A self-assembled nanocomposite is prepared from an aqueous mixture of aptamer-modified gold nanoparticles (Apt–Au NPs), bismuth ions and chloride ions. The Apt–Au NPs are immobilized on bismuth ...oxychloride (BiOCl) nanosheets in situ to form Apt–Au NPs/BiOCl nanocomposites. The as-prepared nanocomposites exhibit high peroxidase-like activity for the catalytic conversion of Amplex Red (AR) to fluorescent resorufin in the presence of H2O2. The catalytic activity of Apt–Au NPs/BiOCl nanocomposites is at least 90-fold higher than that of Apt–Au NPs or BiOCl nanosheets, revealing synergistic effects on their activity. The catalytic activity of Apt–Au NPs/BiOCl nanocomposites is suppressed by vascular endothelial growth factor-A165 (VEGF-A165) molecules that specifically interact with the aptamer units (Del-5-1 and v7t-1) on the nanocomposite surface. The AR/H2O2–Apt–Au NPs/BiOCl nanocomposites probe shows high selectivity (>1000-fold over other proteins) and sensitivity (detection limit ~0.5nM) for the detection of VEGF-A165. Furthermore, the probe is employed for the detection of VEGF isoforms and for the study of interactions between VEGF and VEGF receptors. The practicality of this simple, rapid, cost-effective probe is validated by the analysis of VEGF-A165 in cell culture media, showing its great potential for the analysis of VEGF in biological samples.
Aptamer-modified gold nanoparticles (Apt–Au NPs) are immobilized onto bismuth oxychloride (BiOCl) nanosheets in situ to form Apt–Au NPs/BiOCl nanocomposites. The peroxidase-like activity of Apt–Au NPs/BiOCl nanocomposites is suppressed by vascular endothelial growth factor-A165 (VEGF-A165) molecules that specifically interact with the aptamer units on the nanocomposite surface.
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•Aptamer-modified gold nanoparticles are immobilized on BiOCl nanosheets.•The nanocomposites exhibit high peroxidase-like activity.•Catalytic activity of the nanocomposites is suppressed by VEGF.•Analysis of VEGF isoforms and their interaction to receptors.
Rheumatoid arthritis (RA) is associated with a high risk of osteoporosis and fracture. Interleukin (IL)-6 inhibitors may suppress osteoclast activation. Anticitrullinated protein antibody (ACPA) ...titers are inversely associated with bone mineral density (BMD). However, the differential effect of ACPA on bone turnover marker (BTM) and BMD changes after IL-6 inhibition remains unclear. This prospective study recruited patients with active RA with inadequate response to methotrexate or biologics. BMD was measured before and after 2-year tocilizumab (TCZ) treatment. Serum osteocalcin, N-terminal propeptide of type I collagen (P1NP), and C-terminal cross-linking telopeptide of type I collagen (CTX) levels were assessed at the baseline and after treatment. We enrolled 76 patients with RA (89.5% women, age: 57.2 ± 13.3 years) receiving TCZ. The 28-joint disease activity score was negatively correlated with BMD and T-scores of the lumbar spine and bilateral femoral neck. ACPA-positive patients had lower lumbar spine and femoral neck T-scores. After 2-year TCZ treatment, CTX levels significantly decreased (0.32 ± 0.21 vs. 0.26 ± 0.17, p = 0.038). Femoral neck BMD increased significantly (0.71 ± 0.22 vs. 0.69 ± 0.55, p = 0.008). Decreased CTX levels and improved BMD were observed only in ACPA-positive patients. After treatment, femoral neck BMD significantly increased only in patients receiving a glucocorticoid dose of ≥5 mg/day. Two-year TCZ treatment reduced bone resorption and increased femoral BMD in ACPA-positive patients. The net effects of glucocorticoids and IL-6 inhibition on BMD imply that strict inflammation control might affect bone metabolism.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
Evidence supporting that glucose metabolic abnormalities occur prior to Alzheimer’s disease (AD) symptoms. Reduced O‐GlcNAc (OGN) levels likely arise from impaired glucose metabolism or ...availability and correlates with AD pathogenesis. So far, the mechanism of sAD and the role of OGN in AD pathology remained largely unknown due to a lack of human sAD model.
Method
We generated human cortical neurons from human‐induced pluripotent stem cells and treated neurons with glucose reduction media. FluoroJADE staining and cell viability assays were used to study the effects of low glucose on the degenerative status and cell viability of neurons. Abnormal protein production, phosphorylation, and accumulation were detected by western blotting and immunofluorescence staining using antibody against p‐tau and beta‐amyloid. Neurite and synaptic structure were observed by immunofluorescence staining, while neuronal network activity was detected by multi‐electrode array electrophysiological analyses. Mitochondrial abnormalities, including increased oxidative stress, reduced membrane potential, and mitochondrial dysfunction, were evaluated using CM‐H2DCFDA, JC‐1 and Seahorse, respectively.
Result
We show that lowering glucose level to 2mM leads to dramatic increases of neuron degeneration on day 3 and 5 of treatment and decreased cell viability on day 7. Interestingly, long‐term low glucose treatment induces AD features in neurons, including abnormal hyperphosphorylated tau accumulation and increasing beta‐amyloid production. Besides, glucose deficiency also causes decreased neurite coverage, synapse density, and neuron network activity. Furthermore, we find that O‐GlcNAc levels are significantly reduced soon after low glucose treatment and remain low until the end of experiment. Raising O‐GlcNAc levels by thiamet‐G, inhibitor of O‐GlcNAcase, even in low glucose treated neurons, rescues low glucose‐induced AD phenotypes. Moreover, our data shows that O‐GlcNAc dysregulation causes mitochondrial abnormalities, which occur before any other degenerative phenotype appeared, and may be one of the underlying mechanisms of sAD onset and pathogenesis.
Conclusion
We established a human neuron model in which the pathological features are reproduced by glucose deficiency. This platform can serve as a tool for better understanding molecular processes involved in neurodegeneration in sAD. Our results also suggest that dysregulated O‐GlcNAc levels and mitochondrial dysfunction by glucose deficiency are involved in the onset and progression of sAD.
Esophageal adenocarcinoma (EAC) is the most prevalent esophageal cancer type in the United States. The TNF-α/mTOR pathway is known to mediate the development of EAC. Additionally, aberrant activation ...of Gli1, downstream effector of the Hedgehog (HH) pathway, has been observed in EAC. In this study, we found that an activated mTOR/S6K1 pathway promotes Gli1 transcriptional activity and oncogenic function through S6K1-mediated Gli1 phosphorylation at Ser84, which releases Gli1 from its endogenous inhibitor, SuFu. Moreover, elimination of S6K1 activation by an mTOR pathway inhibitor enhances the killing effects of the HH pathway inhibitor. Together, our results established a crosstalk between the mTOR/S6K1 and HH pathways, which provides a mechanism for SMO-independent Gli1 activation and also a rationale for combination therapy for EAC.
► mTOR/S6K1 activates Gli1 in a SMO-independent manner ► Activated S6K1 phosphorylates Gli1 at Ser 84 and promotes Gli1 function ► S6K1-mediated Gli1 activation links the mTOR and HH pathways ► Combination therapy targeting mTOR/HH pathways may provide benefit for EAC therapy
Add‐On Pricing in a Distribution Channel Yin, Qianbo; Huang, Kwei‐Long; Kuo, Chia‐Wei ...
Production and operations management,
11/2021, Letnik:
30, Številka:
11
Journal Article
Recenzirano
Odprti dostop
We consider add‐on pricing in a distribution channel where a retailer sells a base good and an add‐on, supplied by two manufacturers, respectively, to consumers. The retailer decides whether to sell ...the two products through either bundling or add‐on pricing and sets the corresponding retail prices. Under add‐on pricing, the add‐on price is unobservable to consumers when they make the purchase decision of the base good. Each manufacturer, if independent of the retailer, sets the wholesale price. Under four channel structures differed by whether either manufacturer is independent of the retailer, we specify the scenario that is optimal for the retailer to adopt add‐on pricing and show the contrasting impact from the two manufacturers. When all three firms are integrated, the retailer in general prefers add‐on pricing to bundling when the cost of base good is low and the cost of add‐on is high. Using this case as the benchmark, we show that add‐on pricing is more (less) likely to be adopted when the add‐on (base) manufacturer is independent, and add‐on pricing is again more likely to be adopted when all three firms are independent. In addition to the demand smoothing effect of bundling, we identify two drivers from the supply side: the margin squeezing effect of bundling from the add‐on manufacturer and the margin smoothing effect of bundling from the base manufacturer, where the former encourages add‐on pricing whereas the latter discourages it. The interplay of these drivers largely influences the retailer's add‐on strategy and renders the preceding results. Several extensions are discussed, including correlated consumer valuations of base good and add‐on, an alternate decision sequence, knowledgeable consumers (about add‐on price), simultaneous offering of bundling and add‐on pricing, and bilateral monopoly.
Understanding the magnetic and ferroelectric ordering of magnetoelectric multiferroic materials at the nanoscale necessitates a versatile imaging method with high spatial resolution. Here, soft X‐ray ...ptychography is employed to simultaneously image the ferroelectric and antiferromagnetic domains in an 80 nm thin freestanding film of the room‐temperature multiferroic BiFeO3 (BFO). The antiferromagnetic spin cycloid of period 64 nm is resolved by reconstructing the corresponding resonant elastic X‐ray scattering in real space and visualized together with mosaic‐like ferroelectric domains in a linear dichroic contrast image at the Fe L3 edge. The measurements reveal a near perfect coupling between the antiferromagnetic and ferroelectric ordering by which the propagation direction of the spin cycloid is locked orthogonally to the ferroelectric polarization. In addition, the study evinces both a preference for in‐plane propagation of the spin cycloid and changes of the ferroelectric polarization by 71° between multiferroic domains in the epitaxial strain‐free, freestanding BFO film. The results provide a direct visualization of the strong magnetoelectric coupling in BFO and of its fine multiferroic domain structure, emphasizing the potential of ptychographic imaging for the study of multiferroics and non‐collinear magnetic materials with soft X‐rays.
The ferroelectric and magnetic structure of a freestanding thin film of multiferroic bismuth ferrite are imaged with soft x‐ray ptychography at the Fe L‐edge. This scanning coherent diffractive imaging technique directly visualizes the strong magnetoelectric coupling between the antiferromagnetic spin cycloid and ferroelectric domains on the nanoscale.
In this work we introduce a tunable GMR filter based on continuously period-chirped (ΔP = 130 nm) gratings using a Ta
O
waveguide layer with graded thickness (ΔT = 36 nm). The structure of the ...gradient-period grating is defined using a modified Lloyd's mirror interferometer with a convex mirror, and Ta
O
film used for the gradient is deposited using masked e-beam evaporation. The as-realized chirped GMR filter provides sharp transmission dips at resonant wavelengths with a filter bandwidth of approximately 4.2 nm and 0.78 nm when respectively applied to TE and TM polarized light under normal incidence. Gradually sweeping the chirped GMR filter makes it possible to monotonically sweep through resonant wavelengths from 500 to 700 nm, while maintaining stable filter bandwidth and transmission intensity. The optical spectrum of the incoming light can then be loyally reconstructed accordingly. We successfully demonstrate the spectrum reconstruction of a white light emitting diode and a dual-peak laser beam using the proposed chirped GMR filter as a dispersive device.
Background
We hypothesized that patients with head and neck squamous cell carcinoma (HNSCC) with smoking cessation during curative chemoradiotherapy (CRT) had fewer complications and lower tumor ...progression risks.
Methods
Sixty‐three patients with nonmetastatic HNSCC who were smokers at diagnosis (carbon monoxide CO breath concentrations ≥3 ppm) and underwent curative CRT were prospectively enrolled. Successful smoking cessation throughout CRT was confirmed by CO breath concentrations <3 ppm at CRT completion.
Results
Forty‐one patients (65%) successfully discontinued smoking throughout CRT. With a median 33‐month follow‐up, patients with successful smoking cessation during CRT had significantly fewer, greater, and lower probabilities of grade ≥3 acute toxicities (P = .01), progression‐free survival (P = .03), and permanent gastrostomy or tracheostomy (P = .04), respectively, than those continuing smoking throughout CRT. In multivariate analysis, successful smoking cessation during CRT significantly reduced tumor progression risks (hazard ratio: 0.4, P = .05).
Conclusion
Smoking cessation during curative CRT reduced treatment‐related toxicities and tumor progression risks in patients with HNSCC.
Zearalenone (ZEN) is a prevalent mycotoxin that severely impacts human and animal health. However, the possible interactions between ZEN exposure, pathogen infection, immune system, and reactive ...oxygen species (ROS) were rarely investigated. We studied the effects of early-life ZEN (50 µM) exposure on the immune response of Caenorhabditis elegans against Bacillus thuringiensis infection and the associated mechanisms. The transcriptomic responses of C. elegans after early-life ZEN exposure were investigated using RNA sequencing and followed by verification using quantitative PCR analysis. We also investigated the immune responses of the worms through B. thuringiensis killing assays and by measuring oxidative stress. The transcriptomics result showed that early-life exposure to ZEN resulted in 44 differentially expressed genes, 7 of which were protein-coding genes with unknown functions. The Gene Ontology analysis suggested that metabolic processes and immune response were among the most significantly enriched biological processes, and the KEGG analysis suggested that lysosomes and metabolic pathways were the most significantly enriched pathways. The ZEN-exposed worms exhibited significantly reduced survival after 24-h B. thuringiensis infection, reaching near 100% mortality compared to 60% of the controls. Using qRT-PCR assay, we found that ZEN further enhanced the expression of immunity genes lys-6, spp-1, and clec-60 after B. thuringiensis infection. A concurrently enhanced ROS accumulation was also observed for ZEN-exposed worms after B. thuringiensis infection, which was 1.2-fold compared with the controls. Moreover, ZEN exposure further enhanced mRNA expression of catalases (ctl-1 and ctl-2) and increased catalase protein activity after B. thuringiensis exposure compared with their non-exposed counterparts, suggesting an elevated oxidative stress. This study suggests that early-life exposure to mycotoxin zearalenone overstimulates immune responses involving spp-17, clec-52, and clec-56, resulting in excessive ROS production, enhanced oxidative stress as indicated by aggravated ctl expression and activity, and a decline in host resistance to pathogenic infection which ultimately leads to increased mortality under B. thuringiensis infection. Our findings provide evidence that could improve our understanding on the potential interactions between mycotoxin zearalenone and pathogens.
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•RNA-sequencing reveals that immunity was significantly affected by zearalenone.•Zearalenone reduces worm survival under Bacillus thuringiensis exposure.•Zearalenone induces over-reaction of immune response via lys-6, spp-1, and clec-60.•Zearalenone exaggerates oxidative stress during pathogen infection.
Calcium (Ca
) is an important mediator of multicellular homeostasis and is involved in several diseases. The interplay among the kidney, bone, intestine, and parathyroid gland in Ca
homeostasis is ...strictly modulated by numerous hormones and signaling pathways. The calcium-sensing receptor (CaSR) is a G protein-coupled receptor, that is expressed in calcitropic tissues such as the parathyroid gland and the kidney, plays a pivotal role in Ca
regulation. CaSR is important for renal Ca
, as a mutation in this receptor leads to hypercalciuria and calcium nephrolithiasis. In addition, CaSR is also widely expressed in the vascular system, including vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs) and participates in the process of vascular calcification. Aberrant Ca
sensing by the kidney and VSMCs, owing to altered CaSR expression or function, is associated with the formation of nephrolithiasis and vascular calcification. Based on emerging epidemiological evidence, patients with nephrolithiasis have a higher risk of vascular calcification, but the exact mechanism linking the two conditions is unclear. However, a dysregulation in Ca
homeostasis and dysfunction in CaSR might be the connection between the two. This review summarizes renal calcium handling and calcium signaling in the vascular system, with a special focus on the link between nephrolithiasis and vascular calcification.
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