Experimental investigation on the invert stability of operating railway tunnels with different drainage systems using 3D printing technology

In recent years, the invert anomalies of operating railway tunnels in water-rich areas occur frequently, which greatly affect the transportation capacity of the railway lines. Tunnel drainage system is a crucial factor to ensure the invert stability by regulating the external water pressure (EWP). By means of a three-dimensional (3D) printing model, this paper experimentally investigates the deformation behavior of the invert for the tunnels with the traditional drainage system (TDS) widely used in China and its optimized drainage system (ODS) with bottom drainage function. Six test groups with a total of 110 test conditions were designed to consider the design factors and environmental factors in engineering practice, including layout of the drainage system, blockage of the drainage system and groundwater level fluctuation. It was found that there are significant differences in the water discharge, EWP and invert stability for the tunnels with the two drainage systems. Even with a dense arrangement of the external blind tubes, TDS was still difficult to eliminate the excessive EWP below the invert, which is the main cause for the invert instability. Blockage of drainage system further increased the invert uplift and aggravated the track irregularity, especially when the blockage degree is more than 50%. However, ODS can prevent these invert anomalies by reasonably controlling the EWP at tunnel bottom. Even when the groundwater level reached 60 m and the blind tubes were fully blocked, the invert stability can still be maintained and the railway track experienced a settlement of only 1.8 mm. Meanwhile, the on-site monitoring under several rainstorms further showed that the average EWP of the invert was controlled within 84 kPa, while the maximum settlement of the track slab was only 0.92 mm, which also was in good agreement with the results of model test.     

Applications of sketches in network traffic measurement: A survey

Accurate and timely network traffic measurement is essential for network status monitoring, network fault analysis, network intrusion detection, and network security management. With the rapid development of the network, massive network traffic brings severe challenges to network traffic measurement. However, existing measurement methods suffer from many limitations for effectively recording and accurately analyzing big-volume traffic. Recently, sketches, a family of probabilistic data structures that employ hashing technology for summarizing traffic data, have been widely used to solve these problems. However, current literature still lacks a thorough review on sketch-based traffic measurement methods to offer a comprehensive insight on how to apply sketches for fulfilling various traffic measurement tasks. In this paper, we provide a detailed and comprehensive review on the applications of sketches in network traffic measurement. To this end, we classify the network traffic measurement tasks into four categories based on the target of traffic measurement, namely cardinality estimation, flow size estimation, change anomaly detection, and persistent spreader identification. First, we briefly introduce these four types of traffic measurement tasks and discuss the advantages of applying sketches. Then, we propose a series of requirements with regard to the applications of sketches in network traffic measurement. After that, we perform a fine-grained classification for each sketch-based measurement category according to the technologies applied on sketches. During the review, we evaluate the performance, advantages and disadvantages of current sketch-based traffic measurement methods based on the proposed requirements. Through the thorough review, we gain a number of valuable implications that can guide us to choose and design proper traffic measurement methods based on sketches. We also review a number of general sketches that are highly expected in modern network systems to simultaneously perform multiple traffic measurement tasks and discuss their performance based on the proposed requirements. Finally, through our serious review, we summarize a number of open issues and identify several promising research directions.     

Adaptation to Endoplasmic Reticulum Stress Enhances Resistance of Oral Cancer Cells to Cisplatin by Up-Regulating Polymerase η and Increasing DNA Repair Efficiency

Endoplasmic reticulum (ER) stress response is an adaptive program to cope with cellular stress that disturbs the function and homeostasis of ER, which commonly occurs during cancer progression to late stage. Late-stage cancers, mostly requiring chemotherapy, often develop treatment resistance. Chemoresistance has been linked to ER stress response; however, most of the evidence has come from studies that correlate the expression of stress markers with poor prognosis or demonstrate proapoptosis by the knockdown of stress-responsive genes. Since ER stress in cancers usually persists and is essentially not induced by genetic manipulations, we used low doses of ER stress inducers at levels that allowed cell adaptation to occur in order to investigate the effect of stress response on chemoresistance. We found that prolonged tolerable ER stress promotes mesenchymal–epithelial transition, slows cell-cycle progression, and delays the S-phase exit. Consequently, cisplatin-induced apoptosis was significantly decreased in stress-adapted cells, implying their acquisition of cisplatin resistance. Molecularly, we found that proliferating cell nuclear antigen (PCNA) ubiquitination and the expression of polymerase η, the main polymerase responsible for translesion synthesis across cisplatin-DNA damage, were up-regulated in ER stress-adaptive cells, and their enhanced cisplatin resistance was abrogated by the knockout of polymerase η. We also found that a fraction of p53 in stress-adapted cells was translocated to the nucleus, and that these cells exhibited a significant decline in the level of cisplatin-DNA damage. Consistently, we showed that the nuclear p53 coincided with strong positivity of glucose-related protein 78 (GRP78) on immunostaining of clinical biopsies, and the cisplatin-based chemotherapy was less effective for patients with high levels of ER stress. Taken together, this study uncovers that adaptation to ER stress enhances DNA repair and damage tolerance, with which stressed cells gain resistance to chemotherapeutics.     

Implication of the NLRP3 Inflammasome in Bovine Age-Related Sarcopenia

Sarcopenia is defined as the age-related loss of skeletal muscle mass, quality, and strength. The pathophysiological mechanisms underlying sarcopenia are still not completely understood. The aim of this work was to evaluate, for the first time, the expression of NLRP3 inflammasome in bovine skeletal muscle in order to investigate the hypothesis that inflammasome activation may trigger and sustain a pro-inflammatory environment leading to sarcopenia. Samples of skeletal muscle were collected from 60 cattle belonging to three age-based groups. Morphologic, immunohistochemical and molecular analysis were performed to assess the presence of age-related pathologic changes and chronic inflammation, the expression of NLRP3 inflammasome and to determine the levels of interleukin-1β, interleukin-18 and tumor necrosis factor alpha in muscle tissue. Our results revealed the presence of morphologic sarcopenia hallmark, chronic lymphocytic inflammation and a type II fibers-selective NLRP3 expression associated to a significant decreased number of immunolabeled-fibers in aged animals. Moreover, we found a statistically significant age-related increase of pro-inflammatory cytokines such as interleukin-1β and interleukin-18 suggesting the activation of NLRP3 inflammasome. Taken together, our data suggest that NLRP3 inflammasome components may be normally expressed in skeletal muscle, but its priming and activation during aging may contribute to enhance a pro-inflammatory environment altering normal muscular anabolism and metabolism.     

A Novel LRRK2 Variant p.G2294R in the WD40 Domain Identified in Familial Parkinson’s Disease Affects LRRK2 Protein Levels

Leucine-rich repeat kinase 2 (LRRK2) is a major causative gene of late-onset familial Parkinson’s disease (PD). The suppression of kinase activity is believed to confer neuroprotection, as most pathogenic variants of LRRK2 associated with PD exhibit increased kinase activity. We herein report a novel LRRK2 variant—p.G2294R—located in the WD40 domain, detected through targeted gene-panel screening in a patient with familial PD. The proband showed late-onset Parkinsonism with dysautonomia and a good response to levodopa, without cognitive decline or psychosis. Cultured cell experiments revealed that p.G2294R is highly destabilized at the protein level. The LRRK2 p.G2294R protein expression was upregulated in the patient’s peripheral blood lymphocytes. However, macrophages differentiated from the same peripheral blood showed decreased LRRK2 protein levels. Moreover, our experiment indicated reduced phagocytic activity in the pathogenic yeasts and α-synuclein fibrils. This PD case presents an example wherein the decrease in LRRK2 activity did not act in a neuroprotective manner. Further investigations are needed in order to elucidate the relationship between LRRK2 expression in the central nervous system and the pathogenesis caused by altered LRRK2 activity.     

Meta-Analysis of Methamphetamine Modulation on Amyloid Precursor Protein through HMGB1 in Alzheimer’s Disease

The deposition of amyloid-beta (Aβ) through the cleavage of amyloid-beta precursor protein (APP) is a biomarker of Alzheimer’s disease (AD). This study used QIAGEN Ingenuity Pathway Analysis (IPA) to conduct meta-analysis on the molecular mechanisms by which methamphetamine (METH) impacts AD through modulating the expression of APP. All the molecules affected by METH and APP were collected from the QIAGEN Knowledge Base (QKB); 78 overlapping molecules were identified. Upon simulation of METH exposure using the “Molecule Activity Predictor” feature, eight molecules were found to be affected by METH and exhibited activation relationships on APP expression at a confidence of p = 0.000453 (Z-score = 3.51, two-tailed). Core Analysis of these eight molecules identified High Mobility Group Box protein 1 (HMGB1) signaling pathway among the top 5 canonical pathways with most overlap with the 8-molecule dataset. Simulated METH exposure increased APP expression through HMGB1 at a confidence of p < 0.00001 (Z-score = 7.64, two-tailed). HMGB1 is a pathogenic hallmark in AD progression. It not only increases the production of inflammatory mediators, but also mediates the disruption of the blood-brain barrier. Our analyses suggest the involvement of HMGB1 signaling pathway in METH-induced modulation of APP as a potential casual factor of AD.     

Granulation Tissue Enhanced with Aspirin and Omega-3 PUFAs as a Local Adjunct to the Surgical Treatment of Periodontitis

The topical application of aspirin and omega-3 polyunsaturated fatty acids (PUFAs) may trigger the resolution of inflammation by inducing the biosynthesis of pro-resolvers such as lipoxins and resolvins while also avoiding the side effects of systemic aspirin intake. This study assessed the effect of enhanced granulation tissue (EGT) on periodontal tissue regeneration through the local application of aspirin and omega-3 PUFAs directly to granulation tissue (GT) during periodontal surgery. This randomized controlled experiment assesses 38 pockets in 19 patients. In every patient, two similar intrabony periodontal defects are treated with an open flap debridement, one with EGT (GT extracted, enhanced with aspirin and omega-3 PUFAs, and replaced) and the other with standard GT removal. Clinical attachment level (CAL) and probing pocket depth (PPD) are assessed at baseline and 2 and 6 months after surgery. The experimental protocol (EGT) results in a greater CAL gain as compared to that in the controls at 6 months (p < 0.05), while PPD reduction is not affected. The retained GT does not compromise healing. EGT is proposed as a promising, inexpensive, and simple method that may improve the outcome of periodontal regenerative treatment. However, the described protocol requires optimization and further assessment. Practical Applications : The biosynthesis of mediators including resolvins and lipoxins triggered by aspirin and omega-3 PUFAs promote the resolution of inflammation, eventually leading to faster regeneration of inflamed tissues. While granulation tissue is a necessary component in wound healing, enhancing granulation tissue with aspirin and omega-3 PUFAs results in CAL gain in the surgical treatment of periodontal defects. Retained granulation tissue does not compromise periodontal healing. The EGT strategy is an inexpensive and simple method that may improve the clinical outcomes of regenerative periodontal procedures.     

Neoagarooligosaccharide Protects against Hepatic Fibrosis via Inhibition of TGF-β/Smad Signaling Pathway

Hepatic fibrosis occurs when liver tissue becomes scarred from repetitive liver injury and inflammatory responses; it can progress to cirrhosis and eventually to hepatocellular carcinoma. Previously, we reported that neoagarooligosaccharides (NAOs), produced by the hydrolysis of agar by β-agarases, have hepatoprotective effects against acetaminophen overdose-induced acute liver injury. However, the effect of NAOs on chronic liver injury, including hepatic fibrosis, has not yet been elucidated. Therefore, we examined whether NAOs protect against fibrogenesis in vitro and in vivo. NAOs ameliorated PAI-1, α-SMA, CTGF and fibronectin protein expression and decreased mRNA levels of fibrogenic genes in TGF-β-treated LX-2 cells. Furthermore, downstream of TGF-β, the Smad signaling pathway was inhibited by NAOs in LX-2 cells. Treatment with NAOs diminished the severity of hepatic injury, as evidenced by reduction in serum alanine aminotransferase and aspartate aminotransferase levels, in carbon tetrachloride (CCl₄)-induced liver fibrosis mouse models. Moreover, NAOs markedly blocked histopathological changes and collagen accumulation, as shown by H&E and Sirius red staining, respectively. Finally, NAOs antagonized the CCl₄-induced upregulation of the protein and mRNA levels of fibrogenic genes in the liver. In conclusion, our findings suggest that NAOs may be a promising candidate for the prevention and treatment of chronic liver injury via inhibition of the TGF-β/Smad signaling pathway.