment markedly reduced tumor volumes and numbers of osteolytic lesions. Melatonin also substantially lowered the numbers of TRAP-positive osteoclasts in tibia bone marrow and RANKL expression in tumor tissue. These findings show promise for melatonin in the treatment of bone metastases.
The effect of particle shape on the suffusion of gap-graded soils is an essential although poorly understood subject in geotechnical engineering that requires further investigation. This work ...presents a macroscale and microscale numerical investigation into the effect of particle shape on the suffusion of gap-graded granular materials. Rounded, elliptical, and convex particles with the same volume-equivalent diameter and varying shape coefficients were generated and used to produce samples. Next, a series of resolved coupled computational fluid dynamics (CFD) and discrete-element method (DEM) simulations were performed to provide evidence of the effect of particle shape on the suffusion susceptibility of gap-graded soils. The evolution of particle orientation, moment, and drag force coefficient were analyzed to determine the mechanisms by which particle shape exerts influence. The fine angular particles under seepage flow were found to adjust their orientation, reducing the projected area of the particle perpendicular to the fluid flow direction. Fine particles in high-flow-velocity regions had a smaller projected area and drag force coefficient. The continuous rotation of the irregularly shaped particles during suffusion implies that their migration should counteract the moments exerted by the surrounding particles. In the sample containing various irregularly shaped particles, the initial position of the most irregularly shaped particle was closer to the outlet, implying that irregularly shaped particles are less susceptible to suffusion.
Mulberry extract has been proven to have the effect of resisting alcohol damage, but its mechanism is still unclear. In this study, the composition of mulberry ethanol extract (MBE) was identified by ...LC-MS/MS and the main components of MBE were ascertained by measuring. Gastric mucosal epithelial (GES-1) cells were used to elucidate the mechanism of MBE and rutin (the central part of MBE) helped protect against alcohol damage. The results revealed that phenolics accounted for the majority of MBE, accounting for 308.6 mg/g gallic acid equivalents and 108 substances were identified, including 37 flavonoids and 50 non-flavonoids. The treatment of 400 μg/mL MBE and 320 μM rutin reduced early cell apoptosis and the content of intracellular reactive oxygen species, malondialdehyde and increased glutathione. The qPCR results indicated that the MBE inhibits the expression of genes in the mitogen-activated protein kinase (MAPK) pathway, including p38, JNK, ERK and caspase-3; rutin inhibits the expression of p38 and caspase-3. Overall, MBE was able to reduce the oxidative stress of GES-1 cells and regulated apoptosis-related genes of the MAPK pathway. This study provides information for developing anti-ethanol injury drugs or functional foods.
NK cells directly kill mycobacteria through a contactdependent mechanism leading to the release of perforin and granulysin.
Although the mechanisms underlying the cytotoxic effect of NK cells on ...tumor cells and intracellular bacteria have been studied extensively, it remains unclear how these cells kill extracellular bacterial pathogens. In this study, we examine how human NK cells kill Mycobacterium kansasii and M.tb. The underlying mechanism is contact dependent and requires two cytolytic proteins: perforin and granulysin. Mycobacteria induce enhanced expression of the cytolytic proteins via activation of the NKG2D/NCR cell‐surface receptors and intracellular signaling pathways involving ERK, JNK, and p38 MAPKs. These results suggest that NK cells use similar cellular mechanisms to kill both bacterial pathogens and target host cells. This report reveals a novel role for NK cells, perforin, and granulysin in killing mycobacteria and highlights a potential alternative defense mechanism that the immune system can use against mycobacterial infection.
In the AI era, it has become crucial to evaluate information found on the Internet critically. This research aimed to investigate the impact of a sourcing organizer on sixth graders' online ...multimodal and multiple document reading (MMDR) abilities, focusing on aspects such as source-content link and text integration in relation to reading on the Internet. Cognitive and affective factors associated with MMDR were examined. The study involved 52 sixth-graders (55.77% males) from two typical elementary school classes in the northern region of Taiwan. Two intact classes were randomly assigned to either the experimental or control group with the quasi-experimental design. The experimental group (n = 26) received a pre-outlined sourcing organizer, guiding them to record the article title, author, publication date, website name, and major assertions from six assigned multimodal texts. In contrast, the control group (n = 26) received a regular organizer, prompting them to summarize the main ideas from the same six assigned multimodal texts. The study's findings indicated that employing sourcing organizers positively impacted students' performance in text integration. However, it was observed that both groups, regardless of whether they used regular organizers or sourcing organizers, experienced benefits in terms of source-content links. Furthermore, reading ability emerged as the sole significant predictor for source-content links, whereas both reading ability and the use of sourcing organizers predicted text integration. The implications of these findings were discussed to provide insights into instructional strategies to develop online MMDR competencies in elementary students.
•The sourcing organizer effect is tested on children's multiple document reading.•Sourcing organizers benefit children's text integration but not source-content link.•Reading ability is the only factor that predicts scores in the source-content link.•Reading ability and sourcing organizers predict better text integration.•Strategies to foster epistemic cognition in multiple document reading are discussed.
Major depressive disorder (MDD) is a common but severe psychiatric illness characterized by depressive mood and diminished interest. Both nucleotide-binding oligomerization domain, leucine-rich ...repeat and pyrin domain-containing 1 (NLRP1) inflammasome and autophagy have been reported to implicate in the pathological processes of depression. However, the mechanistic interplay between NLRP1 inflammasome, autophagy, and depression is still poorly known.
Animal model of depression was established by chronic social defeat stress (CSDS). Depressive-like behaviors were determined by social interaction test (SIT), sucrose preference test (SPT), open field test (OFT), forced swim test (FST), and tail-suspension test (TST). The protein expression levels of NLRP1 inflammasome complexes, pro-inflammatory cytokines, phosphorylated-phosphatidylinositol 3-kinase (p-PI3K)/PI3K, phosphorylated-AKT (p-AKT)/AKT, phosphorylated-mechanistic target of rapamycin (p-mTOR)/mTOR, brain-derived neurotrophic factor (BDNF), phosphorylated-tyrosine kinase receptor B (p-TrkB)/TrkB, Bcl-2-associated X protein (Bax)/B-cell lymphoma-2 (Bcl2) and cleaved cysteinyl aspartate-specific proteinase-3 (caspase-3) were examined by western blotting. The mRNA expression levels of pro-inflammatory cytokines were tested by quantitative real-time PCR. The interaction between proteins was detected by immunofluorescence and coimmunoprecipitation. Neuronal injury was assessed by Nissl staining. The autophagosomes were visualized by transmission electron microscopy. Nlrp1a knockdown was performed using an adeno-associated virus (AAV) vector containing Nlrp1a-shRNA-eGFP infusion.
CSDS exposure caused a bidirectional change in hippocampal autophagy function, which was activated in the initial period but impaired at the later stage. In addition, CSDS exposure increased the expression levels of hippocampal NLRP1 inflammasome complexes, pro-inflammatory cytokines, p-PI3K, p-AKT and p-mTOR in a time-dependent manner. Interestingly, NLRP1 is immunoprecipitated with mTOR but not PI3K/AKT and CSDS exposure facilitated the immunoprecipitation between them. Hippocampal Nlrp1a knockdown inhibited the activity of PI3K/AKT/mTOR signaling, rescued the impaired autophagy and ameliorated depressive-like behavior induced by CSDS. In addition, rapamycin, an autophagy inducer, abolished NLRP1 inflammasome-driven inflammatory reactions, alleviated depressive-like behavior and exerted a neuroprotective effect.
Autophagy dysfunction contributes to NLRP1 inflammasome-linked depressive-like behavior in mice and the regulation of autophagy could be a valuable therapeutic strategy for the management of depression.
Smart structures with manipulatable properties are highly demanded in many fields. However, there is a critical challenge in the pursuit of transparent windows that allow optical waves (wavelength of ...µm–nm) for transmitting while blocking microwave (wavelength of cm) in terms of absorbing electromagnetic energy, specifically for meeting the frequency requirement for the 5th generation (5G) mobile networks. For fundamentally establishing novel manipulatable microwave absorbing structures, here, new polymeric aqueous gels as both optically transparent materials and microwave absorbing materials are demonstrated, in which polar networks play significant roles in attenuating electromagnetic energy. By manipulating the hydrogen bonding networks, the resulting optically transparent solid‐state gels are able to offer the capabilities for absorbing microwaves. Interestingly, such gels can be switched into an optically opaque state via converting the amorphous state into a polycrystal state when the temperature is decreased. Such ionic conductive gels can endow the assembled sandwich windows with effective microwave absorbing capability in the range of 15–40 GHz, covering a branch of 5G frequency bands. The results highlight a new strategy for using ionic conductive gels to design and fabricate manipulatable microwave stealth structures for various applications.
Novel transparent ionic conductive gels are developed to fabricate optically manipulatable microwave stealth structures, which can be employed as transparent windows while blocking microwaves in terms of absorbing electromagnetic energy. Such smart gels can endow the assembled windows with effective microwave absorbing capability in the range of 15–40 GHz, advancing smart windows with upgraded manipulatable capabilities and functions.
Maternal metabolism dysregulation during pregnancy predisposes offspring to major diseases, including hypertension, in later life, but the mechanism involved remains to be fully elucidated. A ...high-fat-diet (HFD) pregnant rat model was used to investigate whether excessive intrauterine lipid exposure was associated with elevated blood pressure in offspring and increased levels of leptin, an important biomarker and mediator of vascular dysfunction and hypertension. We found that gestational hyperlipidemia predisposed offspring to blood pressure elevation and sustained increases in leptin levels with no difference in body weight in the rat model. Increased leptin expression and leptin promoter hypomethylation were found in adipose tissues of HFD-exposed offspring. The treatment of mesenchymal stem cells with free fatty acids during adipogenic differentiation resulted in increased leptin expression, accompanied by leptin promoter hypomethylation. In addition, we also followed up 121 children to evaluate the association between maternal triglyceride levels and offspring blood pressure. Consistent with the animal study results, we observed elevated serum leptin levels and blood pressure in the offspring born to women with gestational hypertriglyceridemia. Our findings provide new insights that maternal hyperlipidemia is associated with elevated blood pressure in offspring and is associated with increases in leptin levels through epigenetic memory.
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