State Of Memory Cell Research Articles

Regulation of the Transcriptional Repressor BACH2 Overcomes Tonic Signaling-Driven CAR T Cell Dysfunction

Unlike endogenous T cell receptors (TCRs), chimeric antigen receptors (CARs) have an intrinsic predisposition to initiate intracellular signaling in the absence of target antigen (Long AH, Nature Medicine 2015). This phenomenon, referred to as tonic signaling, has previously been shown to be a potent driver of T cell exhaustion when CARs contain the CD28 costimulatory domain (Lynn R, Nature 2019). We previously showed that, in contrast to CD28, CARs containing the 41BB costimulatory domain acquire enhanced functionality from tonic signaling (Singh N, Nature Medicine 2021). These data indicate that the impact of tonic CAR signaling is directly dependent on the CAR costimulatory domain. To understand the molecular regulators responsible for this divergent functionality, we generated CARs targeting CD22, an established immunotherapy target for B cell malignancies, that contained either CD28 or 41BB costimulatory domains and either did or did not signal tonically (22/28+, 22/BB+, 22/28-, 22/BB-). We confirmed that tonic signaling of CD28 drove impaired cytotoxic function, T cell expansion and cytokine secretion in response to antigen, while tonic 41BB improved all parameters of T cell function. Bulk RNA sequencing of CAR T cell products at the conclusion of manufacturing, when the impact of tonic CAR signaling was predicted to be most impactful, revealed significantly more transcriptional activity in both tonic CARs. Comparison of differentially expressed genes demonstrated that 22/28+ had high expression of targets of NFAT and AP1, transcription factors that promote T cell effector function but are also drivers of T cell exhaustion when persistently active (Martinez GJ, Immunity 2015; Lynn R, Nature 2019). 22/BB+ instead demonstrated high activity of BACH2, a transcriptional repressor that has recently been shown to preserve naïve and memory cell states by antagonizing effector programs (Yao C, Nature Immunology 2021; Roychoudhuri R, Nature Immunology 2016). We generated 22/28+ cells that overexpressed BACH2 (22/28+_BACH2) and found that this intervention completely rescued acute anti-tumor function, with cytotoxic activity of these cells equivalent to 22/BB+. Mass cytometry revealed that 22/28+_BACH2 cells were phenotypically very similar to 22/BB+ cells at the conclusion of manufacturing and after stimulation with target cells, expressing high levels of granzyme B, perforin, IFNγ and markers of memory differentiation. Intriguingly, 22/28+_BACH2 cells expressed very high levels of the transcription factor TCF7, known to play a role in maintaining memory, suggesting that transgenic BACH2 expression play a broad role in lineage regulation. To interrogate how BACH2 overexpression impacted long-term T cell function, we chronically stimulated these cells using our established in vitro protocol (Selli ME, STAR Protocols 2023) in which co-cultures of CAR T cells and tumors are continually replenished with additional tumor to maintain a persistent and high antigen burden. Similar to our previous studies, early function of 22/28+_BACH2 cells was significantly improved over 22/28+ but BACH2 overexpressing cells lost the ability to proliferate and kill tumor cells much earlier than either 22/28+ or 22/BB+. Phenotypic analysis revealed at time of cell failure revealed that almost all 22/28+_BACH2 cells expressed markers of a central memory phenotype (CD62L hiCD45RO hi). Collectively, these data suggest that BACH2 overexpression can overcome tonic CAR signaling-induced dysfunction by antagonizing exhaustion programs but simultaneously “locks” these cells into a memory state with restrained effector function, thus limiting their long-term efficacy.

End-to-end LSTM based estimation of volcano event epicenter localization

Locating sources of volcano-seismic event is very relevant to monitor and comprehend volcanic processes. Ordinary estimation of source seismic events is based on phase picking. The most accurate procedure of phase selection is the visual inspection of the records by experts, who employ local characteristics for phase detection and comparison with observed signals from other stations. This activity is highly time demanding, which in turn is a strong motivation to automatize the epicenter estimation process. However, automatic phase picking in volcano signals is highly inaccurate because of the short distances between the event epicenters and the seismograph stations. In this paper, an end-to-end based LSTM (Long-Short Term Memory) scheme is proposed to address the problem of volcano event localization without any a priori model relating phase picking with localization estimation. LSTM was chosen due to its capability to capture the dynamics of time varying signals, and to remove or add information within the memory cell state and model long-term dependencies. A brief insight into LSTM is also discussed here to justify the use of this neural network. The results presented in this paper show that the LSTM based architecture provided a success rate, i.e., an error smaller than 1.0 km, equal to 48.5%, which in turn is dramatically superior to the one delivered by automatic phase picking. Moreover, the proposed end-to-end LSTM based method gave a success rate (18%) higher than CNN (Convolutional Neural Network). The results presented suggest that the approach proposed here for automatic volcano event epicenter localization can be applied to other geophysics problems.

Role of transcription factor RUNX1 in the maintenance of T helper cell epigenome and rapid recall response

Abstract Memory T cells exhibit an accelerated response after a second encounter with the same antigen. In our previous studies, we showed that the ability to produce effector molecules within minutes of the secondary exposure to antigen (“rapid recall response”) is associated with the epigenetic state of the rapid recall genes. This memory epigenome is established during the primary T cell encounter with its cognate antigen. To maintain a “rapid recall response” even when antigen is eliminated, resting memory T cells would have to maintain open chromatin signature for years despite episodic homeostatic T cell proliferation. However, the mechanisms underlying the long-term maintenance of this epigenetic pattern remains unclear. Here, we used 10X Multiome (scRNA-seq and scATAC-seq obtained from the same cells) analysis to show that the association between the chromatin state of memory cells and their cytokine expression upon activation is Th lineage specific. Bioinformatic analysis showed that open chromatin specific for memory but not naïve CD4 T cells is enriched with motifs of constitutively expressed transcription factors RUNX, SP1, and ETS. Our preliminary Cut&Tag data in total human resting CD4 T cells demonstrates that RUNX1 binds DNA close to T helper cytokines genes (IL3, IL4, IL9, IL10, IL13, IFNG) at “memory-specific” ATAC-seq regions, suggesting the role of RUNX1 in maintaining this “rapid recall” epigenome. Together with the dynamic model of transcriptome and epigenome rearrangements this data could help us to understand how memory T cells establish a platform that enables and maintains their unique ability to respond more rapidly to subsequent encounters with antigen. Supported by R01AI153442-01A1 from NIAID, NIH

Технологии создания радиационно-стойких СБИС

The technology of radiation-resistant CMOS VLSI is based on industrial IC technology. The design uses feedback circuits and guard rings to compensate for single effects of cosmic particles (SEE). In most critical cases, these influences in digital circuits lead to single faults (SEU), which temporarily disrupt the state of memory cells, to latching (SEL), and in the long term to a catastrophic change of state. Various space programs confirm great prospects for their use in future space structures. The article discusses the effects of using radiation-resistant CMOS technology, technology based on a silicon-on-sapphire structure, CMOS technology on an insulating substrate taking into account typical characteristics, SIMOX-SOI technology, which consists in separation by implantation of oxygen ions. In new designs of circuits, more advanced algorithms should be implemented for the future.

Motility Matters: How CD8+ T-Cell Trafficking Influences Effector and Memory Cell Differentiation.

Immunological memory is a hallmark of adaptive immunity that confers long-lasting protection from reinfections. Memory CD8+ T cells provide protection by actively scanning for their cognate antigen and migrating into inflamed tissues. Trafficking patterns of CD8+ T cells are also a major determinant of cell fate outcomes during differentiation into effector and memory cell states. CD8+ T-cell trafficking must therefore be dynamically and tightly regulated to ensure that CD8+ T cells arrive at the correct locations and differentiate to acquire appropriate effector functions. This review aims to discuss the importance of CD8+ T-cell trafficking patterns in regulating effector and memory differentiation, maintenance, and reactivation.

Delineation of a molecularly distinct terminally differentiated memory CD8 T cell population

Memory CD8 T cells provide durable protection against diverse intracellular pathogens and can be broadly segregated into distinct circulating and tissue-resident populations. Paradigmatic studies have demonstrated that circulating memory cells can be further divided into effector memory (Tem) and central memory (Tcm) populations based on discrete functional characteristics. Following resolution of infection, we identified a persisting antigen-specific CD8 T cell population that was terminally fated with potent effector function but maintained memory T cell qualities and conferred robust protection against reinfection. Notably, this terminally differentiated effector memory CD8 T cell population (terminal-Tem) was conflated within the conventional Tem population, prompting redefinition of the classical characteristics of Tem cells. Murine terminal-Tem were transcriptionally, functionally, and developmentally unique compared to Tem cells. Through mass cytometry and single-cell RNA sequencing (RNA-seq) analyses of human peripheral blood from healthy individuals, we also identified an analogous terminal-Tem population of CD8 T cells that was transcriptionally distinct from Tem and Tcm Key findings from this study show that parsing of terminal-Tem from conventionally defined Tem challenge the reported characteristics of Tem biology, including enhanced presence in lymphoid tissues, robust IL-2 production, and recall potential, greater than expected homeostatic fitness, refined transcription factor dependencies, and a distinct molecular phenotype. Classification of terminal-Tem and clarification of Tem biology hold broad implications for understanding the molecular regulation of memory cell states and harnessing immunological memory to improve immunotherapies.

Representation Learning of Logic Words by an RNN: From Word Sequences to Robot Actions.

An important characteristic of human language is compositionality. We can efficiently express a wide variety of real-world situations, events, and behaviors by compositionally constructing the meaning of a complex expression from a finite number of elements. Previous studies have analyzed how machine-learning models, particularly neural networks, can learn from experience to represent compositional relationships between language and robot actions with the aim of understanding the symbol grounding structure and achieving intelligent communicative agents. Such studies have mainly dealt with the words (nouns, adjectives, and verbs) that directly refer to real-world matters. In addition to these words, the current study deals with logic words, such as “not,” “and,” and “or” simultaneously. These words are not directly referring to the real world, but are logical operators that contribute to the construction of meaning in sentences. In human–robot communication, these words may be used often. The current study builds a recurrent neural network model with long short-term memory units and trains it to learn to translate sentences including logic words into robot actions. We investigate what kind of compositional representations, which mediate sentences and robot actions, emerge as the network's internal states via the learning process. Analysis after learning shows that referential words are merged with visual information and the robot's own current state, and the logical words are represented by the model in accordance with their functions as logical operators. Words such as “true,” “false,” and “not” work as non-linear transformations to encode orthogonal phrases into the same area in a memory cell state space. The word “and,” which required a robot to lift up both its hands, worked as if it was a universal quantifier. The word “or,” which required action generation that looked apparently random, was represented as an unstable space of the network's dynamical system.

Artificial memory optimization

To solve some complicated optimization problems, an artificial memory optimization (AMO) is constructed based on the human memory mechanism. In AMO, a memory cell is used to trace an alternative solution of a problem to be solved; memorizing and forgetting rules of the human memory mechanism are used to control state transition of each memory cell; the state of a memory cell consists of two components, one is the solution state which associates with an alternative solution being traced; another is the memory state which associates with the memory information resulting from tracing results, where the memory residual value (MRV) is stored; the states of memory cells are divided into three types: instantaneous, short- and long-term memory state, each of which can be strengthened or weakened by accepted stimulus strength. If the solution state of a memory cell has transferred to a good position, its MRV will increase, and then the memory cell is not easily to be forgotten; when the solution state of a memory cell is at sticky state, its MRV will decrease until the memory cell is forgotten; this will effectively prevent invalid iteration. In the course of evolution, a memory cell may strive to evolve from the instantaneous, short-term memory state to long-term memory state, it makes search to be various. Because AMO has 6 operators at the curent version, it has wider adaptability to solve different types of optimization problems. Besides, these operators are automatically dispatched according to their executing efficiency. Results show that AMO possesses of strong search capability and high convergence speed when solving some complicated function optimization problems.

Morphable Resistive Memory Optimization for Mobile Virtualization

Virtualization offers significant benefits, such as better isolation and security for mobile systems. However, the limited amount of memory and virtualization’s memory-demanding nature make it challenging to virtualize mobile systems efficiently. In this paper, we utilize morphable resistive memories to design a high-performance mobile system with an extensible memory space. With morphable resistive memories, a simple and effective page management technique, Balloonfish, is proposed to convert the memory cell state between multilevel and single-level for achieving a balance between performance and memory space. First, an application-specific page allocation is proposed for managing morphable resistive memories in virtualized mobile systems. Besides, we use a balloon-style algorithm to balance memory allocation among multiple virtual machines. Our evaluation based on the Samsung Exynos 5250 system-on-chip with various real Android applications shows that our system achieves 28.63% performance improvement compared with the baseline scheme.

Dynamic model of a memory cell based on tunnel magnetoresistance

A dynamic behavioral model of an integrated memory cell based on the effect of tunnel magnetoresistance is developed in which the hysteresis and time characteristics are described by a Landau-Lifshitz-Gilbert equation. The use of the model is demonstrated by an example of a next-generation magnetoresisitve memory cell integrated on silicon. The transient and current-voltage characteristics of the memory cell are calculated for different thicknesses of a tunnel insulator; the variation in the magnetization angle of a free ferromagnetic layer as a function of the current flowing in a write line is shown. The tunnel magnetoresistance value, memory-cell state switching delay, and maximum operating frequency are calculated.

Improved Resistive Switching Uniformity in $ \hbox{Cu/HfO}_{2}/\hbox{Pt}$ Devices by Using Current Sweeping Mode

In this letter, current sweeping programming mode is proposed as an efficient method to improve the uniformity of the switching properties of resistive memory devices. Based on the measurement results of the reset process of filament-based Cu/HfO2/Pt devices, current sweeping mode (CSM) can significantly reduce the distributions of Roff values, as compared with the standard voltage sweeping mode. The improvement is attributed to the elimination of the intermediate resistive states due to the positive feedback of joule heat generation by the use of current sweeping. Furthermore, the uniform distribution of the Vset values of the set process is also obtained by current sweeping, which stems from the localization of conductive filaments formation and rupture. CSM provides an effective way to achieve uniform resistance state of memory cell.

Conduction properties of electrically erasable read only memory tunnel oxides under dynamic stress

The write and erase programmable operations in electrically erasable read only memories (EEPROM) which are based on Fowler–Nordheim tunneling injection through a thin tunnel oxide window have been reproduced on specific large area double polycrystalline (poly) test capacitors. These structures integrate the different stacked layers (upper control gate polysilicon layer; interpoly dielectric layer; floating gate polysilicon layer; tunnel oxide; N + substrate) of the active area of a memory cell state transistor. Stress pulses similar to those used in the programming memory cells were applied to the upper polysilicon layer. The variations of the tunnel oxide electrical conduction properties after numerous write-erase cycles were studied by measuring the current as a function of voltage characteristics of the structure. The Fowler–Nordheim constants were obtained as a function of the number of stress cycles. A model based on a simple equivalent electrical circuit was then implemented to simulate the resulting variations of the floating polysilicon gate charge and of the threshold voltage of the structure in both write and erase modes. These variations were compared to those directly measured on a memory cell. It is shown that the closure of the programmable window in memory devices can be unambiguously attributed to a decrease of the tunnel oxide conductivity.

Lymphokine profile and activation pattern of two unrelated antigen- or idiotype-specific T suppressor cell clones.

Two T suppressor (Ts) clones of different specificity have been analyzed for their lymphokine spectrum. BVI/5 is an I-Ek-restricted bovine serum albumin (BSA)-specific Ts cell clone from a CBA/J mouse tolerized by low doses of BSA. It affects directly or indirectly the function of BSA-specific T helper (Th) cells. The Ts cell clone 178-4 from a BALB/c mouse is I-Ed restricted and recognizes the public J558 Id on B cells. It prevents alpha(1----3)dextran B 1355S (Dex)-specific IgG antibody production and drives Dex-specific J558 idiotype-bearing B cells into an anergic B IgG memory cell state. Both Ts cell clones thus cause specific suppression, yet in different experimental systems using different effector mechanisms. Upon stimulation with concanavalin A or fixed CD3-specific monoclonal antibody, both clones produce high levels of interferon (IFN)-gamma and tumor necrosis factor (TNF) but in contrast to Th1 cells no interleukin (IL)-2. Both clones produce low levels of IL-3 and IL-6 but no IL-4, IL-5 and IL-9. Furthermore, unlike Th2 cells, both clones do not respond to IL-1. The mechanism of the idiotype-specific induction of anergy in Dex-specific B IgG memory cells by 178-4 Ts cells is not yet understood. BVI/5 Ts cells suppress in vitro the BSA-specific proliferation of the BSA-specific Th cell clone 83/1, as well as the response of BSA-primed CBA/LN cells. Whereas the suppressive effect on 83/1 cells is due to IFN-gamma alone the suppression of BSA-specific lymph node cells can be simulated neither by IFN-gamma nor the combination of IFN-gamma and TNF. Thus these mediators cannot account for the antigen-specific suppression by BVI/5 Ts cells in polyclonal in vitro responses from lymph node cells and probably not for the induction of in vivo unresponsiveness.

A high-speed 1-kbit high electron mobility transistor static RAM

A 1-kbit static RAM with enhancement and depletion-mode devices was designed and fabricated using the high electron mobility transistor (HEMT) technology. The RAM circuit was optimized to achieve ultra-high-speed performance. A subnanosecond address access time of 0.6 ns was measured at room temperature for a total power dissipation of 450 mW. The minimum WRITE-ENABLE pulse width required to change the state of memory cell is less than 2 ns on probe testing. The best chip has 3 bits that failed to function, which corresponds to a bit yield of 99.7 percent. According to the simulation, variations of the threshold voltage inside the memory cell greatly reduce its stable functional range. High-speed operation requires more uniform threshold voltage control to achieve fully operational LSI memory circuits.

Analysis of ceramic semiconductor packages for trace uranium by fission track counting

The passage of ionizing radiation through semiconductor memories has been observed to change the state of memory cells. An accurate analytical technique is described which determines the trace uranium generating the majority of these ionizing particles in ceramic materials. The technique is highly selective and extremely sensitive with a detection limit for uranium below 0.04 ppB. It is more sensitive, is faster for large numbers of samples, and provides more information than currently used ..cap alpha..-counting systems.