Expression of a large LINE-1-driven antisense RNA is linked to epigenetic silencing of the metastasis suppressor gene TFPI-2 in cancer

LINE-1 retrotransposons are abundant repetitive elements of viral origin, which in normal cells are kept quiescent through epigenetic mechanisms. Activation of LINE-1 occurs frequently in cancer and can enable LINE-1 mobilization but also has retrotransposition-independent consequences. We previously reported that in cancer, aberrantly active LINE-1 promoters can drive transcription of flanking unique sequences giving rise to LINE-1 chimeric transcripts (LCTs). Here, we show that one such LCT, LCT13, is a large transcript (>300 kb) running antisense to the metastasis-suppressor gene TFPI- 2. We have modelled antisense RNA expression at TFPI-2 in transgenic mouse embryonic stem (ES) cells and demonstrate that antisense RNA induces silencing and deposition of repressive histone modifications implying a causal link. Consistent with this, LCT13 expression in breast and colon cancer cell lines is associated with silencing and repressive chromatin at TFPI-2. Furthermore, we detected LCT13 transcripts in 56% of colorectal tumours exhibiting reduced TFPI-2 expression. Our findings implicate activation of LINE-1 elements in subsequent epigenetic remodelling of surrounding genes, thus hinting a novel retrotransposition-independent role for LINE-1 elements in malignancy

Decoupling of DNA methylation and activity of intergenic LINE-1 promoters in colorectal cancer

<p>Hypomethylation of LINE-1 repeats in cancer has been proposed as the main mechanism behind their activation; this assumption, however, was based on findings from early studies that were biased toward young and transpositionally active elements. Here, we investigate the relationship between methylation of 2 intergenic, transpositionally inactive LINE-1 elements and expression of the LINE-1 chimeric transcript (LCT) 13 and LCT14 driven by their antisense promoters (L1-ASP). Our data from DNA modification, expression, and 5′RACE analyses suggest that colorectal cancer methylation in the regions analyzed is not always associated with LCT repression. Consistent with this, in HCT116 colorectal cancer cells lacking DNA methyltransferases DNMT1 or DNMT3B, LCT13 expression decreases, while cells lacking both DNMTs or treated with the DNMT inhibitor 5-azacytidine (5-aza) show no change in LCT13 expression. Interestingly, levels of the H4K20me3 histone modification are inversely associated with LCT13 and LCT14 expression. Moreover, at these LINE-1s, H4K20me3 levels rather than DNA methylation seem to be good predictor of their sensitivity to 5-aza treatment. Therefore, by studying individual LINE-1 promoters we have shown that in some cases these promoters can be active without losing methylation; in addition, we provide evidence that other factors (e.g., H4K20me3 levels) play prominent roles in their regulation.</p

Condorcet Attack Against Fair Transaction Ordering

We introduce the Condorcet attack, a new threat to fair transaction ordering. Specifically, the attack undermines batch-order-fairness, the strongest notion of transaction fair ordering proposed to date. The batch-order-fairness guarantees that a transaction tx is ordered before tx' if a majority of nodes in the system receive tx before tx'; the only exception (due to an impossibility result) is when tx and tx' fall into a so-called "Condorcet cycle". When this happens, tx and tx' along with other transactions within the cycle are placed in a batch, and any unfairness inside a batch is ignored. In the Condorcet attack, an adversary attempts to undermine the system's fairness by imposing Condorcet cycles to the system. In this work, we show that the adversary can indeed impose a Condorcet cycle by submitting as few as two otherwise legitimate transactions to the system. Remarkably, the adversary (e.g., a malicious client) can achieve this even when all the nodes in the system behave honestly. A notable feature of the attack is that it is capable of "trapping" transactions that do not naturally fall inside a cycle, i.e. those that are transmitted at significantly different times (with respect to the network latency). To mitigate the attack, we propose three methods based on three different complementary approaches. We show the effectiveness of the proposed mitigation methods through simulations and explain their limitations

Assessing the cooling/lubricating agencies for sustainable alternatives during machining of nimonic 80: Economic and environmental impacts

Developing sustainable manufacturing methods that balance environmental and economic aspects is challenging. A comprehensive analysis of the economics of machining and carbon emissions is essential to encourage adopting sustainable practices. This work presents the machinability and comparative sustainability analysis of Nimonic 80 superalloy when it is machined utilizing a novel, environmentally friendly vegetable oil-based hybrid nanofluid-minimum quantity lubrication (MQL) and liquid carbon dioxide (LCO2) technique. The main objective is to comprehend the efficacy of the proposed approach on tool life, surface roughness, power consumption, total machining costs, and carbon emissions. Compared to other machining conditions, the use of hybrid nanofluid-MQL under 100 m/min cutting speed prevented rapid flank wear and considerably increased tool life by about 17–59 %. The change in cutting speed from 100 to 150 m/min has resulted in reduced tool life about 13–42 % under the selected environments. In addition, when compared to dry, flood, and MQL machining, the use of hybrid nanofluid-MQL and LCO2 reduced surface roughness by around 16–45 % at 150 m/min. Sustainability analysis revealed that machining at 150 m/min resulted in decreased costs ranging from 6.1 % to 36.4 % for selected cutting environments. Applying hybrid nanofluid-MQL lowered carbon emissions by 16.83 %, whereas LCO2 reduced carbon emissions by 14.6 % at 100 m/min. At 150 m/min, hybrid nanofluid-MQL and LCO2 lowered carbon emission by 22.3 % and 21.5 % at 150 m/min compared to dry machining. Compared to alternative cutting environments, hybrid nanofluid-MQL and LCO2 applications have longer tool lives, lower machining costs, and carbon emissions. As a result, they are economical and environmentally friendly

Circular RNAs in cancer: New insights into functions and implications in ovarian cancer

Circular RNAs (circRNAs) are a class of long non-coding RNAs (lncRNAs) which have a circular and closed loop structure. They are ubiquitous, stable, conserved and diverse RNA molecules with a range of activities such as translation and splicing regulation, which are able to interacting with RNA-binding proteins and specially miRNA sponge. The expression patterns of the circRNAs exhibited tissue specificity and also, step and stage specificity. Accumulating evidences approved the critical role of circular RNAs in many cancers such as ovarian cancer. Given that these molecules exert their effects through multiple cellular and molecular mechanisms (i.e., angiogenesis, apoptosis, growth, and metastasis) which are involved in cancer pathogenesis, circular RNAs, in particular, act by controlling cell proliferation in ovarian cancer, so that, it has been shown that the deregulation of these molecules is associated with initiation and progression of ovarian cancer. Therefore, they are attractive molecules which have introduced them as cancer biomarkers. Moreover, they could be used as new therapeutic candidates for developing novel treatment strategies. Here, for first time, we have provided a comprehensive review on the recent knowledge of circular RNAs and their pathological roles in the ovarian cancer. © 2019 The Author(s)

Quercetin and cancer: New insights into its therapeutic effects on ovarian cancer cells

Ovarian cancer is known as a serious malignancy that affects women's reproductive tract and can considerably threat their health. A wide range of molecular mechanisms and genetic modifications have been involved in ovarian cancer pathogenesis making it difficult to develop effective therapeutic platforms. Hence, discovery and developing new therapeutic approaches are required. Medicinal plants, as a new source of drugs, could potentially be used alone or in combination with other medicines in the treatment of various cancers such as ovarian cancer. Among various natural compounds, quercetin has shown great anti-cancer and anti-inflammatory properties. In vitro and in vivo experiments have revealed that quercetin possesses a cytotoxic impact on ovarian cancer cells. Despite obtaining good results both in vitro and in vivo, few clinical studies have assessed the anti-cancer effects of quercetin particularly in the ovarian cancer. Therefore, it seems that further clinical studies may introduce quercetin as therapeutic agent alone or in combination with other chemotherapy drugs to the clinical setting. Here, we not only summarize the anti-cancer effects of quercetin but also highlight the therapeutic effects of quercetin in the ovarian cancer. © 2020 The Author(s)

Rationalising the role of Keratin 9 as a biomarker for Alzheimer’s disease

Keratin 9 was recently identified as an important component of a biomarker panel which demonstrated a high diagnostic accuracy (87%) for Alzheimer’s disease (AD). Understanding how a protein which is predominantly expressed in palmoplantar epidermis is implicated in AD may shed new light on the mechanisms underlying the disease. Here we use immunoassays to examine blood plasma expression patterns of Keratin 9 and its relationship to other AD-associated proteins. We correlate this with the use of an in silico analysis tool VisANT to elucidate possible pathways through which the involvement of Keratin 9 may take place. We identify possible links with Dickkopf-1, a negative regulator of the wnt pathway, and propose that the abnormal expression of Keratin 9 in AD blood and cerebrospinal fluid may be a result of blood brain barrier dysregulation and disruption of the ubiquitin proteasome system. Our findings suggest that dysregulated Keratin 9 expression is a consequence of AD pathology but, as it interacts with a broad range of proteins, it may have other, as yet uncharacterized, downstream effects which could contribute to AD onset and progression

Comparison of electronic versus conventional assessment methods in ophthalmology residents; a learner assessment scholarship study

Background: Assessment is a necessary part of training postgraduate medical residents. The implementation of methods located at the �shows how� level of Miller�s pyramid is believed to be more effective than previous conventional tools. In this study, we quantitatively compared electronic and conventional methods in assessing ophthalmology residents. Methods: In this retrospective study, eight different conventional methods of assessment including residents� attendance, logbook, scholarship and research skills, journal club, outpatient department participation, Multiple Choice Question (MCQ), Objective Structured Clinical Examination (OSCE), and professionalism/360-degree (as one complex) were used to assess 24 ophthalmology residents of all grades. Electronic media consisting of an online Patient Management Problem (e-PMP), and modified electronic OSCE (me-OSCE) tests performed 3 weeks later were also evaluated for each of the 24 residents. Quantitative analysis was then performed comparing the conventional and electronic assessment tools, statistically assessing the correlation between the two approaches. Results: Twenty-four ophthalmology residents of different grades were included in this study. In the electronic assessment, average e-PMP scores (48.01 ± 12.40) were much lower than me-OSCE (65.34 ± 17.11). The total average electronic score was 56.67 ± 11.28, while the total average conventional score was 80.74 ± 5.99. Female and male residents� average scores in the electronic and conventional method were (59.15 ± 12.32 versus 83.01 ± 4.95) and (55.19 ± 10.77 versus 79.38 ± 6.29), respectively. The correlation between modified electronic OSCE and all conventional methods was not statistically significant (P-value >0.05). Correlation between e-PMP and six conventional methods, consisting of professionalism/360-degree assessment tool, logbook, research skills, Multiple Choice Questions, Outpatient department participation, and Journal club active participation was statistically significant (P-value < 0.05). The overall correlation between conventional and electronic methods was significant (P-value = 0.017). Conclusion: In this study, we conclude that electronic PMP can be used alongside all conventional tools, and overall, e-assessment methods could replace currently used conventional methods. Combined electronic PMP and me-OSCE can be used as a replacement for currently used gold-standard assessment methods, including 360-degree assessment. © 2021, The Author(s)

Motion Rail: A Virtual Reality Level Crossing Training Application

This paper presents the development and usability testing of a Virtual Reality (VR) based system named 'Motion Rail' for training children on railway crossing safety. The children are to use a VR head mounted device and a controller to navigate the VR environment to perform a level crossing task and they will receive instant feedback on pass or failure on a display in the VR environment. Five participants consisting of two male and three females were considered for the usability test. The outcomes of the test was promising, as the children were very engaging and will like to adopt this training approach in future safety training