Nrf2 Deficiency Exaggerates Doxorubicin-Induced Cardiotoxicity and Cardiac Dysfunction

The anticancer therapy of doxorubicin (Dox) has been limited by its acute and chronic cardiotoxicity. In addition to a causative role of oxidative stress, autophagy appears to play an important role in the regulation of Dox-induced cardiotoxicity. However, the underlying mechanisms remain unclear. Accordingly, we explored a role of nuclear factor erythroid-2 related factor 2 (Nrf2) in Dox-induced cardiomyopathy with a focus on myocardial oxidative stress and autophagic activity. In wild type (WT) mice, a single intraperitoneal injection of 25 mg/kg Dox rapidly induced cardiomyocyte necrosis and cardiac dysfunction, which were associated with oxidative stress, impaired autophagy, and accumulated polyubiquitinated protein aggregates. However, these Dox-induced adverse effects were exaggerated in Nrf2 knockout (Nrf2−/−) mice. In cultured cardiomyocytes, overexpression of Nrf2 increased the steady levels of LC3-II, ameliorated Dox-induced impairment of autophagic flux and accumulation of ubiquitinated protein aggregates, and suppressed Dox-induced cytotoxicity, whereas knockdown of Nrf2 exerted opposite effects. Moreover, the exaggerated adverse effects in Dox-intoxicated Nrf2 depleted cardiomyocytes were dramatically attenuated by forced activation of autophagy via overexpression of autophagy related gene 5 (Atg5). Thus, these results suggest that Nrf2 is likely an endogenous suppressor of Dox-induced cardiotoxicity by controlling both oxidative stress and autophagy in the heart

Ticagrelor vs Clopidogrel in CYP2C19 loss-of-function carriers with Stroke or TIA

BACKGROUNDComparisons between ticagrelor- aspirin and clopidogrel-aspirin in CYP2C19 loss-of-function carriers have not been well studied for secondary stroke prevention.METHODSWe conducted a randomized, double-blind, placebo-controlled trial of 6,412 patients with a minor ischemic stroke or TIA who carried CYP2C19 LOF alleles determined by point-of-care testing. Patients were randomly assigned within 24 hours after symptom onset, in a 1:1 ratio to receive ticagrelor (180 mg loading dose on day 1 followed by 90 mg twice daily for days 2 through 90) or clopidogrel (300 mg loading dose on day 1 followed by 75 mg per day for days 2 through 90), plus aspirin (75-300 mg loading dose followed by 75 mg daily for 21 days). The primary efficacy outcome was stroke and the primary safety outcome was severe or moderate bleeding, both within 90 days. RESULTSStroke occurred within 90 days in 191 (6.0%) versus 243 (7.6%), respectively (hazard ratio, 0.77; 95% confidence interval, 0.64 to 0.94; P=0.008). Moderate or severe bleeding occurred in 9 patients (0.3%) in the ticagrelor-aspirin group and in 11 patients (0.3%) in the clopidogrel-aspirin group; any bleeding event occurred in 170 patients (5.3%) vs 80 (2.5%), respectively. CONCLUSIONSAmong Chinese patients with minor ischemic stroke or TIA within 24 hours after symptoms onset who were carriers of CYP2C19 loss-of-function alleles, ticagrelor- aspirin was modestly better than clopidogrel-aspirin for reducing the risk of stroke but was associated with more total bleeding events at 90 days. (CHANCE-2 ClinicalTrials.gov number, NCT04078737.

The complete mitochondrial genome sequence of Sinopoppia nigroflagella Wei, 1997 (Hymenoptera: Tenthredinidae) reveals a new gene order

The complete mitochondrial genome of Sinopoppia nigroflagella Wei, 1997 was sequenced and assembled. The circular genome is 15,940 bp long, with an A + T content of 80.33%, 37 genes, and a 658-bp control region. Specifically, trnL1 was translocated into the MQI gene cluster, and the other tRNA cluster was arranged as ARENS1F. The two gene clusters were thus arranged as ML1QI and ARENS1F. The phylogenetic results indicated that S. nigroflagella forms a sister group with Blennocampinae and Fenusinae

A Voltage Sag Severity Evaluation Method for the System Side Which Considers the Influence of the Voltage Tolerance Curve and Sag Type

Considering the influence of user equipment voltage tolerance characteristics and sag types on the evaluation results, this paper proposes a voltage sag severity evaluation method for the system side which considers the influence of the voltage tolerance curve and sag type. As such, a quantitative evaluation of the severity of voltage sag events can be achieved. Firstly, the user’s voltage tolerance curve is used to construct the comparison reference value of the energy index, in order to realize the rapid analysis of the severity of the sag event in the normal area and the abnormal area. Secondly, aiming at the problem of insufficient descriptions of the severity difference of sag events in uncertain areas, an improved energy index evaluation model combined with user tolerance characteristics is established through an interval division and interval weight calculation, so as to divide and evaluate the severity of sag events in uncertain areas. Considering the influence of the sag type on the voltage tolerance curve and user equipment, the energy index correction factor is then constructed, and the measurement function is used for an interval evaluation to obtain the ranking result of the voltage sag severity, which is more in line with the actual situation. Finally, the rationality and effectiveness of the proposed method are verified by analyzing 24 voltage sag events at a monitoring node

High temperature deformation behavior and constitutive model of Zirlo zirconium alloy

In order to study the thermal deformation behavior of Zirlo alloy at ranges of 550-700 ℃ deformation temperature and 0.01-10 s-1 strain rate, the Zirlo alloy was subjected to compression under condition of isothermal and constant strain rate by using the Gleeble-3800 thermal simulated test machine. Through introducing strains on the basis of the Arrhenius type hyperbolic sine function equation, an Arrhenius constitutive model was developed based on strain compensation, and founded on a combination of dislocation density evolution causing work hardening model and phenomenological softening model, a segmented phenomenological constitutive model was constructed. The results show that the flow stress of Zirlo zirconium alloy increases with the decrease of temperature and the increase of strain rate, the flow stress exhibits higher temperature sensitivity at low strain rate, and flow stress curves separately exhibit characteristics as work hardening, dynamic recovery and dynamic recrystallization under different deformation conditions. Through error analysis, it was revealed that errors of the most stresses predicted by the Arrhenius constitutive model based on strain compensation are within 15%, which exhibits high accuracy. The maximum relative average absolute errors of the segmented phenomenological constitutive model are less than 3%, exhibiting an accuracy of over 97%. The segmented phenomenological constitutive model can accurately predict the stress-strain curve of the Zirlo alloy and has good expansibility; moreover, it can preliminarily predict the type of the stress-strain curve and has good practicability

Highly cooperative individuals’ clustering property in myopic strategy groups

As the driving force of the evolutionary game, the strategy update mechanism is crucial to the evolution of cooperative behavior. At present, there has been a lot of research on the update mechanism, which mainly involves two aspects. On one hand, all players in the network use the same rule to update strategies; on the other hand, players use heterogeneous update rules, such as imitate and innovate. A sophisticated update mechanism is available. However, most of these studies are based on node dynamics, that is, individuals adopt the same strategy to their neighbors at the same time. Considering that in real life, faced with complex social relationships, the code of conduct generally followed by individuals is to adopt different decision-making behaviors for different opponents. Therefore, here, we are based on edge dynamics, which allows each player to adopt different strategies for different opponents. We analyze how the mixing ratio of the two mechanisms in the network affects the evolution of cooperative behavior based on imitation and myopic. The parameter u is introduced to represent the proportion of myopic players. The simulation results show that in the edge dynamics behavior patterns, compared with the myopic rule, the imitate rule plays a leading role in promoting the group to achieve a high level of cooperation, even when the temptation to defect is relatively large. Furthermore, for players who adopt the imitate update mechanism, individuals with high cooperation rate dominate when u is relatively high, and individuals with low cooperation rate dominate when u is relatively large. For players who adopt the myopic update rule, regardless of the value of u, the individual’s cooperation rate is 0.25 and 0.5 is dominant

The pseudogene DUXAP10 contributes to gefitinib resistance in NSCLC by repressing OAS2 expression

Gefitinib, an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI),is the currently recommended first-line therapy for advanced EGFR-mutant lung cancer, and understanding the mechanism of resistance is the key to formulating therapeutic strategies for EGFR-TKIs. In this study, we evaluate the expression patterns and potential biological functions of the pseudogene DUXAP10 in gefitinib resistance. We find that pseudogene DUXAP10 expression is significantly upregulated in NSCLC gefitinib-resistant cells and tissues. Gain and loss of function assays reveal that knockdown of DUXAP10 by siRNA reverses gefitinib resistance both in vitro and in vivo. Furthermore, DUXAP10 interacts with the histone methyltransferase enhancer of zeste homolog 2 (EZH2) to repress the expression of 2′,5′-oligoadenylate synthetase (OAS2). Overall, our study highlights the pivotal role of DUXAP10 in gefitinib resistance, and the DUXAP10/EZH2/OAS2 axis might be a promising therapeutic target to overcome acquired gefitinib resistance in NSCLC

Phylogenomic Analyses of the Tenthredinoidea Support the Familial Rank of Athaliidae (Insecta, Tenthredinoidea)

International audienceThe systematic status of the genus Athalia and related genera is a perennial controversy in sawfly taxonomy. Several authors have hypothesized that the placement of Athalia within the Tenthredinidae is artificial, but no studies have focused on this topic. If the hypothesis that Athalia does not belong to Tenthredinidae can be supported, the taxonomic framework of Tenthredinoidea needs revision. We present a comprehensive phylogenomic study of Tenthredinoidae, focusing on the positions of Athalia and related genera by sampling 97 representatives mainly of the Tenthredinoidea, including Heptamelinae and Blasticotomidae. Our phylogenetic reconstructions based on nuclear genes and mitochondrial (mt) sequences support Athalia and related genera as a distinct clade sister to Tenthredinidae + (Cimbicidae + Diprionidae). A comparison of symphytan mitochondrial genomes reveals an innovative gene rearrangement pattern in Athaliidae, in which Dentathalia demonstrates a more ancestral pattern than Athalia and Hypsathalia. The lineage specificity of mt rRNA secondary structures also provides sufficient support to consider Athaliidae as a separate family. In summary, the phylogeny and genomic structural changes unanimously support the taxonomic treatment of Athaliidae as a family and the re-establishment of Dentathalia as a valid genu

Porcine Epidemic Diarrhea Virus Replication in Human Intestinal Cells Reveals Potential Susceptibility to Cross-Species Infection

Various coronaviruses have emerged as a result of cross-species transmission among humans and domestic animals. Porcine epidemic diarrhea virus (PEDV; family Coronaviridae, genus Alphacoronavirus) causes acute diarrhea, vomiting, dehydration, and high mortality in neonatal piglets. Porcine small intestinal epithelial cells (IPEC-J2 cells) can be used as target cells for PEDV infection. However, the origin of PEDV in pigs, the host range, and cross-species infection of PEDV remain unclear. To determine whether PEDV has the ability to infect human cells in vitro, human small intestinal epithelial cells (FHs 74 Int cells) were inoculated with PEDV LJX and PEDV CV777 strains. The results indicated that PEDV LJX, but not PEDV CV777, could infect FHs 74 Int cells. Furthermore, we observed M gene mRNA transcripts and N protein expression in infected FHs 74 Int cells. A one-step growth curve showed that the highest viral titer of PEDV occurred at 12 h post infection. Viral particles in vacuoles were observed in FHs 74 Int cells at 24 h post infection. The results proved that human small intestinal epithelial cells are susceptible to PEDV infection, suggesting the possibility of cross-species transmission of PEDV