Оценка требуемых скоростей передачи данных при организации беспроводной связи между ядрами центрального процессора

In this paper, a principal architecture of common purpose CPU and its main components are discussed, CPUs evolution is considered and drawbacks that prevent future CPU development are mentioned. Further, solutions proposed so far are addressed and a new CPU architecture is introduced. The proposed architecture is based on wireless cache access that enables a reliable interaction between cores in multicore CPUs using terahertz band, 0.1-10THz. The presented architecture addresses the scalability problem of existing processors and may potentially allow to scale them to tens of cores. As in-depth analysis of the applicability of the suggested architecture requires accurate prediction of traffic in current and next generations of processors, we consider a set of approaches for traffic estimation in modern CPUs discussing their benefits and drawbacks. The authors identify traffic measurements by using existing software tools as the most promising approach for traffic estimation, and they use Intel Performance Counter Monitor for this purpose. Three types of CPU loads are considered including two artificial tests and background system load. For each load type the amount of data transmitted through the L2-L3 interface is reported for various input parameters including the number of active cores and their dependences on the number of cores and operational frequency.Рассматривается современная архитектура процессоров общего назначения, ее основные компоненты, описывается эволюция, а также подчеркиваются проблемы, препятствующие дальнейшему развитию такой архитектуры. Далее рассмотрены предложенные ранее пути развития процессоров, подчеркиваются их недостатки и предлагается новая архитектура, основанная на беспроводном доступе к кеш-памяти в многоядерных процессорах. В основе предлагаемого решения лежит организация надежного обмена данными между кешем третьего уровня и ядрами процессора через беспроводной канал в терагерцовом диапазоне. Таким образом, масштабируемость системы повышается до десятков и, потенциально, сотен ядер. В то же время, детальный анализ применимости предложенного решения требует точного предсказания количества информации, передаваемой между ядрами и кеш-памятью в процессорах текущего и следующего поколения. В данной работе рассматриваются основные подходы к построению оценки количества передаваемых данных, выделены их достоинства и недостатки. Авторы останавливают свой выбор на непосредственных измерениях количества данных с помощью существующих программных инструментов. Для измерений используется программный инструмент Intel Performance Counter Monitor, позволяющей оценить количе- ство данных, передаваемых между кеш-памятью второго и третьего уровней каждого ядра. В работе рассматриваются три варианта нагрузки на ядро – два искусственных теста и фоновая нагрузка от операционной системы. Для каждого типа нагрузки в работе приведены численные значения количества данных, проходящих по шине между кешем второго и третьего уровней, и показана их зависимость от тактовой частоты работы процессора и количества ядер

THE MAIN PARAMETERS OF CELLULAR IMMUNITY IN PATIENTS WITH TRIPLE-NEGATIVE BREAST CANCER: RELATIONSHIP WITH EFFICIENCY OF CHEMOTHERAPY

Chemotherapy is among the primary methods of treating advanced breast cancer. It was shown that clinical efficacy of various chemotherapeutic agents in many cases depends not only on their direct cytostatic and/or cytotoxic effect upon tumor cells, but also on their ability to modulate phenotype of the tumor cells and to influence anti-tumor immune response. Initial state of the immune system and its response to treatment is crucial. Antitumor response involves cells of innate and adaptive immunity (NK, NKT, T cells). These populations are heterogeneous and contain, e.g., cells with antitumor activity and regulatory (suppressor) cells that suppress immune response and promote tumor progression. The aim of this work was to determine the relationship between the initial state of cellular immunity of patients suffering from locally advanced breast cancer with triple negative phenotype, and clinical effect of chemotherapy (cisplatin + doxorubicin/paclitaxel), and studying effects of the therapy upon subpopulation profiles of peripheral blood lymphocytes in the patients. We registered the terms of the disease progression as well as overall survival and progression-free survival. The disease progressed in 25 of 53 cases (47.2%) whereas 28 of 53 patients (52.8%) remained progression-free. The observation period was 35.5 months. Laboratory examination of the patients included immunophenotyping of peripheral blood lymphocytes and determination of NK cell cytotoxic activity before and after chemotherapy. Percentages of effectors and regulatory lymphocyte populations were determined. The results obtained showed that, for some lymphocyte subsets, the pre-treatment differences of cell percentage deviations from control were found between the progression-free groups and patients with progression of the disease. The differences in percentages of NKT cells and lymphocytes expressing CD25 activation marker proved to be most significant. Decreased number of NKT cells and activated CD25+ lymphocytes prior to chemotherapy was associated with increased probability of disease progression. Reduced percentage of NKT cells against control was observed in 56% of patients from the progression group (PD), and only 21.4% in the group free of disease progression (DF). [OR = 4.6 (95% CI 1.4 to 15.4)]. Percentage of CD25+ lymphocytes was decreased from 68.2% in the PD group, and 28.6% for DF patients [OR = 5.4 (95% CI 1.6-18.1)]. We studied relationships between the overall survival (OS) and percentage of perforin-containing NK, NKT, and T cells, and mean perforin fluorescence density (PFD) in these lymphocyte subsets in 26 of the 53 patients before treatment. A statistically significant positive correlation was revealed between OS and perforin PFD in all the three cell populations under study. Normalization of the parameters altered before treatment, and an increase of T cell numbers was observed in the disease-free patients

Противоопухолевая активность кураксина CBL0137 на моделях острых лейкозов in vitro

Background. Curaxin CBL0137 is a novel non-genotoxic compound with anti-cancer activity based on CBL0137 ability of non-covalent interaction with DNA causing histone chaperone FACT relocation. Anti-cancer activity of this drug was demonstrated previously on the wide panel of solid cancer models in vitro and in vivo.Objectives. Estimation of anticancer effects of CBL0137 on the acute myeloblastic leukemia cells (THP-1) and acute lymphoblastic leukemia (CCRF-CEM).Materials and methods. CBL0137 cytotoxicity was analyzed using the MTT test, the effects on the cell cycle and the induction of apoptosis was assessed by flow cytometry, the activity of signaling pathways in cells treated with CBL0137 was determined by real-time polymerase chain reaction.Results. Cell treatment with CBL0137 led to cell cycle arrest and apoptosis induction. In the study of CBL0137 effect on target gene clusters of 10 signal transduction pathways involved in the pathogenesis of acute leukemia we have showed that CBL0137 inhibited the expression of down-stream genes of WNT and Hedgehog signaling in both cell lines. In THP-1 cells we also observed the inhibition of the expression of PPARγ target and hypoxia-activated genes. In CCRF-CEM cells CBL0137 also induced the expression of Notch signaling target genes.Conclusion. The antitumor activity of CBL0137 was demonstrated on acute leukemia cell cultures, the drug possesses cytotoxicity, causes cell cycle arrest and activation of apoptosis. Significant changes in the expression of efferent gene clusters of several signaling pathways were observed in the cells treated with CBL0137.Введение. Кураксин CBL0137 – новое негенотоксичное соединение, обладающее противоопухолевой активностью, в основе которой лежит способность препарата нековалентно взаимодействовать с ДНК, вызывая транслокацию гистонового шаперона FACT в хроматиновую фракцию. Ранее противоопухолевая активность этого агента была продемонстрирована относительно широкого спектра солидных опухолей in vitro и in vivo.Цель исследования – изучение противоопухолевой активности CBL0137 в отношении клеток острого миелобластного лейкоза (THP-1) и острого лимфобластного лейкоза (CCRF-CEM) in vitro.Материалы и методы. Для определения цитотоксичности CBL0137 использовали МТТ-тест, влияние на клеточный цикл и индукцию апоптоза оценивали с помощью проточной цитофлуориметрии, активность функционирования сигнальных путей при действии на клетки CBL0137 определяли с помощью полимеразной цепной реакции в реальном времени.Результаты. Обработка клеток CBL0137 приводит к аресту клеточного цикла и активации апоптоза. При исследовании влияния CBL0137 на кластеры таргетных генов 10 сигнальных путей, вовлеченных в онкогенез острых лейкозов, его ингибирующее действие было выявлено для сигнальных путей WNT и Hedgehog в обеих клеточных линиях. В клеточной линии THP-1 также наблюдалось ингибирование эфферентных генов PPARγ и генов, активирующихся при гипоксии. В клетках CCRF-CEM при действии CBL0137, кроме того, наблюдалось усиление экспрессии всех исследованных таргетных генов сигнального пути Notch.Заключение. На культурах клеток острых лейкозов продемонстрирована противоопухолевая активность CBL0137, препарат обладает цитотоксичностью, вызывает арест клеточного цикла и активацию апоптоза. При действии CBL0137 наблюдаются значительные изменения в экспрессии кластеров эфферентных генов сразу нескольких сигнальных путей

Активация сигнального пути интерферона-альфа ресвератролом, генистеином и кверцетином

Resveratrol, genistein and quercetin from the group of polyphenols from secondary plant metabolites reveal cancer preventive and antivirus effects realized via their pleiotropic influence on the different macromolecules in cells. These compounds can interact with DNA without the formation of covalent bonds. This process is usually followed by changes in spatial, physical-chemical and structural DNA characteristics that can result in disfunction of DNA metabolism enzymes and chromatin destabilization. Similar effects were described for anticancer drug Curaxine CBL0137 in association with activation of interferon-α signaling. We demonstrated dose-dependent stimulating effects of resveratrol, genistein and quercetin on interferon-α signaling using HeLa cells expressed mCherry protein with interferon-stimulated response elements (ISRE) in promoter. Furthermore, it was shown by live-cell fluorescent microscopy in HT1080 cells with mCherry-labeled histone H1.5 that described polyphenols induced the redistribution of this linker histone in cell nuclei. The data obtained suggest an existence of DNA-dependent mechanism of anticancer effects of plant polyphenols and a need for further study of crosslinks between the polyphenols’ influence on chromatin structure and the changes in genome function, in particular, induction of interferon- interferon-α signaling.Ресвератрол, кверцетин и генистеин, относящиеся к полифенолам вторичных метаболитов растений, обладают антиканцерогенным и противовирусным эффектами, реализуемыми в результате их плейотропного действия на различные макромолекулы клетки. Эти соединения могут взаимодействовать с ДНК, не образуя ковалентные связи. При этом может происходить изменение пространственных, физико-химических и структурных характеристик ДНК, что может приводить к нарушению функционирования белков метаболизма ДНК и вызывать дестабилизацию хроматина. Такие эффекты были описаны для нового противоопухолевого препарата Кураксина CBL0137, причем индуцированная данным соединением дестабилизация хроматина приводила к активации сигнального пути интерферона-α. Используя клеточную линию HeLa с трансгенным флуоресцентным белком mCherry, содержащим в промоторной области консенсусный сайт связывания интерферона-α (ISRE), мы продемонстрировали дозозависимый стимулирующий эффект ресвератрола, кверцетина и генистеина на активность сигнального пути интерферона-α. Использование прижизненной флуоресцентной микроскопии на клеточной линии HT1080 c трансгенным флуоресцентно-меченным гистоном H1.5 позволило продемонстрировать, что данные полифенолы вызывают перераспределение данного линкерного гистона в ядрах клеток. Полученные нами данные свидетельствуют о возможности существования ДНК-зависимого механизма реализации противоопухолевого действия растительных полифенолов и необходимости дальнейшего изучения влияния полифенолов на структуру хроматина и связанного с этим изменения функционирования генома, в частности регуляции сигнального пути интерферона-α

RNA-dependent nuclear matrix contains a 33k globin full domain transcript as well as prosomes but no 26S proteasomes

Previously, we have shown that in murine myoblasts prosomes are constituents of the nuclear matrix; a major part of the latter was found to be RNase sensitive. Here, we further define the RNA-dependent matrix in avian erythroblastosis virus (AEV) transformed erythroid cells in relation to its structure, presence of specific RNA, prosomes and/ or proteasomes. These cells transcribe but do not express globin genes prior to induction. Electron micrographs show little difference in matrices treated with DNase alone or with both, DNase and RNase. In situ hybridization with alpha globin riboprobes shows that this matrix includes globin transcripts. Of particular interest is that, apparently, a nearly 35 kb long globin full domain transcript (FDT), including genes, intergenic regions and a large upstream domain is a part of the RNAdependent nuclear matrix. The 23K-type of prosomes, previously shown to be co-localized with globin transcripts in the nuclear RNA processing centers, were found all over the nuclear matrix. Other types of prosomes show different distributions in the intact cell but similar distribution patterns on the matrix. Globin transcripts and at least 80% of prosomes disappear from matrices upon RNase treatment. Interestingly, the 19S proteasome modulator complex is insensitive to RNase treatment. Only 20S prosomes but not 26S proteasomes are thus part of the RNA-dependent nuclear matrix. We suggest that giant pre-mRNA and FDTs in processing, aligning prosomes and other RNA-binding proteins are involved in the organization of the dynamic nuclear matrix. It is proposed that the putative function of RNA within the nuclear matrix and, thus, the nuclear dynamic architecture, might explain the giant size and complex organization of primary transcripts and their introns

Activation of interferon-α signaling by resveratrol, genistein and quercetin

Resveratrol, genistein and quercetin from the group of polyphenols from secondary plant metabolites reveal cancer preventive and antivirus effects realized via their pleiotropic influence on the different macromolecules in cells. These compounds can interact with DNA without the formation of covalent bonds. This process is usually followed by changes in spatial, physical-chemical and structural DNA characteristics that can result in disfunction of DNA metabolism enzymes and chromatin destabilization. Similar effects were described for anticancer drug Curaxine CBL0137 in association with activation of interferon-α signaling. We demonstrated dose-dependent stimulating effects of resveratrol, genistein and quercetin on interferon-α signaling using HeLa cells expressed mCherry protein with interferon-stimulated response elements (ISRE) in promoter. Furthermore, it was shown by live-cell fluorescent microscopy in HT1080 cells with mCherry-labeled histone H1.5 that described polyphenols induced the redistribution of this linker histone in cell nuclei. The data obtained suggest an existence of DNA-dependent mechanism of anticancer effects of plant polyphenols and a need for further study of crosslinks between the polyphenols’ influence on chromatin structure and the changes in genome function, in particular, induction of interferon- interferon-α signaling

Activation of interferon-α signaling by resveratrol, genistein and quercetin

Resveratrol, genistein and quercetin from the group of polyphenols from secondary plant metabolites reveal cancer preventive and antivirus effects realized via their pleiotropic influence on the different macromolecules in cells. These compounds can interact with DNA without the formation of covalent bonds. This process is usually followed by changes in spatial, physical-chemical and structural DNA characteristics that can result in disfunction of DNA metabolism enzymes and chromatin destabilization. Similar effects were described for anticancer drug Curaxine CBL0137 in association with activation of interferon-α signaling. We demonstrated dose-dependent stimulating effects of resveratrol, genistein and quercetin on interferon-α signaling using HeLa cells expressed mCherry protein with interferon-stimulated response elements (ISRE) in promoter. Furthermore, it was shown by live-cell fluorescent microscopy in HT1080 cells with mCherry-labeled histone H1.5 that described polyphenols induced the redistribution of this linker histone in cell nuclei. The data obtained suggest an existence of DNA-dependent mechanism of anticancer effects of plant polyphenols and a need for further study of crosslinks between the polyphenols’ influence on chromatin structure and the changes in genome function, in particular, induction of interferon-interferon-α signaling. © 2019, Tomsk National Research Medical Center of the Russian Academy of Sciences. All rights reserved