The vagus nerve can control inflammatory response through a ＇cholinergic anti-inflammatory pathway＇, which is mediated by the α7-nicotinic acetylcholine receptor （α7nAChR） on macrophages. However, ...the intracellular mechanisms that link a7nAChR activation and pro-inflammatory cytokine production remain not well understood. In this study, we found that miR-124 is upregulated by cholinergic agonists in LPS-exposed cells and mice. Utilizing miR-124 mimic and siRNA knockdown, we demonstrated that miR-124 is a critical mediator for the cholinergic anti-inflammatory action. Furthermore, our data indicated that miR-124 modulates LPS-induced cytokine production by targeting signal transducer and activator of transcription 3 （STAT3） to decrease IL-6 production and TNF-o converting enzyme （TACE） to reduce TNF-α release. These results also indicate that miR-124 is a potential therapeutic target for the treatment of inflammatory diseases.
Inflammasomes are newly recognized, vital players in innate immunity. The best characterized is the NLRP3 inflammasome, so-called because the NLRP3 protein in the complex belongs to the family of ...nucleotide-binding and oligomerization domain-like receptors (NLRs) and is also known as "pyrin domain-containing protein 3". The NLRP3 inflammasome is associated with onset and progression of various diseases, including metabolic disorders, multiple sclerosis, inflammatory bowel disease, cryopyrin-associated periodic fever syndrome, as well as other auto-immune and auto-inflammatory diseases. Several NLRP3 inflammasome inhibitors have been described, some of which show promise in the clinic. The present review will describe the structure and mechanisms of activation of the NLRP3 inflammasome, its association with various auto-immune and auto-inflammatory diseases, and the state of research into NLRP3 inflammasome inhibitors.
The impulse signal is an instant change signal in very short time. It is widely used in signal processing, electronic technique, communication and system identification. This paper considers the ...parameter estimation problems for dynamical systems by means of the impulse response measurement data. Since the cost function is highly nonlinear, the nonlinear optimization methods are adopted to derive the parameter estimation algorithms to enhance the estimation accuracy. By using the iterative scheme, the Newton iterative algorithm and the gradient iterative algorithm are proposed for estimating the parameters of dynamical systems. Also, a damping factor is introduced to improve the algorithm stability. Finally, using simulation examples, this paper analyzes and compares the merit and weakness of the proposed algorithms.
Objective:
Stroke is a leading cause of mortality and disability. Nicotinamide phosphoribosyltransferase (Nampt) is the rate‐limiting enzyme in mammalian nicotinamide adenine dinucleotide (NAD)+ ...biosynthesis and contributes to cell fate decisions. However, the role of Nampt in brain and stroke remains to be investigated.
Methods:
We used lentivirus‐mediated Nampt overexpression and knockdown to manipulate Nampt expression and explore the effects of Nampt in neuronal survival on ischemic stress both in vivo and in vitro. We also used adenosine monophosphate (AMP)‐activated kinase‐α2 (AMPKα2) and silent mating type information regulation 2 homolog 1 (SIRT1) knockout mice to investigate the underlying mechanisms of Nampt neuroprotection.
Results:
Nampt inhibition by a highly‐specific Nampt inhibitor, FK866, aggravated brain infarction in experimentally cerebral ischemia rats, whereas Nampt overexpression in local brain and Nampt enzymatic product nicotinamide mononucleotide (NMN) reduced ischemia‐induced cerebral injuries. Nampt overexpression and knockdown regulated neuron survival via the AMPK pathway. Neuroprotection of Nampt was abolished in AMPKα2−/− neurons. In neurons, Nampt positively modulated NAD+ levels and thereby controlled SIRT1 activity. SIRT1 coprecipitated with serine/threonine kinase 11 (LKB1), an upstream kinase of AMPK, and promoted LKB1 deacetylation in neurons. Nampt‐induced LKB1 deacetylation and AMPK activation disappeared in SIRT1−/− neurons. In contrast, Ca2+/calmodulin‐dependent protein kinase kinase‐β (CaMKK‐β), another upstream kinase of AMPK, was not involved in the neuroprotection of Nampt. More important, Nampt overexpression‐induced neuroprotection was abolished in SIRT1+/− and AMPKα2−/− mice.
Interpretation:
Our findings reveal that Nampt protects against ischemic stroke through rescuing neurons from death via the SIRT1‐dependent AMPK pathway and indicate that Nampt is a new therapeutic target for stroke. Ann Neurol 2011.
Precise methods for postoperative risk stratification to guide the administration of adjuvant chemotherapy (ACT) in localized colorectal cancer (CRC) are still lacking. Here, we conducted a ...prospective, observational, and multicenter study to investigate the utility of circulating tumor DNA (ctDNA) in predicting the recurrence risk.
From September 2017 to March 2020, 276 patients with stage II/III CRC were prospectively recruited in this study and 240 evaluable patients were retained for analysis, of which 1290 serial plasma samples were collected. Somatic variants in both the primary tumor and plasma were detected via a targeted sequencing panel of 425 cancer-related genes. Patients were treated and followed up per standard of care.
Preoperatively, ctDNA was detectable in 154 of 240 patients (64.2%). At day 3-7 postoperation, ctDNA positivity was associated with remarkably high recurrence risk (hazard ratio HR, 10.98; 95%CI, 5.31-22.72; P < 0.001). ctDNA clearance and recurrence-free status was achieved in 5 out of 17 ctDNA-positive patients who were subjected to ACT. Likewise, at the first sampling point after ACT, ctDNA-positive patients were 12 times more likely to experience recurrence (HR, 12.76; 95%CI, 5.39-30.19; P < 0.001). During surveillance after definitive therapy, ctDNA positivity was also associated with extremely high recurrence risk (HR, 32.02; 95%CI, 10.79-95.08; P < 0.001). In all multivariate analyses, ctDNA positivity remained the most significant and independent predictor of recurrence-free survival after adjusting for known clinicopathological risk factors. Serial ctDNA analyses identified recurrence with an overall accuracy of 92.0% and could detect disease recurrence ahead of radiological imaging with a mean lead time of 5.01 months.
Postoperative serial ctDNA detection predicted high relapse risk and identified disease recurrence ahead of radiological imaging in patients with stage II/III CRC. ctDNA may be used to guide the decision-making in postsurgical management.
Fatigue of miners is caused by intensive workloads, long working hours, and shift-work schedules. It is one of the major factors increasing the risk of safety problems and work mistakes. Examining ...the detection of miner fatigue is important because it can potentially prevent work accidents and improve working efficiency in underground coal mines. Many previous studies have introduced feature-based machine-learning methods to estimate miner fatigue. This work proposes a method that uses electroencephalogram (EEG) signals to generate topographic maps containing frequency and spatial information. It utilizes a convolutional neural network (CNN) to classify the normal state, critical state, and fatigue state of miners. The topographic maps are generated from the EEG signals and contrasted using power spectral density (PSD) and relative power spectral density (RPSD). These two feature extraction methods were applied to feature recognition and four representative deep-learning methods. The results showthat RPSD achieves better performance than PSD in classification accuracy with all deep-learning methods. The CNN achieved superior results to the other deep-learning methods, with an accuracy of 94.5%, precision of 97.0%, sensitivity of 94.8%, and F1 score of 96.3%. Our results also show that the RPSD–CNN method outperforms the current state of the art. Thus, this method might be a useful and effective miner fatigue detection tool for coal companies in the near future.
Activation of cannabinoid receptor 2 (CB2R) ameliorates inflammation, but the underlying mechanism remains unclear. In the present study, we examined whether activation of CB2R could suppress the ...nucleotide-binding domain and leucine-rich repeat protein 3 (NLRP3) inflammasome. In peritoneal macrophages isolated from C57BL/6 mice, LPS/DSS challenge for 24 h increased the expression of the components of NLRP3 inflammasome NLRP3, Casp-1 p20/Casp-1 p45 ratio, proIL-1β and IL-1β and also enhanced autophagy (LC3-II/LC3-I ratio, Beclin-1 and SQSTM1). Pretreatment of peritoneal macrophages with HU 308, a selective CB2R agonist, attenuated LPS/DSS-induced NLRP3 inflammasome activation, but further enhanced autophagy. In comparison with wild-type (WT) control, peritoneal macrophages from CB2R knockout (KO) mice had more robust NLRP3 inflammasome activation and attenuated autophagy upon LPS/DSS challenge. Knockdown autophagy-related gene 5 (Atg5) with a siRNA in peritoneal macrophages attenuated the inhibitory effects of HU 308 on LPS/DSS-induced NLRP3 inflammasome activation in vitro. In vivo, HU308 treatment attenuated DSS-induced colitis mice associated with reduced colon inflammation and inhibited NLRP3 inflammasome activation in wild-type mice. In CB2R KO mice, DSS-induced inflammation and NLRP3 inflammasome activation were more pronounced than those in WT control. Finally, we demonstrated that AMPK-mTOR-P70S6K signaling pathway was involved in this CB2R-mediated process. We conclude that activation of CB2R ameliorates DSS-induced colitis through enhancing autophagy that may inhibit NLRP3 inflammasome activation in macrophages.
Carbon nanotubes have many material properties that make them attractive for applications. In the context of nanoelectronics, interest has focused on single-walled carbon nanotubes (SWNTs) because ...slight changes in tube diameter and wrapping angle, defined by the chirality indices (n, m), will shift their electrical conductivity from one characteristic of a metallic state to one characteristic of a semiconducting state, and will also change the bandgap. However, this structure-function relationship can be fully exploited only with structurally pure SWNTs. Solution-based separation methods yield tubes within a narrow structure range, but the ultimate goal of producing just one type of SWNT by controlling its structure during growth has proved to be a considerable challenge over the last two decades. Such efforts aim to optimize the composition or shape of the catalyst particles that are used in the chemical vapour deposition synthesis process to decompose the carbon feedstock and influence SWNT nucleation and growth. This approach resulted in the highest reported proportion, 55 per cent, of single-chirality SWNTs in an as-grown sample. Here we show that SWNTs of a single chirality, (12, 6), can be produced directly with an abundance higher than 92 per cent when using tungsten-based bimetallic alloy nanocrystals as catalysts. These, unlike other catalysts used so far, have such high melting points that they maintain their crystalline structure during the chemical vapour deposition process. This feature seems crucial because experiment and simulation both suggest that the highly selective growth of (12, 6) SWNTs is the result of a good structural match between the carbon atom arrangement around the nanotube circumference and the arrangement of the catalytically active atoms in one of the planes of the nanocrystal catalyst. We anticipate that using high-melting-point alloy nanocrystals with optimized structures as catalysts paves the way for total chirality control in SWNT growth and will thus promote the development of SWNT applications.
Whether target organ damage is associated with blood pressure (BP) variability independent of level remains debated. We assessed these associations from 10-minute beat-to-beat, 24-hour ambulatory, ...and 7-day home BP recordings in 256 untreated subjects referred to a hypertension clinic. BP variability indices were variability independent of the mean, maximum-minimum difference, and average real variability. Effect sizes (standardized β) were computed using multivariable regression models. In beat-to-beat recordings, left ventricular mass index (n=128) was not (P≥0.18) associated with systolic BP but increased with all 3 systolic variability indices (+2.97-3.53 g/m(2); P<0.04); the urinary albumin-to-creatinine ratio increased (P≤0.03) with systolic BP (+1.14-1.17 mg/mmol) and maximum-minimum difference (+1.18 mg/mmol); and pulse wave velocity increased with systolic BP (+0.69 m/s; P<0.001). In 24-hour recordings, all 3 indices of organ damage increased (P<0.03) with systolic BP, whereas the associations with BP variability were nonsignificant (P≥0.15) except for increases in pulse wave velocity (P<0.05) with variability independent of the mean (+0.16 m/s) and maximum-minimum difference (+0.17 m/s). In home recordings, the urinary albumin-to-creatinine ratio (+1.27-1.30 mg/mmol) and pulse wave velocity (+0.36-0.40 m/s) increased (P<0.05) with systolic BP, whereas all associations of target organ damage with the variability indices were nonsignificant (P≥0.07). In conclusion, while accounting for BP level, associations of target organ damage with BP variability were readily detectable in beat-to-beat recordings, least noticeable in home recordings, with 24-hour ambulatory monitoring being informative only for pulse wave velocity.
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