Search results for: Ofer Levi
Commenced in January 2007
Frequency: Monthly
Edition: International
Paper Count: 16

Search results for: Ofer Levi

16 End-to-End Pyramid Based Method for Magnetic Resonance Imaging Reconstruction

Authors: Omer Cahana, Ofer Levi, Maya Herman

Abstract:

Magnetic Resonance Imaging (MRI) is a lengthy medical scan that stems from a long acquisition time. Its length is mainly due to the traditional sampling theorem, which defines a lower boundary for sampling. However, it is still possible to accelerate the scan by using a different approach such as Compress Sensing (CS) or Parallel Imaging (PI). These two complementary methods can be combined to achieve a faster scan with high-fidelity imaging. To achieve that, two conditions must be satisfied: i) the signal must be sparse under a known transform domain, and ii) the sampling method must be incoherent. In addition, a nonlinear reconstruction algorithm must be applied to recover the signal. While the rapid advances in Deep Learning (DL) have had tremendous successes in various computer vision tasks, the field of MRI reconstruction is still in its early stages. In this paper, we present an end-to-end method for MRI reconstruction from k-space to image. Our method contains two parts. The first is sensitivity map estimation (SME), which is a small yet effective network that can easily be extended to a variable number of coils. The second is reconstruction, which is a top-down architecture with lateral connections developed for building high-level refinement at all scales. Our method holds the state-of-art fastMRI benchmark, which is the largest, most diverse benchmark for MRI reconstruction.

Keywords: magnetic resonance imaging, image reconstruction, pyramid network, deep learning

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15 F-VarNet: Fast Variational Network for MRI Reconstruction

Authors: Omer Cahana, Maya Herman, Ofer Levi

Abstract:

Magnetic resonance imaging (MRI) is a long medical scan that stems from a long acquisition time. This length is mainly due to the traditional sampling theorem, which defines a lower boundary for sampling. However, it is still possible to accelerate the scan by using a different approach, such as compress sensing (CS) or parallel imaging (PI). These two complementary methods can be combined to achieve a faster scan with high-fidelity imaging. In order to achieve that, two properties have to exist: i) the signal must be sparse under a known transform domain, ii) the sampling method must be incoherent. In addition, a nonlinear reconstruction algorithm needs to be applied to recover the signal. While the rapid advance in the deep learning (DL) field, which has demonstrated tremendous successes in various computer vision task’s, the field of MRI reconstruction is still in an early stage. In this paper, we present an extension of the state-of-the-art model in MRI reconstruction -VarNet. We utilize VarNet by using dilated convolution in different scales, which extends the receptive field to capture more contextual information. Moreover, we simplified the sensitivity map estimation (SME), for it holds many unnecessary layers for this task. Those improvements have shown significant decreases in computation costs as well as higher accuracy.

Keywords: MRI, deep learning, variational network, computer vision, compress sensing

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14 Baring Witness, Bearing Withness: Paradoxes of Testimony in J.M. Coetzee’s Waiting for the Barbarians

Authors: Alexandra Sweny

Abstract:

This paper contends with the intersection between the act of witnessing and the act of reading in order to consider the relevance of literary testimony and fiction as tools for postcolonial readings of history. J. M. Coetzee's Waiting for the Barbarians elucidates what Primo Levi deems the 'paradoxical' task of testimony: that suffering can only be fully narrated by the sufferer themselves, whose voice and narrative capacity is often foreclosed by the very extent of their trauma. By examining the fictional Magistrate's position as both a reader and translator of history, this paper posits Waiting for the Barbarians as an ethical command against the appropriation of trauma.

Keywords: ethical criticism, limit-experience, postcolonialism, psychic trauma in literature, testimony

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13 Pueblos Mágicos in Mexico: The Loss of Intangible Cultural Heritage and Cultural Tourism

Authors: Claudia Rodriguez-Espinosa, Erika Elizabeth Pérez Múzquiz

Abstract:

Since the creation of the “Pueblos Mágicos” program in 2001, a series of social and cultural events had directly affected the heritage conservation of the 121 registered localities until 2018, when the federal government terminated the program. Many studies have been carried out that seek to analyze from different perspectives and disciplines the consequences that these appointments have generated in the “Pueblos Mágicos.” Multidisciplinary groups such as the one headed by Carmen Valverde and Liliana López Levi, have brought together specialists from all over the Mexican Republic to create a set of diagnoses of most of these settlements, and although each one has unique specificities, there is a constant in most of them that has to do with the loss of cultural heritage and that is related to transculturality. There are several factors identified that have fostered a cultural loss, as a direct reflection of the economic crisis that prevails in Mexico. It is important to remember that the origin of this program had as its main objective to promote the growth and development of local economies since one of the conditions for entering the program is that they have less than 20,000 inhabitants. With this goal in mind, one of the first actions that many “Pueblos Mágicos” carried out was to improve or create an infrastructure to receive both national and foreign tourists since this was practically non-existent. Creating hotels, restaurants, cafes, training certified tour guides, among other actions, have led to one of the great problems they face: globalization. Although by itself it is not bad, its impact in many cases has been negative for heritage conservation. The entry into and contact with new cultures has led to the undervaluation of cultural traditions, their transformation and even their total loss. This work seeks to present specific cases of transformation and loss of cultural heritage, as well as to reflect on the problem and propose scenarios in which the negative effects can be reversed. For this text, 36 “Pueblos Mágicos” have been selected for study, based on those settlements that are cited in volumes I and IV (the first and last of the collection) of the series produced by the multidisciplinary group led by Carmen Valverde and Liliana López Levi (researchers from UNAM and UAM Xochimilco respectively) in the project supported by CONACyT entitled “Pueblos Mágicos. An interdisciplinary vision”, of which we are part. This sample is considered representative since it forms 30% of the total of 121 “Pueblos Mágicos” existing at that moment. With this information, the elements of its intangible heritage loss or transformation have been identified in every chapter based on the texts written by the participants of that project. Finally, this text shows an analysis of the effects that this federal program, as a public policy applied to 132 populations, has had on the conservation or transformation of the intangible cultural heritage of the “Pueblos Mágicos.” Transculturality, globalization, the creation of identities and the desire to increase the flow of tourists have impacted the changes that traditions (main intangible cultural heritage) have had in the 18 years that the federal program lasted.

Keywords: public policies, cultural tourism, heritage preservation, pueblos mágicos program

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12 Impact of Brand Image, Brand Personality and Brand Love on Word of Mouth: Pakistani Fashion Brands

Authors: Amna Asif, Rabia Naseem

Abstract:

In the domain of consumer-brand relationship, love for a fashion brand is a dominant idea. Brand executives incline to build more endearing brands, for example, Levi’s “Quality never goes out of style”. Though, the significance of this notion is not often debated in the literature of marketing. Moreover, the effect of brand image and personality on brand love has not been examined in any quantitative study in Pakistan. The current research aims to fill this study gap by evolving a causal framework integrating word-of-mouth, brand love, image, and personality to examine the relationships among them. Data was gathered through questionnaires survey, and it was filled by 409 university students. AMOS 20 was used to draw a path analysis and test the hypotheses. Results discovered that brand personality and brand image leads to brand love that ultimately impacts word-of-mouth. Results give thorough suggestions on which future research can be constructed.

Keywords: brand love, brand personality, brand image, fashion brands, word-of-mouth

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11 Removal of Heavy Metals from Water in the Presence of Organic Wastes: Fruit Peels

Authors: Özge Yılmaz Gel, Berk Kılıç, Derin Dalgıç, Ela Mia Sevilla Levi, Ömer Aydın

Abstract:

In this experiment, our goal was to remove heavy metals from water. Most recent studies have used removing toxic heavy elements: Cu⁺², Cr⁺³ and Fe⁺³ ions from aqueous solutions has been previously investigated with different kinds of plants like kiwi and tangerines. However, in this study, three different fruit peels were used. We tested banana, peach, and potato peels to remove heavy metal ions from their solution. The first step of the experiment was to wash the peels with distilled water and then dry the peels in an oven for 48 hrs at 80°C. Once the peels were washed and dried, 0.2 grams were weighed and added into 200 mL of %0.1 percent heavy metal solutions by mass. The mixing process was done via a magnetic stirrer. Each sample was taken in 15-minute intervals, and absorbance changes of the solutions were detected using a UV-Vis Spectrophotometer. Among the used waste products, banana peel was the most efficient one. Moreover, the amount of fruit peel, pH values of the initial heavy metal solution, and initial concentration of heavy metal solutions were investigated to determine the effect of fruit peels.

Keywords: absorbance, heavy metal, removal of heavy metals, fruit peels

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10 Controlling the Expense of Political Contests Using a Modified N-Players Tullock’s Model

Authors: C. Cohen, O. Levi

Abstract:

This work introduces a generalization of the classical Tullock’s model of one-stage contests under complete information with multiple unlimited numbers of contestants. In classical Tullock’s model, the contest winner is not necessarily the highest bidder. Instead, the winner is determined according to a draw in which the winning probabilities are the relative contestants’ efforts. The Tullock modeling fits well political contests, in which the winner is not necessarily the highest effort contestant. This work presents a modified model which uses a simple non-discriminating rule, namely, a parameter to influence the total costs planned for an election, for example, the contest designer can control the contestants' efforts. The winner pays a fee, and the losers are reimbursed the same amount. Our proposed model includes a mechanism that controls the efforts exerted and balances competition, creating a tighter, less predictable and more interesting contest. Additionally, the proposed model follows the fairness criterion in the sense that it does not alter the contestants' probabilities of winning compared to the classic Tullock’s model. We provide an analytic solution for the contestant's optimal effort and expected reward.

Keywords: contests, Tullock's model, political elections, control expenses

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9 Comparison of Techniques for Detection and Diagnosis of Eccentricity in the Air-Gap Fault in Induction Motors

Authors: Abrahão S. Fontes, Carlos A. V. Cardoso, Levi P. B. Oliveira

Abstract:

The induction motors are used worldwide in various industries. Several maintenance techniques are applied to increase the operating time and the lifespan of these motors. Among these, the predictive maintenance techniques such as Motor Current Signature Analysis (MCSA), Motor Square Current Signature Analysis (MSCSA), Park's Vector Approach (PVA) and Park's Vector Square Modulus (PVSM) are used to detect and diagnose faults in electric motors, characterized by patterns in the stator current frequency spectrum. In this article, these techniques are applied and compared on a real motor, which has the fault of eccentricity in the air-gap. It was used as a theoretical model of an electric induction motor without fault in order to assist comparison between the stator current frequency spectrum patterns with and without faults. Metrics were purposed and applied to evaluate the sensitivity of each technique fault detection. The results presented here show that the above techniques are suitable for the fault of eccentricity in the air gap, whose comparison between these showed the suitability of each one.

Keywords: eccentricity in the air-gap, fault diagnosis, induction motors, predictive maintenance

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8 Waste Identification Diagrams Effectiveness: A Case Study in the Manaus Industrial Pole

Authors: José Dinis-Carvalho, Levi Guimarães, Celina Leão, Rui Sousa, Rosa Eliza Vieira, Larissa Thomaz, Kelliane Guerreiro

Abstract:

This research paper investigates the efficacy of waste identification diagrams (WIDs) as a tool for waste reduction and management within the Manaus Industrial Pole. The study focuses on assessing the practical application and effectiveness of WIDs in identifying, categorizing, and mitigating various forms of waste generated across industrial processes. Employing a mixed-methods approach, including a qualitative questionnaire applied to 5 companies and quantitative data analysis with SPSS statistical software, the research evaluates the implementation and impact of WIDs on waste reduction practices in select industries within the Manaus Industrial Pole. The findings contribute to understanding the utility of WIDs as a proactive strategy for waste management, offering insights into their potential for fostering sustainable practices and promoting environmental stewardship in industrial settings. The study also discusses challenges, best practices, and recommendations for optimizing the utilization of WIDs in industrial waste management, thereby addressing the broader implications for sustainable industrial development.

Keywords: waste identification diagram, value stream mapping, overall equipment effectiveness, lean manufacturing

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7 How Unicode Glyphs Revolutionized the Way We Communicate

Authors: Levi Corallo

Abstract:

Typed language made by humans on computers and cell phones has made a significant distinction from previous modes of written language exchanges. While acronyms remain one of the most predominant markings of typed language, another and perhaps more recent revolution in the way humans communicate has been with the use of symbols or glyphs, primarily Emojis—globally introduced on the iPhone keyboard by Apple in 2008. This paper seeks to analyze the use of symbols in typed communication from both a linguistic and machine learning perspective. The Unicode system will be explored and methods of encoding will be juxtaposed with the current machine and human perception. Topics in how typed symbol usage exists in conversation will be explored as well as topics across current research methods dealing with Emojis like sentiment analysis, predictive text models, and so on. This study proposes that sequential analysis is a significant feature for analyzing unicode characters in a corpus with machine learning. Current models that are trying to learn or translate the meaning of Emojis should be starting to learn using bi- and tri-grams of Emoji, as well as observing the relationship between combinations of different Emoji in tandem. The sociolinguistics of an entire new vernacular of language referred to here as ‘typed language’ will also be delineated across my analysis with unicode glyphs from both a semantic and technical perspective.

Keywords: unicode, text symbols, emojis, glyphs, communication

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6 Novel Method of In-Situ Tracking of Mechanical Changes in Composite Electrodes during Charging-Discharging by QCM-D

Authors: M. D. Levi, Netanel Shpigel, Sergey Sigalov, Gregory Salitra, Leonid Daikhin, Doron Aurbach

Abstract:

We have developed an in-situ method for tracking ions adsorption into composite nanoporous carbon electrodes based on quartz-crystal microbalance (QCM). In these first papers QCM was used as a simple gravimetric probe of compositional changes in carbon porous composite electrodes during their charging since variation of the electrode potential did not change significantly width of the resonance. In contrast, when we passed from nanoporous carbons to a composite Li-ion battery material such as LiFePO4 olivine, the change in the resonance width was comparable with change of the resonance frequency (polymeric binder PVdF was shown to be completely rigid when used in aqueous solutions). We have provided a quantitative hydrodynamic admittance model of ion-insertion processes into electrode host accompanied by intercalation-induced dimensional changes of electrode particles, and hence the entire electrode coating. The change in electrode deformation and the related porosity modify hydrodynamic solid-liquid interactions tracked by QCM with dissipation monitoring. Using admittance modeling, we are able to evaluate the changes of effective thickness and permeability/porosity of composite electrode caused by applied potential and as a function of cycle number. This unique non-destructive technique may have great advantage in early diagnostics of cycling life durability of batteries and supercapacitors.

Keywords: Li-ion batteries, particles deformations, QCM-D, viscoelasticity

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5 Development of a Classification Model for Value-Added and Non-Value-Added Operations in Retail Logistics: Insights from a Supermarket Case Study

Authors: Helena Macedo, Larissa Tomaz, Levi Guimarães, Luís Cerqueira-Pinto, José Dinis-Carvalho

Abstract:

In the context of retail logistics, the pursuit of operational efficiency and cost optimization involves a rigorous distinction between value-added and non-value-added activities. In today's competitive market, optimizing efficiency and reducing operational costs are paramount for retail businesses. This research paper focuses on the development of a classification model adapted to the retail sector, specifically examining internal logistics processes. Based on a comprehensive analysis conducted in a retail supermarket located in the north of Portugal, which covered various aspects of internal retail logistics, this study questions the concept of value and the definition of wastes traditionally applied in a manufacturing context and proposes a new way to assess activities in the context of internal logistics. This study combines quantitative data analysis with qualitative evaluations. The proposed classification model offers a systematic approach to categorize operations within the retail logistics chain, providing actionable insights for decision-makers to streamline processes, enhance productivity, and allocate resources more effectively. This model contributes not only to academic discourse but also serves as a practical tool for retail businesses, aiding in the enhancement of their internal logistics dynamics.

Keywords: lean retail, lean logisitcs, retail logistics, value-added and non-value-added

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4 Analyzing the Place of Technology in Communication: Case Study of Kenya during COVID-19

Authors: Josephine K. Mule, Levi Obonyo

Abstract:

Technology has changed human life over time. The COVID-19 pandemic has altered the work set-up, the school system, the shopping experience, church attendance, and even the way athletes train in Kenya. Although the use of technology to communicate and maintain interactions has been on the rise in the last 30 years, the uptake during the COVID-19 pandemic has been unprecedented. Traditionally, ‘paid’ work has been considered to take place outside the “home house” but COVID-19 has resulted in what is now being referred to as “the world’s largest work-from-home experiment” with up to 43 percent of employees working at least some of the time remotely. This study was conducted on 90 respondents from across remote work set-ups, school systems, merchants and customers of online shopping, church leaders and congregants and athletes, and their coaches. Data were collected by questionnaires and interviews that were conducted online. The data is based on the first three months since the first case of coronavirus was reported in Kenya. This study found that the use of technology is in the center of working remotely with work interactions being propelled on various online platforms including, Zoom, Microsoft Teams, and Google Meet, among others. The school system has also integrated the use of technology, including students defending their thesis/dissertations online and university graduations being conducted virtually. Kenya is known for its long-distance runners, due to the directives to reduce interactions; coaches have taken to providing their athletes with guidance on training on social media using applications such as WhatsApp. More local stores are now offering the shopping online option to their customers. Churches have also felt the brunt of the situation, especially because of the restrictions on crowds resulting in online services becoming more popular in 2020 than ever before. Artists, innovatively have started online musical concerts. The findings indicate that one of the outcomes in the Kenyan society that is evident as a result of the COVID-19 period is a population that is using technology more to communicate and get work done. Vices that have thrived in this season where the use of technology has increased, include the spreading of rumors on social media and cyberbullying. The place of technology seems to have been cemented by demand during this period.

Keywords: communication, coronavirus, COVID-19, Kenya, technology

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3 Examining the European Central Bank's Marginal Attention to Human Rights Concerns during the Eurozone Crisis through the Lens of Organizational Culture

Authors: Hila Levi

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Respect for human rights is a fundamental element of the European Union's (EU) identity and law. Surprisingly, however, the protection of human rights has been significantly restricted in the austerity programs ordered by the International Monetary Fund (IMF), the European Central Bank (ECB) and the European Commission (EC) (often labeled 'the Troika') in return for financial aid to the crisis-hit countries. This paper focuses on the role of the ECB in the crisis management. While other international financial institutions, such as the IMF or the World Bank, may opt to neglect human rights obligations, one might expect a greater respect of human rights from the ECB, which is bound by the EU Charter of Fundamental Rights. However, this paper argues that ECB officials made no significant effort to protect human rights or strike an adequate balance between competing financial and human rights needs while coping with the crisis. ECB officials were preoccupied with the need to stabilize the economy and prevent a collapse of the Eurozone, and paid only marginal attention to human rights concerns in the design and implementation of Troikas' programs. This paper explores the role of Organizational Culture (OC) in explaining this marginalization. While International Relations (IR) research on Intergovernmental Organizations (IGOs) behavior has traditionally focused on external interests of powerful member states, and on national and economic considerations, this study focuses on particular institutions' internal factors and independent processes. OC characteristics have been identified in OC literature as an important determinant of organizational behavior. This paper suggests that cultural characteristics are also vital for the examination of IGOs, and particularly for understanding the ECB's behavior during the crisis. In order to assess the OC of the ECB and the impact it had on its policies and decisions during the Eurozone crisis, the paper uses the results of numerous qualitative interviews conducted with high-ranking officials and staff members of the ECB involved in the crisis management. It further reviews primary sources of the ECB (such as ECB statutes, and the Memoranda of Understanding signed between the crisis countries and the Troika), and secondary sources (such as the report of the UN High Commissioner for Human Rights on Austerity measures and economic, social, and cultural rights). It thus analyzes the interaction between the ECBs culture and the almost complete absence of human rights considerations in the Eurozone crisis resolution scheme. This paper highlights the importance and influence of internal ideational factors on IGOs behavior. From a more practical perspective, this paper may contribute to understanding one of the obstacles in the process of human rights implementation in international organizations, and provide instruments for better protection of social and economic rights.

Keywords: European central bank, eurozone crisis, intergovernmental organizations, organizational culture

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2 A Second Chance to Live and Move: Lumbosacral Spinal Cord Ischemia-Infarction after Cardiac Arrest and the Artery of Adamkiewicz

Authors: Anna Demian, Levi Howard, L. Ng, Leslie Simon, Mark Dragon, A. Desai, Timothy Devlantes, W. David Freeman

Abstract:

Introduction: Out-of-hospital cardiac arrest (OHCA) can carry a high mortality. For survivors, the most common complication is hypoxic-ischemic brain injury (HIBI). Rarely, lumbosacral spinal cord and/or other spinal cord artery ischemia can occur due to anatomic variation and variable mean arterial pressure after the return of spontaneous circulation. We present a case of an OHCA survivor who later woke up with bilateral leg weakness with preserved sensation (ASIA grade B, L2 level). Methods: We describe a clinical, radiographic, and laboratory presentation, as well as a National Library of Medicine (NLM) search engine methodology, characterizing incidence/prevalence of this entity is discussed. A 70-year-old male, a longtime smoker, and alcohol user, suddenly collapsed at a bar surrounded by friends. He had complained of chest pain before collapsing. 911 was called. EMS arrived, and the patient was in pulseless electrical activity (PEA), cardiopulmonary resuscitation (CPR) was initiated, and the patient was intubated, and a LUCAS device was applied for continuous, high-quality CPR in the field by EMS. In the ED, central lines were placed, and thrombolysis was administered for a suspected Pulmonary Embolism (PE). It was a prolonged code that lasted 90 minutes. The code continued with the eventual return of spontaneous circulation. The patient was placed on an epinephrine and norepinephrine drip to maintain blood pressure. ECHO was performed and showed a “D-shaped” ventricle worrisome for PE as well as an ejection fraction around 30%. A CT with PE protocol was performed and confirmed bilateral PE. Results: The patient woke up 24 hours later, following commands, and was extubated. He was found paraplegic below L2 with preserved sensation, with hypotonia and areflexia consistent with “spinal shock” or anterior spinal cord syndrome. MRI thoracic and lumbar spine showed a conus medullaris level spinal cord infarction. The patient was given IV steroids upon initial discovery of cord infarct. NLM search using “cardiac arrest” and “spinal cord infarction” revealed 57 results, with only 8 review articles. Risk factors include age, atherosclerotic disease, and intraaortic balloon pump placement. AoA (Artery of Adamkiewicz) anatomic variation along with existing atherosclerotic factors and low perfusion were also known risk factors. Conclusion: Acute paraplegia from anterior spinal cord infarction of the AoA territory after cardiac arrest is rare. Larger prospective, multicenter trials are needed to examine potential interventions of hypothermia, lumbar drains, which are sometimes used in aortic surgery to reduce ischemia and/or other neuroprotectants.

Keywords: cardiac arrest, spinal cord infarction, artery of Adamkiewicz, paraplegia

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1 Relevance of Dosing Time for Everolimus Toxicity in Respect to the Circadian P-Glycoprotein Expression in Mdr1a::Luc Mice

Authors: Narin Ozturk, Xiao-Mei Li, Sylvie Giachetti, Francis Levi, Alper Okyar

Abstract:

P-glycoprotein (P-gp, MDR1, ABCB1) is a transmembrane protein acting as an ATP-dependent efflux pump and functions as a biological barrier by extruding drugs and xenobiotics out of cells in healthy tissues especially in intestines, liver and brain as well as in tumor cells. The circadian timing system controls a variety of biological functions in mammals including xenobiotic metabolism and detoxification, proliferation and cell cycle events, and may affect pharmacokinetics, toxicity and efficacy of drugs. Selective mTOR (mammalian target of rapamycin) inhibitor everolimus is an immunosuppressant and anticancer drug that is active against many cancers, and its pharmacokinetics depend on P-gp. The aim of this study was to investigate the dosing time-dependent toxicity of everolimus with respect to the intestinal P-gp expression rhythms in mdr1a::Luc mice using Real Time-Biolumicorder (RT-BIO) System. Mdr1a::Luc male mice were synchronized with 12 h of Light and 12 h of Dark (LD12:12, with Zeitgeber Time 0 – ZT0 – corresponding Light onset). After 1-week baseline recordings, everolimus (5 mg/kg/day x 14 days) was administered orally at ZT1-resting period- and ZT13-activity period- to mdr1a::Luc mice singly housed in an innovative monitoring device, Real Time-Biolumicorder units which let us monitor real-time and long-term gene expression in freely moving mice. D-luciferin (1.5 mg/mL) was dissolved in drinking water. Mouse intestinal mdr1a::Luc oscillation profile reflecting P-gp gene expression and locomotor activity pattern were recorded every minute with the photomultiplier tube and infrared sensor respectively. General behavior and clinical signs were monitored, and body weight was measured every day as an index of toxicity. Drug-induced body weight change was expressed relative to body weight on the initial treatment day. Statistical significance of differences between groups was validated with ANOVA. Circadian rhythms were validated with Cosinor Analysis. Everolimus toxicity changed as a function of drug timing, which was least following dosing at ZT13, near the onset of the activity span in male mice. Mean body weight loss was nearly twice as large in mice treated with 5 mg/kg everolimus at ZT1 as compared to ZT13 (8.9% vs. 5.4%; ANOVA, p < 0.001). Based on the body weight loss and clinical signs upon everolimus treatment, tolerability for the drug was best following dosing at ZT13. Both rest-activity and mdr1a::Luc expression displayed stable 24-h periodic rhythms before everolimus and in both vehicle-treated controls. Real-time bioluminescence pattern of mdr1a revealed a circadian rhythm with a 24-h period with an acrophase at ZT16 (Cosinor, p < 0.001). Mdr1a expression remained rhythmic in everolimus-treated mice, whereas down-regulation was observed in P-gp expression in 2 of 4 mice. The study identified the circadian pattern of intestinal P-gp expression with an unprecedented precision. The circadian timing depending on the P-gp expression rhythms may play a crucial role in the tolerability/toxicity of everolimus. The circadian changes in mdr1a genes deserve further studies regarding their relevance for in vitro and in vivo chronotolerance of mdr1a-transported anticancer drugs. Chronotherapy with P-gp-effluxed anticancer drugs could then be applied according to their rhythmic patterns in host and tumor to jointly maximize treatment efficacy and minimize toxicity.

Keywords: circadian rhythm, chronotoxicity, everolimus, mdr1a::Luc mice, p-glycoprotein

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