Search

The success of arsenic trioxide (ATO) in acute promyelocytic leukemia has driven a plethora studies to investigate its efficacy in other malignancies. However, the inherent toxicity of ATO limits the expansion of its clinical applications. Such toxicity may be linked to ATO-induced metabolic derangements of endogenous substrates. Therefore, the primary objective of this study was to investigate the effect of ATO on the hepatic formation of arachidonic acid (AA) metabolites, hydroxyeicosatetraenoic acids (HETEs), as well as their most notable producing machinery, cytochrome P450 (CYP) enzymes. For this purpose, C57BL/6 mice were intraperitoneally injected with 8 mg/kg ATO for 6 and 24 h. Total RNA was extracted from harvested liver tissues for qPCR analysis of target genes. Hepatic microsomal proteins underwent incubation with AA, followed by identification/quantification of the produced HETEs. ATO downregulated Cyp2e1, while induced Cyp2j9 and most of Cyp4a and Cyp4f, and this has resulted in a significant increase in 17(S)-HETE and 18(R)-HETE, while significantly decreased 18(S)-HETE. Additionally, ATO induced Cyp4a10, Cyp4a14, Cyp4f13, Cyp4f16, and Cyp4f18, resulting in a significant elevation in 20-HETE formation. In conclusion, ATO altered hepatic AA metabolites formation through modulating the underlying network of CYP enzymes. Modifying the homeostatic production of bioactive AA metabolites, such as HETEs, may entail toxic events that can, at least partly, explain ATO-induced hepatotoxicity. Such modification can also compromise the overall body tolerability to ATO treatment in cancer patients. [ABSTRACT FROM AUTHOR]

Tin dioxide plays a crucial role in gas detection, solar cells, and photocatalysis. This study focuses on nanostructured antimony-doped tin dioxide (ATO) synthesized via a modified sol–gel technique under supercritical co-solvent conditions. The crystalline structure and electrical properties were investigated with varying levels of antimony doping (1, 2, and 3 at.%). X-ray diffraction analysis revealed tetragonal rutile structure nanoparticles with sizes ranging from 13 to 22 nm, depending on the doping content. Impedance spectroscopy confirmed its semiconductor behavior, and dc conductivity exhibited a thermal activation, wherein the energy required for conduction progressively increased alongside Sb content. The ac conductivity followed the Jonscher law, dominated by the tunneling hopping mechanism. Nyquist diagrams assessed grain and grain boundary contributions, modeling samples through an equivalent circuit. The dielectric study identified interfacial polarization as the source of dielectric permittivity. The observed behavior of the imaginary component of impedance (Z′′) indicates a dielectric relaxation phenomenon within the sample, with activation energies closely matching those derived from the conductivity study. These findings elucidate the origins of conductivity and active sites in ATO nanoparticles, with deep implications for optoelectronic applications. [ABSTRACT FROM AUTHOR]

Improvements in clinical assessment have occurred since the last published recommendations on the diagnosis and treatment of acute promyelocytic leukemia in 2013. Here, a committee of specialists of the Brazilian Association of Hematology, Hemotherapy and Cellular Therapy presents a comprehensive review on the current knowledge, focusing on the advances in diagnosis, risk assessment, and frontline and salvage therapy. The concept of urgent diagnosis is explored as well as the management of critical situations such as coagulopathy and differentiation syndrome. Recent adjustments in risk stratification based on white blood cell counts only are presented together with the incorporation of chemo-free regimens for non-high-risk patients. Special conditions such as acute promyelocytic leukemia in children, the elderly and pregnant women are discussed. Finally, acute promyelocytic leukemia is presented as a highly curable disease because of the real possibility of targeted therapy towards differentiation, and, paradoxically, as a serious and urgent condition that deserves prompt recognition and management to avoid early mortality.

A comprehensive analysis of 220 patients diagnosed with APL between 1993 and 2022 is here reported. Overall, 214 patients (97.2%) received induction therapy. Complete response (CR) was achieved in 97.4%, 100%, 100%, and 27% of patients treated with AIDA protocol, AIDA + Ara-C, ATRA + ATO, and ATRA monotherapy, respectively. Molecular complete response (CRMRD-) was achieved in 96.8% cases, and 142 patients proceeded to maintenance therapy. Overall, the 3-year and 5-year overall survival (OS) rates were 80.8% (95% CI, 78.1–83.5) and 79.1% (95% CI, 76.4–81.8), respectively. Considering only patients who completed induction and maintenance therapy, the 5-year OS rates were 82.1% (95% CI, 77.5–86.7) for the AIDA0493 cohort, 87.5% (95% CI, 84.4–91.1) for the AIDA2000 cohort, and 100% for the APL0406 cohort (p = 0.044). Additionally, the disease-free survival (DFS) rates were 65.7% (95% CI, 60.4–70.9), 70% (95% CI, 65.8–75.2), and 95.1% (95% CI, 91.7–98.5) (p = 0.016), respectively. Among low and intermediate-risk patients, age > 70 years (p = 0.027) and relapse (p < 0.001) were significantly associated with reduced outcomes. This study contributes to the advancement of our understanding of APL treatment, underscoring the ongoing need for research to enhance outcomes and explore new therapeutic approaches and prognostic factors. [ABSTRACT FROM AUTHOR]

Summary: All‐trans‐retinoic acid (ATRA) and arsenic trioxide (ATO) represent the standard of care for low‐intermediate risk acute promyelocytic leukaemia (APL). Leucocytosis during induction with ATRA‐ATO represents a common complication with an incidence of up to 60%. To identify predictive factors for this complication, we studied a cohort of 65 low‐intermediate risk APL patients treated with ATRA‐ATO in three highly specialized Italian centres. Overall, 39/65 (60%) patients developed leucocytosis, with a peak in leucocyte count being most frequent in the second week from diagnosis. All cases were successfully managed with hydroxyurea. Predictive factors for leucocytosis in univariate analysis were lower platelet counts (odds ratio [OR] 0.98, 0.97–1.00, p = 0.018), lower fibrinogen levels (OR 0.36, 0.17–0.66, p = 0.003), higher bone marrow blast infiltration (OR 1.03, 1.01–1.07, p = 0.021) and CD117 expression by flow (OR 1.04, 1.01–1.08, p = 0.012). Multivariate analysis confirmed lower levels of fibrinogen at diagnosis as the strongest predictive factor for the development of leucocytosis (OR 0.36, 0.15–0.72, p = 0.009). Differentiation syndrome (DS) occurred only in patients developing leucocytosis showing a strict correlation with rising leucocytes counts (16/39 vs. 0/26, p < 0.001). In addition, other treatment‐related complications including QTc prolongation, cardiac events, liver, and haematological toxicities were significantly more frequent in patients experiencing leucocytosis (22/39 vs. 3/26, p < 0.001). In conclusion, APL patients undergoing ATRA‐ATO therapy with lower fibrinogen levels and platelet counts at diagnosis and with a massive bone marrow blast infiltrate should be carefully monitored for the development of leucocytosis during induction. DS and other treatment‐related complications seem to occur almost exclusively in patients developing leucocytosis, who should necessarily receive DS prophylaxis and more intensive monitoring and supportive therapy to prevent treatment complications. [ABSTRACT FROM AUTHOR]

To calculate yield contributing characteristics, genetic progress, variability, and heritability in tomato genotypes, thirty genotypes were analyzed. In all attributes, the phenotypic coefficient of variation (PCV) was greater in magnitude than the genotypic coefficient of variation (GCV). In terms of the number of fruits/plant, number of fruits/clusters, plant height, average fruit wt, days to first fruit harvest, days to 1st fruit setting, fruit yield/plant, plant height and number of clusters/plant, high genotypic variation was observed along with high PCV, GCV and heritability as a percentage of mean. For every attribute, including the no. of fruits/plants, average fruit wt, days until first fruit harvest, and days until first fruit setting, these estimations showed strong heritability (broad sense) values. The plant height, number of clusters/plant and fruit output/plant were found to have the highest estimated genetic advance. [ABSTRACT FROM AUTHOR]

East Japan Railway Company (JR East) is aiming to “realize driverless train operation” as one of the key measures to respond to rapid changes in the business environment. Currently, Automatic Train Operation (ATO) equipment is not installed on the Shinkansen, but there are plans to introduce ATO or driverless operation in the near future. From 2018–2021, the Ministry of Land, Infrastructure, Transport and Tourism (MLIT) held the “ATO Technology Study Group for Railways” in which the concept of technical requirements necessary for driverless operation was discussed. In 2021, JR East conducted the GOA4 demonstration test on the Joetsu Shinkansen. In this test, we were able to confirm the basic functions of Shinkansen vehicles such as automatic departure control, speed control, fixed position stop control, and remote stop control using ATO. We aim to realize unattended operation (GOA4) for deadhead trains between Niigata Station and the Niigata Shinkansen Rolling Stock Center by the end of the 2020 s, and driverless operation (GOA3) for passenger trains of the Joetsu Shinkansen by the mid-2030s and continue to develop the necessary technologies and build systems.

Arsenic has been shown to be highly toxic and can cause liver damage. Previous studies have shown that arsenic causes severe liver damage and induces accumulation of reactive oxygen species (ROS). This study aimed to investigate the effects of ferroptosis on the liver in arsenic trioxide (ATO) and to explore the underlying mechanisms. We confirmed the hepatotoxic effects of arsenic by in vivo and in vitro experiments. After 28 days of administration of arsenic trioxide (4-mg/kg, 8-mg/kg) by gavage, chickens exhibited body weight loss and liver damage in a dose-dependent manner. In addition, in vivo and in vitro western blot and real-time fluorescence quantitative PCR analyses simultaneously indicated that ferroptosis might be the main pathway of arsenic-induced liver injury. Finally, Mito-TEMPO effectively eliminated the ROS accumulation in mitochondria, significantly attenuating the process of cellular ferroptosis. In summary, the hepatotoxic effects of arsenic are related to ferroptosis, and the hepatic ferroptosis process of arsenic is regulated by mitochondrial ROS (MtROS). Our study reveals new mechanisms of arsenic toxicity to the liver, which may deepen our understanding of arsenic toxicology. [ABSTRACT FROM AUTHOR]

Automatic train operation (ATO) is a critical component of automatic train control (ATC) systems. The ATO automatically adjusts the speed of trains, ensuring the safety of trains and increasing the passenger capacity of urban railway networks. The traditional ATO models employ a linear approximation approach to fit the nonlinear control model of the train, such as proportional–integral–derivative (PID) or model predictive control (MPC). However, due to the complexity of actual train operations, these methods fail to accurately fit train models. Thus, they are unable to shorten the operational intervals of trains and meet the demand for improving system efficiency of ATC. In recent years, machine learning-based methods have been employed for deriving more accurate train control models. However, these methods require trains to offload massive amounts of data to central servers for centralized training, which is challenging in CBTC systems due to limited wireless bandwidth. In this paper, we propose using federated learning (FL)-based edge computing to train the ATO model without transmitting a large amount of data. The onboard computing devices are used to perform local federated learning when the train is idle. Additionally, we present a Tab-Transformer-based machine learning model for ATO policy to improve the prediction accuracy of federally trained models. Our extensive simulation results demonstrate that the proposed federated learning scheme improves the efficiency of model training, and the Tab-Transformer-based ATO model achieves better driving performance. [ABSTRACT FROM AUTHOR]

Abstract Acute promyelocytic leukemia (APL), which was once considered one of the deadliest types of leukemia, has become a curable malignancy since the introduction of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) as clinical treatments. ATO, which has become the first-line therapeutic agent for APL, is derived from the natural mineral product arsenic, exemplifying an important role of natural products in the treatment of APL. Many other natural products, ranging from small-molecule compounds to herbal extracts, have also demonstrated great potential for the treatment and adjuvant therapy of APL. In this review, we summarize the natural products and representative components that have demonstrated biological activity for the treatment of APL. We also discuss future directions in better exploring their medicinal value, which may provide a reference for subsequent new drug development and combination therapy programs.

The Shenmu-Shuozhou Railway of Shenhua Baoshen Railway Group Co., Ltd. operates 10,000t heavy-haul trains using centralized traction on intricate railway conditions. The application of the automatic train operation (ATO) mode has accentuated train impulse issues arising from frequent traction adjustments during train operation, underscoring the need for enhanced stability of ATO. This paper presents an optimization control algorithm based on a dynamic evaluation model of train states, tailored to the specific conditions and operational requirements of the Shenmu-Shuozhou Railway. This algorithm features a multi-particle model and a train state evaluation model for heavy-haul trains, evaluating the development trend of train states while incorporating constraints related to the loading/unloading slope in levels. The proposed algorithm was applied in an experiment on the Shenmu-Shuozhou Railway. During the departing stage, the optimization algorithm effectively improved operational stability on steep grades, and increased the departing speed by about 11.1%. During the cruising stage, train impulses was effectively suppressed pre and post neutral-zone crossings, and the train running speed increased by about 0.9%. Moreover, the trend of simulated coupling force changes aligned closely with actual traction loading, and the maximum locomotive-wagon coupling force was reduced by about 26.3%. During the parking stage, the maximum amplitude of train acceleration decreased by 71.4%, and the average impulse count decreased by 60%. The experimental results demonstrate the effectiveness of the proposed algorithm in improving the ATO stability for 10,000t heavy-haul trains operating under centralized traction.

Copyright of Railway Signalling & Communication Engineering is the property of Railway Signalling & Communication Engineering and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Acute promyelocytic leukemia (APL), which was once considered one of the deadliest types of leukemia, has become a curable malignancy since the introduction of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) as clinical treatments. ATO, which has become the first-line therapeutic agent for APL, is derived from the natural mineral product arsenic, exemplifying an important role of natural products in the treatment of APL. Many other natural products, ranging from small-molecule compounds to herbal extracts, have also demonstrated great potential for the treatment and adjuvant therapy of APL. In this review, we summarize the natural products and representative components that have demonstrated biological activity for the treatment of APL. We also discuss future directions in better exploring their medicinal value, which may provide a reference for subsequent new drug development and combination therapy programs. [ABSTRACT FROM AUTHOR]

New treatments are urgently required for triple-negative breast cancer (TNBC). As TP53 is mutated in approximately 80% of TNBC, it is theoretically an attractive target for new drugs for this disease. Arsenic trioxide (ATO), which is used to treat promyelocytic leukaemia, was recently shown to reactivate mutant p53 and restore wild-type functionality. The aim of this study was to evaluate ATO as a potential new treatment for TNBC. Using a panel of 20 cell lines, we found that TNBC cell lines were more sensitive to ATO than non-TNBC cell lines (P = 0.045). Consistent with its ability to reactivate mutant p53, ATO was a more potent inhibitor of proliferation in cell lines with mutant TP53 than the wildtype TP53 (P = 0.027). Direct evidence of mutant p53 reactivation was the induction of multiple wild-type p53 canonical target genes such as CDKN1A, SLC7A11, BBC3, PMAIP1, SESN2, SRXN1 and TXNRD1. Our findings support the activation of mutant p53 by ATO and, furthermore, the possible repurposing of ATO to treat TP53-mutated TNBC.

RESUMO: Este trabalho visa apresentar a tentativa feita por Ricoeur em sua obra Si mesmo como um outro de aproximar suas interpretações das de Heidegger no que se refere às leituras da filosofia aristotélica. O objetivo de Ricoeur é extrair dessa aproximação um entrecruzamento fecundo entre o conceito de preocupação (Sorge) em Heidegger com termos da filosofia de Aristóteles, como os conceitos de ato e potência para verificar a possiblidade de que possa surgir daí uma teoria da unidade analógica do agir a partir da preocupação heideggeriana. Pretendemos mostrar com essa exposição que os termos heideggerinos guardam, a partir da interpretação de Ricoeur, elementos de ligação com o aristotelismo. Palavras-chave: Ato. Potência. Ipseidade. Preocupação. Agir ABSTRACT: This paper presents an attempt by Ricoeur himself in his work as another approaching their interpretations of Heidegger in relation to the readings of Aristotle. The goal of this approach is to extract Ricoeur an interaction between the fruitful concept of concern (Sorge) in accordance with Heidegger's philosophy of Aristotle, as the concepts of act and potency to verify the possibility that there may arise a theory of action from Heidegger's concern. We intend to show with this exhibition that Heideggerian terms keep, from the interpretation of Ricoeur, connecting elements with Aristotelianism. Key words: Act. Potency. Selfhood. Concern. Acting

Centralized traffic regulation systems are crucial in railway mass transit lines to automatically control the trains to recover delays and provide headway regularity. Traditional traffic regulation systems send control action to trains just at stations, through beacons, when they arrive or depart. The present paper proposes a new predictive traffic regulation model for railway mass transit lines equipped with CBTC (Communications Based Train Control) signalling system. This model takes advantage of continuous communications between the centralized control centre and trains, to send control actions at any moment. The proposed regulation system consists of two modules. The first one is a mathematical predictive control algorithm, which generates the running time and dwell time control actions by an optimization model based on the quantified delays of the trains and the operational constraints. The second module receives the control actions (target times) from the first one and generates in real-time the automatic driving commands to be sent to each train. This allows trains to modify their speed profile to speed up or slow down according to updated target times, at any point along their route. Finally, a traffic simulator based on a real Spanish metro line has been developed to verify the effectiveness of the proposed approach. Simulation results under normal operating conditions, considering random delays, show that adherence to the schedule and nominal headway improves by 33% and 49% respectively, and energy consumption is reduced by 5.4%.

Thermo-electrochemical cells (or thermogalvanic cells or thermocells, TECs) have gained attention as devices able to convert low temperature heat into electricity. Within TECs, Pt is one of the most employed electrodes, since it exhibits a fast transfer of electrons with the redox couple in the electrolyte. However, its high price represents a serious drawback. Here, we analyze the use of nanostructured and porous antimony-doped tin oxide (Sb:SnO2) as electrode material. Electrodes of different thickness (320, 550 and 1550 nm) were fabricated by spin coating to study the effect of the electrode area in contact with the electrolyte. F:SnO2 (FTO) glass was used as a substrate and the typical 0.4 M potassium ferro/ferricyanide aqueous solution served as electrolyte. An impedance spectroscopy analysis under operating conditions (10 K temperature difference) showed that the Sb:SnO2 electrodes exhibit the same excellent kinetics as Pt for all the different thickness. On the other hand, the power output density was thickness independent, since the temperature coefficients and the series and mass-transport resistances were similar, leading to no performance improvements when the electrode area in contact with the electrolyte was significantly increased. Finally, the Carnot-related efficiencies estimated for the Sb:SnO2 cells were in the same order of magnitude as for Pt electrodes. These results open the possibility to use Sb:SnO2 as a suitable electrode in TECs at low cost.

Background: Acute myeloid leukemia (AML) with Fms-like tyrosine kinase 3 gene internal tandem duplication (FLT3-ITD) mutations has a poor prognosis. The combination of arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) has a synergistic killing effect on leukemia cells with FLT3-ITD mutation. However, the mechanism, especially the changes of gene expression and metabolic activity remain unclear. Here we explore the transcriptome and metabolomics changes of FLT3-ITD AML cells treated with ATO/ATRA. Methods: RNA-seq was used to identify differential expressed genes (DEGs), and ultra-high performance liquid chromatography-quadrupole electrostatic field orbital trap mass spectrometry (UHPLC-QE-MS) nontargeted metabolomics method was used to screen out the differential metabolites in FLT3-ITD mutant cell lines treated with ATRA and ATO. KEGG pathway database was utilized for pathway exploration and Seahorse XF24 was used to detect extracellular acidification rate (ECAR). Metabolic polymerase chain reaction (PCR) array and real-time quantitative PCR (RT-qPCR) were used to detect mRNA levels of key metabolic genes of glycolysis and fatty acid after drug treatment. Results: A total of 3873 DEGs were identified and enriched in 281 Gene Ontology (GO) terms, among which 210 were related to biological processes, 43 were related to cellular components, and 28 were related to molecular functions. Besides, 1794 and 927 differential metabolites were screened in positive and negative ion mode separately, and 59 different metabolic pathways were involved, including alanine-aspartate-glutamate metabolic pathway, arginine, and proline metabolic pathway, glycerophospholipid metabolic pathways, etc. According to KEGG Pathway analysis of transcriptome combined with metabolome, glycolysis/gluconeogenesis pathway and fatty acid metabolism pathway were significantly founded enriched. ATRA + ATO may inhibit the glycolysis of FLT3-ITD AML cells by inhibiting FLT3 and its downstream AKT/HK2-VDAC1 signaling pathway. Conclusions: The gene transcription profile and metabolites of FLT3-ITD mutant cells changes significantly after treatment, which might be related to the anti-FLT3-ITD AML effect. The screened DEGs, differential metabolites pathway are helpful in studying the mechanism of anti-leukemia effects and drug targets. [ABSTRACT FROM AUTHOR]

Automatic Train Operation (ATO) has been widely applied to the onboard signaling system of subway trains, which improves the operation efficiency of subway trains. The braking performance of the train has a greater impact on the precise stop controlled by ATO. The train braking performance, especially the air braking performance, may be unstable to a certain extent, and the response to ATO's braking command may have a large deviation. One of the more important factors is the influence of season and temperature. This paper explores the method of optimizing the seasonal deviation of train braking and adding the adaptive ability of ATO system. In combination with the braking performance change of a certain line, a separate braking control strategy group is made for each braking change period, and switch and adjust is conducted automatically in the corresponding time period (or other setting conditions), so that under different train braking performance, ATO system can achieve precise stopping at the platform and improve the efficiency of passengers getting on and off. [ABSTRACT FROM AUTHOR]

The rise of online transactions has led to a corresponding increase in online criminal activities. Account takeover attacks, in particular, are challenging to detect, and novel approaches utilize machine learning to identify compromised accounts. This paper aims to conduct a literature review on account takeover detection and user behavior analysis within the cybersecurity domain. By exploring these areas, the goal is to combat account takeovers and other fraudulent attempts effectively.

Simple Summary: Differentiation syndrome (DS) is a frequent clinical complication of treatment with all-trans retinoic acid (ATRA) and/or arsenic trioxide (ATO), and is typically characterized by non-infectious related fever, dyspnea, hypotension, weight gain > 5 kg, pleural or pericardial effusions, and acute renal failure. DS was initially observed in patients with acute promyelocytic leukemia (APL) treated with ATRA and ATO but was later recognized with other targeted therapies for acute myeloid leukemia (AML). In this review, we discuss the pathogenesis, clinical manifestations, radiological findings, diagnosis, and treatment of DS in patients with APL treated with ATRA and ATO, as well as discuss DS in patients with AML treated with novel therapeutics. Differentiation syndrome (DS) is a frequent and potentially life-threatening clinical syndrome first recognized with the advent of targeted therapeutics for acute promyelocytic leukemia (APL). DS was subsequently observed more broadly with targeted therapeutics for acute myeloid leukemia (AML). DS is typically characterized by fever, dyspnea, hypotension, weight gain, pleural or pericardial effusions, and acute renal failure. The incidence in patients with APL ranges from 2 to 37%, with the wide variation likely attributed to different diagnostic criteria, use of prophylactic treatment, and different treatment regimens. Treatment with corticosteroids +/- cytoreductive therapy should commence as soon as DS is suspected to reduce DS-related morbidity and mortality. The targeted anti-leukemic therapy should be discontinued in patients with severe DS. Here, we discuss the pathogenesis of DS, clinical presentations, diagnostic criteria, management strategies, and implementation of prospective tracking on clinical trials. [ABSTRACT FROM AUTHOR]

Abstract Developing AI systems for automatic train operation (ATO) requires developers to have a deep understanding of the human tasks they are trying to replace. This paper fills this gap and translates the regulatory requirements from the context of German railways for the AI developer community. As a result, tasks such as train’s path monitoring for collision prediction, signal detection, door operation, etc. are identified. Based on this analysis, a functionally justified sensor setup with detailed configuration requirements is presented. This setup was also evaluated by a survey within the railway industry. The evaluated sensors include RGB/IR cameras, LIDARs, radars and ultrasonic sensors. Calculations and estimates for the evaluated sensors are presented graphically and included in this paper. However, the ultimate sensor setup is still a subject of research. The results of this paper also address the lack of training and test datasets for railway AI systems. It is proposed to acquire research datasets that will allow the training of domain adaptation algorithms to transform other datasets, thus increasing the number of available datasets. The sensor setup is also recommended for such research datasets.

This paper introduces the operation mode of CTCS-3+ATO train control system and the relevant parameters of GPRS. By analyzing the monitoring data of the first domestic high-speed railway line using CTCS-3+ATO mode for more than one year, the high-speed railway ATO service fully meets the requirements of the specifications formulated by China Railway Group in terms of function and performance, and has no impact on the original CTCS-3 service, which proves the feasibility of using packet domain GPRS network to carry train control services. In order to enhance the availability of GPRS grouped domain channels and ensure the normal operation of ATO, this paper puts forward reasonable suggestions on BSC resource utilization, cell reset and ATO device protection. [ABSTRACT FROM AUTHOR]

Transglutaminase 2 (TG2) is a critical cancer cell survival factor that activates several signalling pathways to foster drug resistance, cancer stem cell survival, metastasis, inflammation, epithelial-mesenchymal transition, and angiogenesis. All-trans retinoic acid (ATRA) and chemotherapy have been the standard treatments for acute promyelocytic leukaemia (APL), but clinical studies have shown that arsenic trioxide (ATO), alone or in combination with ATRA, can improve outcomes. ATO exerts cytotoxic effects in a variety of ways by inducing oxidative stress, genotoxicity, altered signal transduction, and/or epigenetic modification. In the present study, we showed that ATO increased ROS production and apoptosis ratios in ATRA-differentiated NB4 leukaemia cells, and that these responses were enhanced when TG2 was deleted. The combined ATRA + ATO treatment also increased the amount of nuclear factor erythroid 2-related factor 2 (NRF2) transcription factor, an adaptive regulator of the cellular oxidative stress response, and calpain proteolytic activity, resulting in TG2 degradation and the reduced survival of WT leukaemia cells. We further showed that the induced TG2 protein expression was degraded in the MCF-7 epithelial cell line and primary peripheral blood mononuclear cells upon ATO treatment, thereby sensitising these cell types to apoptotic signals. [ABSTRACT FROM AUTHOR]

Uma reflexão sobre o ato nos campos da clínica e da política a partir da filosofia de Spinoza, partindo da ideia de que ato e pensamento são indissociáveis. Acreditamos que a partir de Spinoza é possível trabalhar simultaneamente nesses dois campos, utilizando as concepções de indivíduo multiplamente composto, razão e direito tanto para pensarmos o indivíduo estritamente considerado, habitando por partes contrárias, quanto os grupos, as instituições, e a vida coletiva. Estabelecendo ressonâncias entre Spinoza, Winnicott e Reich, abordamos a questão da agressividade na clínica enquanto o que permite repelir o que diminui nossa potência, trazendo para clínica o horizonte do conflito e da guerra. Abordamos também o trabalho da imaginação na superação dos afetos tristes, permitindo a afirmação da potência. Chegamos a alguns apontamentos sobre o trabalho clínico no campo da violência de estado e do racismo, o que possibilita pensar as relações entre clínica e militância. Considerando simultaneamente elementos da Ética, e do Tratado Político, chegamos finalmente a fazer aproximações entre o terceiro gênero do conhecimento e o agir humano que nos levarão a uma concepção na qual as “lutas do desejo” são nelas mesmas ilimitadas e eternas.

The Wiskott--Aldrich syndrome (WAS) is an X-linked primary immune deficiency caused by a mutation in the WAS gene. This leads to altered or absent WAS protein (WASp) expression and function resulting in thrombocytopenia, eczema, recurrent infections, and autoimmunity. In T cells, WASp is required for immune synapse formation. Patients with WAS show reduced numbers of peripheral blood T lymphocytes and an altered T-cell receptor repertoire. In vitro, their peripheral T cells show decreased proliferation and cytokine production upon aCD3/aCD28 stimulation. It is unclear whether these T-cell defects are acquired during peripheral activation or are, in part, generated during thymic development. Here, we assessed the role of WASp during T-cell differentiation using artificial thymic organoid cultures and in the thymus of humanized mice. Although CRISPR/Cas9 WAS knockout hematopoietic stem and progenitor cells (HSPCs) rearranged the T-cell receptor and differentiated to T-cell receptor (TCR)+ CD4+ CD8+ double-positive (DP) cells similar to wild-type HSPCs, a partial defect in the generation of CD8 single-positive (SP) cells was observed, suggesting that WASp is involved in their positive selection. TCR repertoire analysis of the DP and CD8+ SP population, however, showed a polyclonal repertoire with no bias toward autoreactivity. To our knowledge, this is the first study of the role of WASp in human T-cell differentiation and on TCR repertoire generation. [ABSTRACT FROM AUTHOR]

Developing AI systems for automatic train operation (ATO) requires developers to have a deep understanding of the human tasks they are trying to replace. This paper fills this gap and translates the regulatory requirements from the context of German railways for the AI developer community. As a result, tasks such as train's path monitoring for collision prediction, signal detection, door operation, etc. are identified. Based on this analysis, a functionally justified sensor setup with detailed configuration requirements is presented. This setup was also evaluated by a survey within the railway industry. The evaluated sensors include RGB/IR cameras, LIDARs, radars and ultrasonic sensors. Calculations and estimates for the evaluated sensors are presented graphically and included in this paper. However, the ultimate sensor setup is still a subject of research. The results of this paper also address the lack of training and test datasets for railway AI systems. It is proposed to acquire research datasets that will allow the training of domain adaptation algorithms to transform other datasets, thus increasing the number of available datasets. The sensor setup is also recommended for such research datasets. [ABSTRACT FROM AUTHOR]

Human intestinal microbiome plays vital role in maintaining intestinal homeostasis and interacting with xenobiotics. Few investigations have been conducted to understand the effect of arsenic-containing medicine exposure on gut microbiome. Most animal experiments are onerous in terms of time and resources and not in line with the international effort to reduce animal experiments. We explored the overall microbial flora by 16S rRNA genes analysis in fecal samples from acute promyelocytic leukemia (APL) patients treated with arsenic trioxide (ATO) plus all-trans retinoic acid (ATRA). Gut microbiomes were found to be overwhelmingly dominated by Firmicutes and Bacteroidetes after taking medicines containing arsenic in APL patients. The fecal microbiota composition of APL patients after treatment showed lower diversity and uniformity shown by the alpha diversity indices of Chao, Shannon, and Simpson. Gut microbiome operational taxonomic unit (OTU) numbers were associated with arsenic in the feces. We evaluated Bifidobacterium adolescentis and Lactobacillus mucosae to be a keystone in APL patients after treatment. Bacteroides at phylum or genus taxonomic levels were consistently affected after treatment. In the most common gut bacteria Bacteroides fragilis, arsenic resistance genes were significantly induced by arsenic exposure in anaerobic pure culture experiments. Without an animal model, without taking arsenicals passively, the results evidence that arsenic exposure by drug treatment is not only associated with alterations in intestinal microbiome development at the abundance and diversity level, but also induced arsenic biotransformation genes (ABGs) at the function levels which may even extend to arsenic-related health outcomes in APL. [ABSTRACT FROM AUTHOR]

Super-high dielectric constant (k) AlOx/TiOy nanolaminates (ATO NLs) are deposited by an atomic layer deposition technique for application in next-generation electronics. Individual multilayers with uniform thicknesses are formed for the ATO NLs. With an increase in AlOx content in each ATO sublayer, the shape of the Raman spectrum has a tendency to approach that of a single AlOx layer. The effects of ATO NL deposition conditions on the electrical properties of the metal/ATO NL/metal capacitors were investigated. A lower deposition temperature, thicker ATO NL, and lower TiOy content in each ATO sublayer can lead to a lower leakage current and smaller loss tangent at 1 kHz for the capacitors. A higher deposition temperature, larger number of ATO interfaces, and higher TiOy content in each ATO sublayer are important for obtaining higher k values for the ATO NLs. With an increase in resistance in the capacitors, the ATO NLs vary from semiconductors to insulators and their k values have a tendency to decrease. For most of the capacitors, the capacitances reduce with increments in absolute measurement voltage. There are semi-circular shapes for the impedance spectra of the capacitors. By fitting them with the equivalent circuit, it is observed that with the increase in absolute voltage, both parallel resistance and capacitance decrease. The variation in the capacitance is explained well by a novel double-Schottky electrode contact model. The formation of super-high k values for the semiconducting ATO NLs is possibly attributed to the accumulation of charges. [ABSTRACT FROM AUTHOR]

The advent of small-molecule inhibitors targeting the components of oncogenic signaling pathways has revolutionized cancer treatment, where the pharmacological approaches have gone from an era of non-specific chemotherapeutic drugs to the golden age of targeted therapies. In the present study, we evaluated the therapeutic value of an isoform-specific inhibitor of PI3K (Idelalisib) in potentiating the anti-leukemic effects of arsenic trioxide (ATO), an eminent drug used in the treatment of acute promyelocytic leukemia (APL). We found that the abrogation of the PI3K axis profoundly reinforced the anti-leukemic effects of the lower concentrations of ATO, as revealed by the superior reduction in the viability, cell number, and metabolic activity of APL-derived NB4 cells as compared to either agent alone. The cytotoxic effect of Idelalisib in combination with ATO was probably mediated through suppression of c-Myc that was coupled with the elevation in the intracellular level of reactive oxygen species and induction of caspase-3-dependent apoptosis. Notably, our results showed that the suppression of autophagy reinforced the ability of the drugs in eradicating the leukemic cells, suggesting that the compensatory activation of this system may probably overshadow the success of Idelalisib-plus-ATO in APL cells. All in all and given the significant efficacy of Idelalisib against NB4 cells, we proposed the application of this PI3K inhibitor as a foreseeable approach with a safe profile in the treatment of APL. [ABSTRACT FROM AUTHOR]

The Wiskott–Aldrich syndrome (WAS) is an X-linked primary immune deficiency caused by a mutation in the WAS gene. This leads to altered or absent WAS protein (WASp) expression and function resulting in thrombocytopenia, eczema, recurrent infections, and autoimmunity. In T cells, WASp is required for immune synapse formation. Patients with WAS show reduced numbers of peripheral blood T lymphocytes and an altered T-cell receptor repertoire. In vitro, their peripheral T cells show decreased proliferation and cytokine production upon aCD3/aCD28 stimulation. It is unclear whether these T-cell defects are acquired during peripheral activation or are, in part, generated during thymic development. Here, we assessed the role of WASp during T-cell differentiation using artificial thymic organoid cultures and in the thymus of humanized mice. Although CRISPR/Cas9 WAS knockout hematopoietic stem and progenitor cells (HSPCs) rearranged the T-cell receptor and differentiated to T-cell receptor (TCR)+ CD4+ CD8+ double-positive (DP) cells similar to wild-type HSPCs, a partial defect in the generation of CD8 single-positive (SP) cells was observed, suggesting that WASp is involved in their positive selection. TCR repertoire analysis of the DP and CD8+ SP population, however, showed a polyclonal repertoire with no bias toward autoreactivity. To our knowledge, this is the first study of the role of WASp in human T-cell differentiation and on TCR repertoire generation.

Introduction: Systemic sclerosis (SSc) is a rare chronic autoimmune disease characterized by diffuse fibrosis of the skin and internal organs and vascular abnormalities. The etiology and physiopathology are complex due to the heterogeneity of its overall clinical presentation. Arsenic trioxide (ATO) has been proven to be effective against SSc, sclerodermatous Graft-versus-Host Disease, multiple sclerosis, Crohn's disease or systemic lupus erythematosus animal models and has demonstrated promising effects in human clinical trials. Its efficacy was shown to be related at least in part to the generation of Reactive Oxygen Species (ROS) and the selective deletion of activated immune cells and fibroblasts. However, ATO can induce some adverse effects that must be considered, especially when used for the treatment of a chronic disease. Methods: We evaluate here, in vitro and in a mouse model of SSc, the improved efficacy of ATO when associated with a Fenton-like divalent cation, namely copper chloride (CuCl2), also known to trigger the production of ROS. Results: In preliminary experiments in vitro, ATO 1 µM + CuCl2 0.5 µM increased ROS production and increased apoptosis of NIH 3T3 murine fibroblasts compared to 1 µM ATO alone. In vivo, in the HOCl-induced mouse model of SSc, co-treatment with ATO 2.5 mg/g + CuCl2 0.5 mg/g significantly alleviated clinical signs such as the thickening of the skin (p<0.01) and cutaneous fibrosis, in a manner equivalent to treatment with ATO 5 µg/g. Our results provide evidence that co-treatment with ATO 2.5 mg/g + CuCl2 0.5 mg/g decreases the number of B cells and the activation of CD4+ T lymphocytes. The co-treatment substantially blocks the NRF2 signaling pathway, increases H2O2 production and results in the improvement of the health status of mice with experimental SSc. Conclusion: In conclusion, copper combined with ATO treatment halved the concentration of ATO needed to obtain the same effect as a high dose of ATO alone for the treatment of SSc mice. The strategy of using lower doses of drugs with different mechanisms of action in combination has many potential advantages, the first being to lessen the potential side effects induced by ATO, a drug with side effects quickly increased with dosage. [ABSTRACT FROM AUTHOR]

Arsenic is a common environmental pollutant and poses a serious threat to human and animal health. In this study, we used the ducks to mimic arsenic trioxide (ATO) exposure and investigated the mechanism of cardiac toxicity. The results indicated that ATO inhibited the body and organ growth of ducks, led to an increase in LDH content, and caused obvious deformity, ischemia infarction. It is found that ATO exacerbated the swell of mitochondrial and the contraction of cell nuclei in the heart of ducks through transmission electron microscopy (TEM). ATO also induced an increase in MDA content; inhibited the activation of the Nrf 2 pathway; downregulated the expression of mRNA and protein of Nrf 2, HO-1, and SOD-1; and upregulated the expression of mRNA and protein of Keap 1. At the same time, ATO induced apoptosis which not only upregulated the expression levels of mRNA and proteins (Caspase 3, Cyt-C, P53, Bax) but also decreased the mRNA and protein expression level of Bcl-2. These results indicated that ATO can lead to oxidative stress and apoptosis in the heart of ducks. In general, our research shows that ATO triggers mitochondrial dysfunction, oxidative stress, and apoptosis via Nrf 2/Caspase 3 signaling pathway in the heart of ducks. [ABSTRACT FROM AUTHOR]

Vanadium pentoxide (V2O5) film was used to fabricate an electrochromic device counterbalanced with a dry-deposited ion storage layer (ISL). For the ISL, a mixture of antimony-doped tin oxide (ATO) and Prussian blue (PB) powders (PB-ATO; 1:4 vol%) was dry deposited to form PB-ATO ISL as the counter electrode of the device, thereby improving electrochromic device characteristics. Dry deposition provided a film with a rough surface, which resulted in improved electrochromic properties because of the large surface area of the ISL, which provided more paths for electron movement. The ISL was deposited using a dry deposition system (i.e., the nanoparticle deposition system [NPDS]) to maximize the surface area of the film. The polyol method was used to fabricate V2O5 film with high crystallinity for better electrochromic properties. The fabricated V2O5-based electrochromic device (ECD) was evaluated by electrochemical analysis. Compared with the ECD without PB-ATO ISL, the difference in reflectance exceeded 50% for the ECD with PB-ATO ISL. Moreover, the ECD without ISL had a diffusion coefficient of 1.88 × 10−10 S2/s, while the ECD with PB-ATO ISL had an order of magnitude higher diffusion coefficient of 2.47 × 10−9 cm2/s. Therefore, the performance of the ECD was improved using dry-deposited ISL composed of PB-ATO. The coloration of the device was dramatically improved using PB-ATO ISL, compared with the device with ATO alone or without any ISL. [ABSTRACT FROM AUTHOR]

Proton exchange membrane water electrolysis (PEMWE) technology commercialization strongly relies on developing efficient and cost-effective anode catalysts. One key challenge is the high cost associated with IrO 2 , which can be mitigated by reducing iridium (Ir) loading. A promising approach to achieving this is using a conductive support material to anchor Ir/IrO 2 . In this study, we explored depositing metallic Ir on antimony-doped tin oxide (ATO) using a solid-state method. This approach is straightforward and time-efficient. Among four samples with 50 wt % Ir loading, one prepared with NaOH in 100% ethanol (Ir/ATO-NE) exhibited the highest specific oxygen evolution reaction (OER) performance. The Ir/ATO-NE catalyst achieved 340 A g Ir -1 at 1.6 V (versus RHE), surpassing a commercial IrO 2 . Additionally, Ir/ATO-NE demonstrated the lowest Tafel slope, indicating enhanced oxygen evolution kinetics and long-term durability comparable to commercial catalysts. Electron microscopy revealed uniform Ir nanoparticle (NP) sizes and a complete layer of Ir NPs on the support, in contrast to other samples. This study introduces a synthesis protocol for Ir catalysts that is efficient, simple, and effective for oxygen evolution in acidic media.Ir -1 . Additionally, Ir/ATO-NE demonstrated the lowest Tafel slope, indicating enhanced oxygen evolution kinetics and long-term durability comparable to commercial catalysts. Electron microscopy revealed uniform Ir nanoparticle (NP) sizes and a complete layer of Ir NPs on the support, in contrast to other samples. This study introduces a synthesis protocol for Ir catalysts that is efficient, simple, and effective for oxygen evolution in acidic media.