Severe infections are common complications of immunosuppressive treatment for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) with renal involvement. We investigated the ...clinical characteristics and risk factors of severe infection in Chinese patients with AAV after immunosuppressive therapy.
A total of 248 patients with a new diagnosis of ANCA-associated vasculitis were included in this study. The incidence, time, site, and risk factors of severe infection by the induction therapies were analysed. Multivariate Cox proportional hazards models were used to calculate hazard ratios (HRs) with 95% confidence intervals (CI).
A total of 103 episodes of severe infection were identified in 86 (34.7%, 86/248) patients during a median follow-up of 15 months. The incidence of infection during induction therapy was 38.5% for corticosteroids (CS), 39.0% for CS+ intravenous cyclophosphamide (IV-CYC), 33.8% for CS+ mycophenolate mofetil and 22.5% for CS + tripterygium glycosides, 76 (73.8%) infection episodes occurred within 6 months, while 66 (64.1%) occurred within 3 months. Pneumonia (71.8%, 74/103) was the most frequent type of infection, and the main pathogenic spectrum included bacteria (78.6%), fungi (12.6%), and viruses (8.7%). The risk factors associated with infection were age at the time of diagnosis (HR = 1.003, 95% CI = 1.000-1.006), smoking (HR = 2.338, 95% CI = 1.236-4.424), baseline secrum creatinine (SCr) ≥5.74 mg/dl (HR = 2.153, 95% CI = 1.323-3.502), CD4
T cell< 281 μl (HR = 1.813, 95% CI = 1.133-2.900), and intravenous cyclophosphamide regimen (HR = 1.951, 95% CI =1.520-2.740). Twelve (13.9%) patients died of severe pneumonia.
The infection rate during induction therapy was high in patients with AAV. Bacterial pneumonia was the main type of infection encountered. Age at the time of diagnosis, smoking, baseline SCr ≥5.74 mg/dl, CD4
T cell< 281 μl, and IV-CYC therapy were identified as risk factors for infection.
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•Nonlinear electric field was effective to improve separation efficiency.•Charged particles separation was simulated by CFD-DEM coupling calculation.•Reasonable conditions and ...parameter was obtained for industrialized application.
Fly ash is solid waste produced by thermal power generation, and its carbon content is a key factor affecting its recycling. Due to the large difference in fly ash quality and insufficient tribocharging, the parallel plate electric field with constant electric field strength cannot meet the practical needs of efficient decarbonization of fly ash particles with wide charge range or small charge to mass ratio (CMR). Therefore, a nonlinear electric field structure is proposed. The separation process of fly ash particles in the nonlinear electric field is explored through the establishment of geometric model and the application of CFD-DEM coupled calculation method, and the main influencing factors of fly ash electrostatic dry separation are studied. The results show that the nonlinear electric field structure is feasible to achieve high efficiency decarbonization of fly ash. With the increase of air flow velocity, the loss on ignition of positive electrode first increases and then decreases. The loss on ignition (LOI) of positive electrode products is directly proportional to the voltage and the CMR of the input, but inversely proportional to the feed quantity. Air flow velocity of 20 m/s, voltage of 30 kV, charge-mass ratio of 1.1–1.2 nC/g and feed quantity of 5000/s are suitable conditions for efficient decarbonization of fly ash. Compared with parallel plates, hyperbolic nonlinear electric field has higher decarbonization efficiency and lower energy consumption in experiment.
Tobacco etch virus protease (TEVp) is a useful tool for removing fusion tags, but wild-type TEVp is less stable under oxidized redox state. In this work, we introduced and combined C19S, C110S and ...C130S into TEVp variants containing T17S, L56V, N68D, I77V and S135G to improve protein solubility, and S219V to inhibit self-proteolysis. The solubility and cleavage activity of the constructed variants in
strains including BL21(DE3), BL21(DE3)pLys, Rossetta(DE3) and Origami(DE3) under the same induction conditions were analyzed and compared. The desirable soluble amounts, activity, and oxidative stability were identified to be reluctantly favored in the TEVp. Unlike C19S, C110S and C130S hardly impacted on decreasing protein solubility in the BL21(DE3), but they contributed to improved tolerance to the oxidative redox state in vivo and in vitro. After two fusion proteins were cleaved by purified TEVp protein containing double mutations under the oxidized redox state, the refolded disulfide-rich bovine enterokinase catalytic domain or maize peroxidase with enhanced yields were released from the regenerated amorphous cellulose via affinity absorption of the cellulose-binding module as the affinity tag.
Thioredoxin reductase 1 (TrxR1) has emerged as a promising target for cancer therapy. In our previous research, we discovered several new TrxR1 inhibitors and found that they all have excellent ...anti-tumor activity. At the same time, we found these TrxR1 inhibitors all lead to an increase in AKT phosphorylation in cancer cells, but the detailed role of AKT phosphorylation in TrxR1 inhibitor-mediated cell death remains unclear. In this study, we identified the combination of AKT and TrxR1 inhibitor displayed a strong synergistic effect in colon cancer cells. Furthermore, we demonstrated that the synergistic effect of auranofin (TrxR1 inhibitor) and MK-2206 (AKT inhibitor) was caused by ROS accumulation. Importantly, we found that ATM inhibitor KU-55933 can block the increase of AKT phosphorylation caused by auranofin, and exhibited a synergistic effect with auranofin. Taken together, our study demonstrated that the activation of ATM/AKT pathway is a compensatory mechanism to cope with ROS accumulation induced by TrxR1 inhibitor, and synergistic targeting of TrxR1 and ATM/AKT pathway is a promising strategy for treating colon cancer.
•The AKT phosphorylation level in colon cancer cells was significantly increased after TrxR1 inhibitors treatment.•ROS mediates the synergism of TrxR1 and ATM/AKT pathway inhibitors.•TrxR1 and ATM/AKT pathway inhibitors can synergistically upregulate the autophagy level in colon cancer cells.•Synergistic targeting of TrxR1 and ATM/AKT pathway is a promising strategy for treating colon cancer.
Eukaryotic initiation factor subunit I (EIF3i), also called as p36 or TRIP-1, is a component of the translation initiation complex and acts as a modulator of TGF-β signaling. We demonstrated earlier ...that this intracellular protein is not only exported to the extracellular matrix via exosomes but also binds calcium phosphate and promotes hydroxyapatite nucleation. To assess other functional roles of TRIP-1, we first examined their phylogeny and showed that it is highly conserved in eukaryotes. Comparing human EIF3i sequence with that of 63 other eukaryotic species showed that more than 50% of its sequence is conserved, suggesting the preservation of its important functional role (translation initiation) during evolution. TRIP-1 contains WD40 domains and predicting its function based on this structural motif is difficult as it is present in a vast array of proteins with a wide variety of functions. Therefore, bioinformatics analysis was performed to identify putative regulatory functions for TRIP-1 by examining the structural domains and post-translational modifications and establishing an interactive network using known interacting partners such as type I collagen. Insight into the function of TRIP-1 was also determined by examining structurally similar proteins such as Wdr5 and GPSß, which contain a ß-propeller structure which has been implicated in the calcification process. Further, proteomic analysis of matrix vesicles isolated from TRIP-1-overexpressing preosteoblastic MC3T3-E1 cells demonstrated the expression of several key biomineralization-related proteins, thereby confirming its role in the calcification process. Finally, we demonstrated that the proteomic signature in TRIP1-OE MVs facilitated osteogenic differentiation of stem cells. Overall, we demonstrated by bioinformatics that TRIP-1 has a unique structure and proteomic analysis suggested that the unique osteogenic cargo within the matrix vesicles facilitates matrix mineralization.
Bone and dentin development requires temporal and spatial deposition of calcium phosphate mineral. A host of proteins works in concert to contribute to this tightly regulated process while ...malfunction in this scheme often leads to pathological defects. We have reported earlier that DMP1 stimulation of preosteoblasts leads to calcium release from internal Ca2+ stores and this store depletion is sensed by the ER Ca2+ sensor STIM1 (stromal interaction molecule 1). In this study, we first assessed the temporal and spatial localization of STIM1 protein during the development of bone and dentin by immunohistochemical methods. We further analyzed the function of STIM1 by establishing a stable MC3T3-E1 cell-line by overexpressing STIM1 (MC3T3-E1/STIM1 OE). Under mineralizing conditions, STIM1 overexpressing cells showed increased calcium deposits with higher expression of key osteogenic markers, such as Runx2 and type I collagen, BMP4 when compared with the control cells. Our results demonstrate that during mineralized matrix formation STIM1, the key ER sensor protein, can promote cellular differentiation in the presence of extracellular calcium.
Autosomal dominant Alzheimer's disease (ADAD) is genetically determined, but variability in age of symptom onset suggests additional factors may influence cognitive trajectories. Although ...apolipoprotein E (APOE) genotype and educational attainment both influence dementia onset in sporadic AD, evidence for these effects in ADAD is limited. To investigate the effects of APOE and educational attainment on age-related cognitive trajectories in ADAD, we analyzed data from 675 Presenilin-1 E280A mutation carriers and 594 non-carriers. Here we show that age-related cognitive decline is accelerated in ADAD mutation carriers who also have an APOE e4 allele compared to those who do not and delayed in mutation carriers who also have an APOE e2 allele compared to those who do not. Educational attainment is protective and moderates the effect of APOE on cognition. Despite ADAD mutation carriers being genetically determined to develop dementia, age-related cognitive decline may be influenced by other genetic and environmental factors.
Grip strength is a biomarker of frailty and an evaluation indicator of brain health, cardiovascular morbidity, and psychological health. Yet, the development of a reliable, interactive, and ...point‐of‐care device for comprehensive multi‐sensing of hand grip status is challenging. Here, a relation between soft buckling metamaterial deformations and built piezoelectric voltage signals is uncovered to achieve multiple sensing of maximal grip force, grip speed, grip impulse, and endurance indicators. A metamaterial computational sensor design is established by hyperelastic model that governs the mechanical characterization, machine learning models for computational sensing, and graphical user interface to provide visual cues. A exemplify grip measurement for left and right hands of seven elderly campus workers is conducted. By taking indicators of grip status as input parameters, human‐computer interactive games are incorporated into the computational sensor to improve the user compliance with measurement protocols. Two elderly female schizophrenic patients are participated in the real‐time interactive point‐of‐care grip assessment and training for potentially sarcopenia screening. The attractive features of this advanced intelligent metamaterial computational sensing system are crucial to establish a point‐of‐care biomechanical platform and advancing the human‐computer interactive healthcare, ultimately contributing to a global health ecosystem.
A reliable, interactive, and point‐of‐care device sensing maximal grip force, grip speed, grip impulse, and endurance indicators for multi‐sensing comprehensive grip strength status is developed. Implemented with interactive games with tactile and visual feedback to increase user interest and compliance, the sensor advances arising fields of point‐of‐care computational sensing, human‐machine interactive system and internet of medical things.
MicroRNAs (miRs) play an important role in the development and remodeling of tissues through the regulation of large cohorts of extracellular matrix (ECM) genes. The purpose of the present study was ...to determine the response of miR-29 family expression to loading forces and their effects on ECM gene expression in periodontal ligament cells, the key effector cell population during orthodontic tooth movement. In a comparison between miRs from human periodontal ligament cells (PDLCs) and alveolar bone cells (ABCs) from healthy human subjects, the ABC cohort of miRs was substantially greater than the corresponding PDLC cohort. Cyclic mechanical stretch forces at 12% deformation at 0.1Hz for 24h decreased expression of miR-29 family member miRs about 0.5 fold while 2g/cm2 compression force for 24h increased miR-29 family member expression in PDLCs 1.8–4 folds. Cyclic stretch up-regulated major ECM genes in PDLCs, such as COL1A1, COL3A1 and COL5A1, while the compression force resulted in a down-regulation of these ECM genes. Direct interactions of miR-29 and Col1a1, Col3a1 and Col5a1 were confirmed using a dual luciferase reporter gene assay. In addition, transient transfection of a miR-29b mimic in mouse PDLCs down-regulated Col1a1, Col3a1 and Col5a1 while the transfection of miR-29b inhibitor up-regulated these genes compared to control transfection indicating that these target ECM genes directly responded to the altered level of miR-29b. These results provided a possible explanation for the effects of the miR-29 family on loaded PDLCS and their roles in extracellular matrix gene expression.
•Stretch and compression forces induce opposite expression patterns of microRNA-29.•Stretch and compression forces induce opposite expression patterns of PDL ECM genes.•MiRNA-29b negatively affects the expression of Col1a1, Col3a1 and Col5a1 in PDLCs.•Col1a1, Col3a1 and Col5a1 are direct targets of miRNA-29b in PDLCs.
Plasma neurofilament light (NfL) is an indicator of neurodegeneration and/or neuroaxonal injury in persons with Alzheimer's disease (AD) and a wide range of other neurological disorders. Here, we ...characterized and compared plasma NfL concentrations in cognitively unimpaired (CU) late-middle-aged and older adults with two, one, or no copies of the APOE ε4 allele, the major genetic risk factor for AD. We then assessed plasma NfL associations with brain imaging measurements of AD-related neurodegeneration (hippocampal atrophy and a hypometabolic convergence index HCI), brain imaging measurements of amyloid-β plaque burden, tau tangle burden and white matter hyperintensity volume (WMHV), and delayed and total recall memory scores.
Plasma NfL concentrations were measured in 543 CU 69 ± 9 year-old participants in the Arizona APOE Cohort Study, including 66 APOE ε4 homozygotes (HM), 165 heterozygotes (HT), and 312 non-carriers (NC). Robust regression models were used to characterize plasma NfL associations with APOE ε4 allelic dose before and after adjustment for age, sex, and education. They were also used to characterize plasma NfL associations with MRI-based hippocampal volume and WMHV measurements, an FDG PET-based HCI, mean cortical PiB PET measurements of amyloid-β plaque burden and meta-region-of-interest (meta-ROI) flortaucipir PET measurements of tau tangle burden, and Auditory Verbal Learning Test (AVLT) Delayed and Total Recall Memory scores.
After the adjustments noted above, plasma NfL levels were significantly greater in APOE ε4 homozygotes and heterozygotes than non-carriers and significantly associated with smaller hippocampal volumes (r = - 0.43), greater tangle burden in the entorhinal cortex and inferior temporal lobes (r = 0.49, r = 0.52, respectively), and lower delayed (r = - 0.27), and total (r = - 0.27) recall memory scores (p < 0.001). NfL levels were not significantly associated with PET measurements of amyloid-β plaque or total tangle burden.
Plasma NfL concentrations are associated with the APOE ε4 allele, brain imaging biomarkers of neurodegeneration, and less good recall memory in CU late-middle-aged and older adults, supporting its value as an indicator of neurodegeneration in the preclinical study of AD.
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