Localisation, activity and targeting of Bcr-Abl in chronic myeloid leukaemia

Chronic myeloid leukaemia (CML) is a myeloproliferative disease of stem cell origin. It is characterised by the Philadelphia chromosome and Bcr-Abl oncoprotein which is a constitutively activated tyrosine kinase that is causative in CML. Treatment of CML was revolutionized by tyrosine kinase inhibitors (TKIs) in the last decade. TKIs target Bcr-Abl and block its tyrosine kinase activity. Despite the success of TKI in eliminating differentiated CML cells, primitive quiescent CML stem cells still resist or persist with TKI treatment. In this study, several strategies have been investigated towards elimination of TKI-insensitive primitive CML stem cells. At first, the effect of nuclear entrapment of Bcr-Abl protein in CML cells was studied. Although Bcr-Abl protein is located in the cytoplasm of CML cells, TKIs, such as imatinib mesylate (IM), can induce the nuclear translocation of Bcr-Abl. Nuclear Bcr-Abl tyrosine kinase is capable of inducing apoptosis after drug washout, and leptomycin B (LMB) can trap translocated Bcr-Abl in the nucleus. Primary CML CD34+ cells were treated with IM and LMB either continuously or sequentially. It was found that neither regimen significantly increased the anti-proliferative effect of IM in primary CML CD34+ cells. It was also observed that the majority of Bcr-Abl was still retained in the cytoplasm of CML cells treated with IM and LMB, suggesting other mechanisms apart from its tyrosine kinase activity retained Bcr-Abl protein in the cytoplasm of CML cells. Next the subcellular distribution of Bcr-Abl was investigated in TKI-insensitive CML progenitors which survived 12-Day treatment of a potent TKI dasatinib (150nM). It was demonstrated that about 50% of Bcr-Abl was still retained in the cytoplasm of TKI-insensitive primary CML progenitors, although there was a significant increase in nuclear Bcr-Abl level in these survived cells compared to the no drug control (NDC). It was hypothesised that the cytoplasmic retention of Bcr-Abl was caused by its cytoplasmic binding partners, and it was found that a proportion of Bcr-Abl protein was associated with 14-3-3 proteins in the surviving cells, indicating the cytoplasmic retention of Bcr-Abl might be due to its binding with 14-3-3 proteins. In addition, due to the rapid nature of kinase inhibition and nuclear transportation, studies are required to measure the earliest time-point of inhibition of Bcr-Abl tyrosine kinase by IM. The common method to do this is to employ p-CrkL which has been widely used as a surrogate marker of Bcr-Abl tyrosine kinase activity, but the accuracy of p-CrkL as an indicator of Bcr-Abl tyrosine kinase status at early time-points during in vitro TKI treatment has not been examined. It was demonstrated that p-CrkL was not a reliable indicator of Bcr-Abl kinase activity within 24 hours of IM treatment in vitro and indicated that the early responses to IM and dasatinib were different. It was also observed that there was a rapid and active dephosphorylation of Bcr-Abl within 1 hour of TKI treatment, driven at least in part by protein tyrosine phosphatase activity. Furthermore, a farnesyltransferase inhibitor (FTI) BMS-214662 preferentially induces apoptosis in CML stem and progenitor cells compared to their normal counterparts, but another similar FTI BMS-225975 does not. However, the mechanism of action of BMS-214662 in inducing apoptosis of CML cells is not clear. When BMS-214662 was used as a negative control in the p-CrkL study, it was unexpectedly observed that the drug accumulated Bcr-Abl protein in CML cells. Thus, it was hypothesised that BMS-214662 may function as a proteasome inhibitor, which could result in accumulation of Bcr-Abl protein and further elevation of intracellular ROS level, leading to apoptosis of CML cells. Although BMS-214662 treatment induced accumulation of total ubiquitinated proteins and specifically Bcr-Abl protein in K562 cells, BMS-225975 had very similar effects, and this might result from the common mechanism of BMS-214662 and BMS-225975, which is their FTI activity. On the other hand, BMS-214662 induced significantly higher levels of intracellular ROS in both proliferating and non-proliferating K562 cells with respect to BMS-225975, indicating the production of ROS may be involved in the non-FTI mechanism of action of BMS-214662. However it was concluded that BMS-214662 was not a proteasome inhibitor like bortezomib. Finally, the use of synthetic low density lipoprotein (sLDL) as a vehicle for drug delivery to overcome the insufficient intracellular drug concentration in CML stem cells was investigated. Uptake and internalization of unloaded sLDL particles by CML cell line K562 and for the first time by CML stem cells was observed, demonstrating the targeting potential of sLDL particles in CML when they are loaded with drugs. Overall, this study provides further understanding of CML treatment and identifies some alternative strategies to target CML stem cells that may be used in combination with TKI to enhance the eradication of this stem cell-driven disease

The significance of M1 macrophage should be highlighted in peripheral nerve regeneration

Macrophage influences peripheral nerve regeneration. According to the classical M1/M2 paradigm, the M1 macrophage is an inhibitor of regeneration, while the M2 macrophage is a promoter. However, several studies have shown that M1 macrophages are indispensable for peripheral nerve repair and facilitate many critical processes in axonal regeneration. In this review, we summarized the information on macrophage polarization and focused on the activities of M1 macrophages in regeneration. We also provided some examples where the macrophage phenotypes were regulated to help regeneration. We argued that the coordination of both macrophage phenotypes might be effective in peripheral nerve repair, and a more comprehensive view of macrophages might contribute to macrophage-based immunomodulatory therapies

Diversity and Adaptation in Large Population Games

We consider a version of large population games whose players compete for resources using strategies with adaptable preferences. The system efficiency is measured by the variance of the decisions. In the regime where the system can be plagued by the maladaptive behavior of the players, we find that diversity among the players improves the system efficiency, though it slows the convergence to the steady state. Diversity causes a mild spread of resources at the transient state, but reduces the uneven distribution of resources in the steady state.Comment: 8 pages, 3 figure

Testing Multi-Subroutine Quantum Programs: From Unit Testing to Integration Testing

Quantum computing has emerged as a promising field with the potential to revolutionize various domains by harnessing the principles of quantum mechanics. As quantum hardware and algorithms continue to advance, the development of high-quality quantum software has become crucial. However, testing quantum programs poses unique challenges due to the distinctive characteristics of quantum systems and the complexity of multi-subroutine programs. In this paper, we address the specific testing requirements of multi-subroutine quantum programs. We begin by investigating critical properties through a survey of existing quantum libraries, providing insights into the challenges associated with testing these programs. Building upon this understanding, we present a systematic testing process tailored to the intricacies of quantum programming. The process covers unit testing and integration testing, with a focus on aspects such as IO analysis, quantum relation checking, structural testing, behavior testing, and test case generation. We also introduce novel testing principles and criteria to guide the testing process. To evaluate our proposed approach, we conduct comprehensive testing on typical quantum subroutines, including diverse mutations and randomized inputs. The analysis of failures provides valuable insights into the effectiveness of our testing methodology. Additionally, we present case studies on representative multi-subroutine quantum programs, demonstrating the practical application and effectiveness of our proposed testing processes, principles, and criteria.Comment: 53 page

Unitarity estimation for quantum channels

The unitarity is a measure giving information on how much a quantum channel is unitary. Learning the unitarity of an unknown quantum channel $\mathcal{E}$ is a basic and important task in quantum device certification and benchmarking. Generally, this task can be performed with either coherent or incoherent access. For coherent access, there are no restrictions on learning algorithms; while for incoherent access, at each time, after preparing the input state and applying $\mathcal{E}$, the output is measured such that no coherent quantum information can survive or be acted upon by $\mathcal{E}$ again. Quantum algorithms with only incoherent access allow practical implementations without the use of persistent quantum memory, and thus is more suitable for near-term devices. In this paper, we study unitarity estimation in both settings. For coherent access, we provide an ancilla-efficient algorithm that uses $O(\epsilon^{-2})$ calls to $\mathcal{E}$ where $\epsilon$ is the required precision; we show that this algorithm is query-optimal, giving a matching lower bound $\Omega(\epsilon^{-2})$. For incoherent access, we provide a non-adaptive, non-ancilla-assisted algorithm that uses $O(\sqrt{d}\cdot \epsilon^{-2})$ calls to $\mathcal{E}$, where $d$ is the dimension of the system that $\mathcal{E}$ acts on; we show that this algorithm cannot be substantially improved, giving an $\Omega(\sqrt{d}+\epsilon^{-2})$ lower bound, even if adaptive strategies and ancilla systems are allowed. As part of our results, we settle the query complexity of the distinguishing problem for depolarizing and unitary channels with incoherent access by giving a matching lower bound $\Omega(\sqrt{d})$, improving the prior best lower bound $\Omega(\sqrt[3]{d})$ by Aharonov, Cotler, and Qi (Nat. Commun. 2022) and Chen, Cotler, Huang, and Li (FOCS 2021).Comment: 35 page

Prompt: Probability-Conserved Cross Section Biasing Monte Carlo Particle Transport System

An open source software package for simulating thermal neutron propagation in geometry is presented. In this system, neutron propagation can be treated by either the particle transport method or the ray-tracing method. Supported by an accurate backend scattering physics engine, this system is capable of reproducing neutron scattering experiments in complex geometries and is expected to be used in the areas of instrument characterisation, optimisation and data analysis. In this paper, the relevant theories are briefly introduced. The simulation flow and the user input syntax to control it are provided in detail. Five benchmarking simulations, focusing on different aspects of simulation and scattering techniques, are given to demonstrate the applications of this simulation system. They include an idealised total scattering instrument, a monochromatic powder diffractometer, a neutron guide, a chopper and an imaging setup for complex geometries. Simulated results are benchmarked against experimental data or well-established software packages when appropriate. Good agreements are observed.Comment: 71 pages, 32 figure

ЭКСПЕРИМЕНТАЛЬНОЕ ИЗУЧЕНИЕ ТЕПЛОВЫХ И ДЕФОРМАЦИОННЫХ ПОЛЕЙ В ПРОЦЕССЕ РАЗРУШЕНИЯ ЭШЕЛОНИРОВАННЫХ РАЗЛОМОВ И ИЗМЕНЕНИЯ ГЕОЛОГИЧЕСКИХ УСЛОВИЙ

The article presents results of experimental studies using a bi-axial servo-control system to apply load on samples with extensional and compressional en echelon faults. During the experiments, variations of temperature and thermal images were recorded synchronously by a multi-path contact-type thermometric apparatus and a thermal image system, respectively. A digital CCD camera was employed to synchronously collect images of specimens’ surfaces. The digital speckle correlation method (DSCM) was utilized to analyze the images and to define displacements and strain fields. Our experimental results show that temperature fields have clear responses to opposite stress states in the jog areas of both types of the en echelon faults. Prior to failure of the jog area, its temperature is the highest at the compressional en echelon faults and the lowest at the extensional en echelon faults. Records by DSCM give evidence that mean strain of the jog area is the highest at compressional en echelon faults and the lowest at the extensional en echelon faults. It is revealed that deformation of the en echelon faults occurs in two stages, developing from stress build-up and fault propagation in the jog area to unstable sliding along the fault. Correspondingly, the mechanism of heating-up converts from strain heating into friction heating. During the period of transformation of the temperature rising mechanism, three events are observed in the jog area and its vicinity. Analyses of our experimental results demonstrate that variations of temperatures in the jog area can be indicative of fault sliding and suggest sliding directions. Observations and studies of temperature changes during transformation of the temperature rising mechanism at sensitive portions of faults are of great importance for early detection of precursors of unstable slip on active faults.В статье представлены результаты экспериментального изучения эшелонированных разломов растяжения и сжатия с приложением нагрузки к двуосной автоматически регулируемой модели. В ходе эксперимента производились синхронные замеры температур и тепловых сигналов. Для этого были использованы, соответственно, многоканальный термометрический прибор контактного типа и система регистрации тепловых сигналов. Синхронные снимки поверхностей экспериментальных образцов были получены при помощи цифровой видеокамеры на основе устройства с зарядовой связью. Был применен цифровой метод спекл-корреляции (DSCM) для анализа снимков и определения смещений и деформационных полей. Была установлена очевидная реакция тепловых полей на состояния напряжения противоположных типов в зонах сочленения эшелонированных разломов обоих типов. Перед полным разрушением зоны сочленения самые высокие значения температуры зарегистрированы на эшелонированных разломах сжатия, самые низкие – на эшелонированных разломах растяжения. С помощью метода DSCM самые высокие значения среднего напряжения в зоне сочленения дислокаций зарегистрированы на эшелонированных разломах сжатия, самые низкие – на эшелонированных разломах растяжения. В процессе деформирования эшелонированных разломов выявлены две стадии, развивающиеся от накопления напряжений и прорастания разлома в зону сочленения дислокаций до неустойчивого скольжения по разлому. Соответственно трансформируется механизм нагревания – с нагревания напряжением до нагревания трением. В самой зоне сочленения дислокаций и поблизости от неё в процессе трансформирования механизма повышения температуры наблюдались три фазы. Анализ полученных нами экспериментальных данных показал, что вариации температуры в зоне сочленения дислокации могут указывать на смещения по разлому и позволяют предположить направление смещения. Наблюдение за изменениями температуры и их изучение в процессе трансформирования механизма повышения температуры на чувствительных отрезках разломов имеют большое значение в плане раннего выявления предвестников неустойчивого смещения по активным разломам