Persistent Memory Research Articles

Coupling of Slow Oscillations in the Prefrontal and Motor Cortex Predicts Onset of Spindle Trains and Persistent Memory Reactivations.

Sleep is known to drive the consolidation of motor memories. During nonrapid eye movement (NREM) sleep, the close temporal proximity between slow oscillations (SOs) and spindles ("nesting" of SO-spindles) is known to be essential for consolidation, likely because it is closely associated with the reactivation of awake task activity. Interestingly, recent work has found that spindles can occur in temporal clusters or "trains." However, it remains unclear how spindle trains are related to the nesting phenomenon. Here, we hypothesized that spindle trains are more likely when SOs co-occur in the prefrontal and motor cortex. We conducted simultaneous neural recordings in the medial prefrontal cortex (mPFC) and primary motor cortex (M1) of male rats training on the reach-to-grasp motor task. We found that intracortically recorded M1 spindles are organized into distinct temporal clusters. Notably, the occurrence of temporally precise SOs between mPFC and M1 was a strong predictor of spindle trains. Moreover, reactivation of awake task patterns is much more persistent during spindle trains in comparison with that during isolated spindles. Together, our work suggests that the precise coupling of SOs across mPFC and M1 may be a potential driver of spindle trains and persistent reactivation of motor memory during NREM sleep.

HDF5 in the exascale era: Delivering efficient and scalable parallel I/O for exascale applications

Accurately modeling real-world systems requires scientific applications at exascale to generate massive amounts of data and manage data storage efficiently. However, parallel input and output (I/O) faces challenges due to new application workflows and the state-of-the-art memory, interconnect, and storage architectures considered in exascale designs. The storage hierarchy has expanded with node-local persistent memory, solid-state storage, and traditional disk and tape-based storage, thus requiring efficiency at each layer and much more efficient data movement among these layers. This paper discusses how the ExaHDF5 project improved the I/O performance and data management for exascale architectures by enhancing HDF5, a widely used parallel I/O library. The team developed an Asynchronous I/O Virtual Object Layer (VOL) connector that allowed overlapping I/O with computation. They also created a Cache VOL to complement asynchronous I/O by incorporating fast storage layers, such as burst buffer and node-local storage, into the parallel I/O workflow through caching and staging data. Additionally, the team enabled data aggregation and I/O at the node level by using a Subfiling Virtual File Driver (VFD). To demonstrate superior I/O performance with HDF5 at exascale, the ExaHDF5 team collaborated with several exascale applications. In this paper, we show I/O performance improvements for three applications: Cabana (a particle-based simulation library), EQSIM (a regional earthquake simulation software), and E3SM (a climate system modeling library).

Leveraging Digital Twins and Intrusion Detection Systems for Enhanced Security in IoT-Based Smart City Infrastructures

In this research, we investigate the integration of an Intrusion Detection System (IDS) with a Digital Twin (DT) to enhance the cybersecurity of physical devices in cyber–physical systems. Using Eclipse Ditto as the DT platform and Snort as the IDS, we developed a near-realistic test environment that included a Raspberry Pi as the physical device and a Kali Linux virtual machine to perform common cyberattacks such as Hping3 flood attacks and NMAP reconnaissance scans. The results demonstrated that the IDS effectively detected Hping3-based flood attacks but showed limitations in identifying NMAP scans, suggesting areas for IDS configuration improvements. Furthermore, the study uncovered significant system resource impacts, including high Central Processing Unit (CPU) usage during SYN and ACK flood attacks and persistent memory usage after Network Mapper (NMAP) scans, highlighting the need for enhanced recovery mechanisms. This research presents a novel approach by coupling a Digital Twin with an IDS, enabling real-time monitoring and providing a dual perspective on both system performance and security. The integration offers a holistic method for identifying vulnerabilities and understanding resource impacts during cyberattacks. The work contributes new insights into the use of Digital Twins for cybersecurity and paves the way for further research into automated defense mechanisms, real-world validation of the proposed model, and the incorporation of additional attack scenarios. The results suggest that this combined approach holds significant promise for enhancing the security and resilience of IoT devices and other cyber–physical systems.

ECMO Survivors' Reflections on Their ICU Experience and Recovery.

As pediatric mortality improves, approaches to pediatric critical care now focus on understanding long-term implications of survivorship on patients and families. We aimed to characterize how patients recall time spent sedated and recovering to identify areas for improvement in patient outcomes. We undertook qualitative analysis using semistructured interviews of pediatric patients requiring extra-corporeal support in our intensive care units from 2018 to 2023. All patients were English-speaking, >12 years old at time of hospitalization, and able to communicate at an age-appropriate level. Priority sampling was given to those with more recent hospitalizations to improve recall. Interviews were recorded and transcribed before thematic, inductive analysis. Forty-one patients met inclusion criteria; 14 patients were enrolled before achieving thematic saturation. Several themes emerged, centering on cognitive, physical, and socioemotional experiences during and after hospitalization. Notable findings include profound awareness under sedation, impaired sleep, challenges with communication, physical discomfort, frustration with activities of daily living limitations, and gratitude for provider and family presence. Postdischarge, patients highlighted persistent memory, concentration, sleep, and physical impairments, as well as emotional processing of their illness and mortality. Our findings describe how pediatric critical illness impacts short and long term cognitive, physical, and socioemotional outcomes for children in the ICU. Future research is necessary to study if there are specific, modifiable factors in patients' care that impacts their experience of critical illness, such as specific medication choices, diagnoses, communication styles, or physical and speech therapy interventions.

Dissociable dorsal medial prefrontal cortex ensembles are necessary for cocaine seeking and fear conditioning in mice

The dorsal medial prefrontal cortex (dmPFC) plays a dual role in modulating drug seeking and fear-related behaviors. Learned associations between cues and drug seeking are encoded by a specific ensemble of neurons. This study explored the stability of a dmPFC cocaine seeking ensemble over 2 weeks and its influence on persistent cocaine seeking and fear memory retrieval. In the first series of experiments, we trained TetTag c-fos-driven-EGFP mice in cocaine self-administration and tagged strongly activated neurons with EGFP during the initial day 7 cocaine seeking session. Subsequently, a follow-up seeking test was conducted 2 weeks later to examine ensemble reactivation between two seeking sessions via c-Fos immunostaining. In the second series of experiments, we co-injected viruses expressing TRE-cre and a cre-dependent inhibitory PSAM-GlyR into the dmPFC of male and female c-fos-tTA mice to enable “tagging” of cocaine seeking ensemble or cued fear ensemble neurons with inhibitory chemogenetic receptors. These c-fos-tTA mice have the c-fos promoter that drives expression of the tetracycline transactivator (tTA). The tTA can bind to the tetracycline response element (TRE) site on the viral construct, resulting in the expression of cre-recombinase, which enables the expression of cre-dependent inhibitory chemogenetic receptors and fluorescent reporters. Then we investigated ensemble contribution to subsequent cocaine seeking and fear recall during inhibition of the tagged ensemble by administering uPSEM792s (0.3 mg/kg), a selective ligand for PSAM-GlyR. In both sexes, there was a positive association between the persistence of cocaine seeking and the proportion of reactivated EGFP+ neurons within the dmPFC. More importantly, inhibition of the cocaine seeking ensemble suppressed cocaine seeking, but not recall of fear memory, while inhibition of the fear ensemble reduced conditioned freezing but not cocaine seeking. The results demonstrate that cocaine and fear recall ensembles in the dmPFC are stable, but largely exclusive from one another.

Disrupted Hippocampal Theta-Gamma Coupling and Spike-Field Coherence Following Experimental Traumatic Brain Injury.

Traumatic brain injury (TBI) often results in persistent learning and memory deficits, likely due to disrupted hippocampal circuitry underlying these processes. Precise temporal control of hippocampal neuronal activity is important for memory encoding and retrieval and is supported by oscillations that dynamically organize single unit firing. Using high-density laminar electrophysiology, we discovered a loss of oscillatory power across CA1 lamina, with a profound, layer-specific reduction in theta-gamma phase amplitude coupling in injured rats. Interneurons from injured animals were less strongly entrained to theta and gamma oscillations, suggesting a mechanism for the loss of coupling, while pyramidal cells were entrained to a later phase of theta. During quiet immobility, we report decreased ripple amplitudes from injured animals during sharp-wave ripple events. These results reveal deficits in information encoding and retrieval schemes essential to cognition that likely underlie TBI-associated learning and memory impairments, and elucidate potential targets for future neuromodulation therapies.

Memory Reconsolidation Updating in Substance Addiction: Applications, Mechanisms, and Future Prospects for Clinical Therapeutics.

Persistent and maladaptive drug-related memories represent a key component in drug addiction. Converging evidence from both preclinical and clinical studies has demonstrated the potential efficacy of the memory reconsolidation updating procedure (MRUP), a non-pharmacological strategy intertwining two distinct memory processes: reconsolidation and extinction-alternatively termed "the memory retrieval-extinction procedure". This procedure presents a promising approach to attenuate, if not erase, entrenched drug memories and prevent relapse. The present review delineates the applications, molecular underpinnings, and operational boundaries of MRUP in the context of various forms of substance dependence. Furthermore, we critically examine the methodological limitations of MRUP, postulating potential refinement to optimize its therapeutic efficacy. In addition, we also look at the potential integration of MRUP and neurostimulation treatments in the domain of substance addiction. Overall, existing studies underscore the significant potential of MRUP, suggesting that interventions predicated on it could herald a promising avenue to enhance clinical outcomes in substance addiction therapy.

Hercules: Enabling Atomic Durability for Persistent Memory with Transient Persistence Domain

Persistent memory (pmem) products bring the persistence domain up to the memory level. Intel recently introduced the eADR feature that guarantees to flush data buffered in CPU cache to pmem on a power outage, thereby making the CPU cache a transient persistence domain . Researchers have explored how to enable the atomic durability for applications’ in-pmem data. In this article, we exploit the eADR-supported CPU cache to do so. A modified cache line, until written back to pmem, is a natural redo log copy of the in-pmem data. However, a write-back due to cache replacement or eADR on a crash overwrites the original copy. We accordingly developed Hercules, a hardware logging design for the transaction-level atomic durability, with supportive components installed in CPU cache, memory controller (MC), and pmem. When a transaction commits, Hercules commits on-chip its data staying in cache lines. For cache lines evicted before the commit, Hercules asks the MC to redirect and persist them into in-pmem log entries and commits them off-chip upon committing the transaction. Hercules lazily conducts pmem writes only for cache replacements at runtime. On a crash, Hercules saves metadata and data for active transactions into pmem for recovery. Experiments show that, by using CPU cache for both buffering and logging, Hercules yields much higher throughput and incurs significantly fewer pmem writes than state-of-the-art designs.

Delaying Crash Consistency for Building A High-Performance Persistent Memory File System

Delaying Crash Consistency for Building A High-Performance Persistent Memory File System

Enabling Reliable Memory-Mapped I/O With Auto-Snapshot for Persistent Memory Systems

Enabling Reliable Memory-Mapped I/O With Auto-Snapshot for Persistent Memory Systems

Overcoming the coherence time barrier in quantum machine learning on temporal data

The practical implementation of many quantum algorithms known today is limited by the coherence time of the executing quantum hardware and quantum sampling noise. Here we present a machine learning algorithm, NISQRC, for qubit-based quantum systems that enables inference on temporal data over durations unconstrained by decoherence. NISQRC leverages mid-circuit measurements and deterministic reset operations to reduce circuit executions, while still maintaining an appropriate length persistent temporal memory in the quantum system, confirmed through the proposed Volterra Series analysis. This enables NISQRC to overcome not only limitations imposed by finite coherence, but also information scrambling in monitored circuits and sampling noise, problems that persist even in hypothetical fault-tolerant quantum computers that have yet to be realized. To validate our approach, we consider the channel equalization task to recover test signal symbols that are subject to a distorting channel. Through simulations and experiments on a 7-qubit quantum processor we demonstrate that NISQRC can recover arbitrarily long test signals, not limited by coherence time.

Hydrogel biomaterials that stiffen and soften on demand reveal that skeletal muscle stem cells harbor a mechanical memory

Muscle stem cells (MuSCs) are specialized cells that reside in adult skeletal muscle poised to repair muscle tissue. The ability of MuSCs to regenerate damaged tissues declines markedly with aging and in diseases such as Duchenne muscular dystrophy, but the underlying causes of MuSC dysfunction remain poorly understood. Both aging and disease result in dramatic increases in the stiffness of the muscle tissue microenvironment from fibrosis. MuSCs are known to lose their regenerative potential if cultured on stiff plastic substrates. We sought to determine whether MuSCs harbor a memory of their past microenvironment and if it can be overcome. We tested MuSCs in situ using dynamic hydrogel biomaterials that soften or stiffen on demand in response to light and found that freshly isolated MuSCs develop a persistent memory of substrate stiffness characterized by loss of proliferative progenitors within the first three days of culture on stiff substrates. MuSCs cultured on soft hydrogels had altered cytoskeletal organization and activity of Rho and Rac guanosine triphosphate hydrolase (GTPase) and Yes-associated protein mechanotransduction pathways compared to those on stiff hydrogels. Pharmacologic inhibition identified RhoA activation as responsible for the mechanical memory phenotype, and single-cell RNA sequencing revealed a molecular signature of the mechanical memory. These studies highlight that microenvironmental stiffness regulates MuSC fate and leads to MuSC dysfunction that is not readily reversed by changing stiffness. Our results suggest that stiffness can be circumvented by targeting downstream signaling pathways to overcome stem cell dysfunction in aged and disease states with aberrant fibrotic tissue mechanics.

The Myofibroblast Fate of Therapeutic Mesenchymal Stromal Cells: Regeneration, Repair, or Despair?

Mesenchymal stromal cells (MSCs) can be isolated from various tissues of healthy or patient donors to be retransplanted in cell therapies. Because the number of MSCs obtained from biopsies is typically too low for direct clinical application, MSC expansion in cell culture is required. However, ex vivo amplification often reduces the desired MSC regenerative potential and enhances undesired traits, such as activation into fibrogenic myofibroblasts. Transiently activated myofibroblasts restore tissue integrity after organ injury by producing and contracting extracellular matrix into scar tissue. In contrast, persistent myofibroblasts cause excessive scarring-called fibrosis-that destroys organ function. In this review, we focus on the relevance and molecular mechanisms of myofibroblast activation upon contact with stiff cell culture plastic or recipient scar tissue, such as hypertrophic scars of large skin burns. We discuss cell mechanoperception mechanisms such as integrins and stretch-activated channels, mechanotransduction through the contractile actin cytoskeleton, and conversion of mechanical signals into transcriptional programs via mechanosensitive co-transcription factors, such as YAP, TAZ, and MRTF. We further elaborate how prolonged mechanical stress can create persistent myofibroblast memory by direct mechanotransduction to the nucleus that can evoke lasting epigenetic modifications at the DNA level, such as histone methylation and acetylation. We conclude by projecting how cell culture mechanics can be modulated to generate MSCs, which epigenetically protected against myofibroblast activation and transport desired regeneration potential to the recipient tissue environment in clinical therapies.

A verified durable transactional mutex lock for persistent x86-TSO

AbstractThe advent of non-volatile memory technologies has spurred intensive research interest in correctness and programmability. This paper addresses both by developing and verifying a durable (aka persistent) transactional memory (TM) algorithm, $$\text {dTML}_{\text {Px86}}$$ dTML Px86 . Correctness of $$\text {dTML}_{\text {Px86}}$$ dTML Px86 is judged in terms of durable opacity, which ensures both failure atomicity (ensuring memory consistency after a crash) and opacity (ensuring thread safety). We assume a realistic execution model, Px86, which represents Intel’s persistent memory model and extends the Total Store Order memory model with instructions that control persistency. Our TM algorithm, $$\text {dTML}_{\text {Px86}}$$ dTML Px86 , is an adaptation of an existing software transactional mutex lock, but with additional synchronisation mechanisms to cope with Px86. Our correctness proof is operational and comprises two distinct types of proofs: (1) proofs of invariants of $$\text {dTML}_{\text {Px86}}$$ dTML Px86 and (2) a proof of refinement against an operational specification that guarantees durable opacity. To achieve (1), we build on recent Owicki–Gries logics for Px86, and for (2) we use a simulation-based proof technique, which, as far as we are aware, is the first application of simulation-based proofs for Px86 programs. Our entire development has been mechanised in the Isabelle/HOL proof assistant.

Persistent polarization effects and memory properties in ionic-liquid gated InAs nanowire transistors

Iontronics exploits mobile ions within electrolytes to control the electronic properties of materials and devices' electrical and optical response. In this frame, ionic liquids are widely exploited for the gating of semiconducting nanostructure devices, offering superior performance compared to conventional dielectric gating. In this work, we engineer ionic liquid gated InAs nanowire-based field effect transistors and adopt the set-and-freeze dual gate device operation to probe the nanowires in several ionic gate regimes. We exploit standard back-gating at 150 K, when the ionic liquid is frozen and any crosstalk between the ionic gate and the back gate is ruled out. We demonstrate that the liquid gate polarization has a persistent effect on the nanowire properties. This effect can be conveniently exploited to fine-tune the properties of the nanowires and enable new device functionalities. Specifically, we correlate the modification of the ionic environment around the nanowire to the transistor threshold voltage and hysteresis, on/off ratio and current level retention times. Based on this, we demonstrate memory operations of the nanowire field effect transistors. Our work shines a new light on the interaction between electrolytes and semiconducting nanostructures, providing useful insights for future applications of nanodevice iontronics.

Enhanced Immune Responses in Mice by Combining the Mpox Virus B6R-Protein and Aluminum Hydroxide-CpG Vaccine Adjuvants.

Novel adjuvants and innovative combinations of adjuvants (Adjuvant Systems) have facilitated the development of enhanced and new vaccines against re-emerging and challenging pathogenic microorganisms. Nonetheless, the efficacy of adjuvants is influenced by various factors, and the same adjuvant may generate entirely different immune responses when paired with different antigens. Herein, we combined the MPXV-B6R antigen with BC02, a novel adjuvant with proprietary technology, to assess its capability to induce both cellular and humoral immunity in mouse models. Mice received two intramuscular injections of B6R-BC02, which resulted in the production of MPXV-specific IgG, IgG1, and IgG2a antibodies. Additionally, it elicited strong MPXV-specific Th1-oriented cellular immunity and persistent effector memory B-cell responses. The advantages of BC02 were further validated, including rapid initiation of the immune response, robust recall memory, and sustained immune response induction. Although the potential of immunized mice to produce serum-neutralizing antibodies against the vaccinia virus requires further improvement, the exceptional performance of BC02 as an adjuvant for the MPXV-B6R antigen has been consistently demonstrated.

Current challenges and improvements in assessing the immunogenicity of bacterial vaccines.

The increase in antimicrobial-resistant bacterial strains has highlighted the need for a new vaccine strategy. The primary goal of a candidate vaccine is to prevent disease, by inducing a persistent immunologic memory, through the activation of pathogen-specific immune response. Antibody titer is the main parameter used to assess the immunogenicity of bacterial vaccine candidates and it is the most widely used as a correlate of protection. On the other hand, the antibody titer alone cannot provide complete information on all the activity mediated by antibodies which can only be assessed by functional assays, like the serum bactericidal assay and the opsonophagocytosis assay. However, due to the involvement of many biological factors, these assays are difficult to standardize. Some improvements have been achieved in recent years, but further optimizations are needed to minimize inter- and intra-laboratories variability and to allow the applicability of these functional assays for the vaccine immunogenicity assessment on a larger scale.

An Introduction to the Compute Express Link (CXL) Interconnect

The Compute Express Link (CXL) is an open industry-standard interconnect between processors and devices such as accelerators, memory buffers, smart network interfaces, persistent memory, and solid-state drives. CXL offers coherency and memory semantics with bandwidth that scales with PCIe bandwidth while achieving significantly lower latency than PCIe. All major CPU vendors, device vendors, and datacenter operators have adopted CXL as a common standard. This enables an inter-operable ecosystem that supports key computing use cases including highly efficient accelerators, server memory bandwidth and capacity expansion, multi-server resource pooling and sharing, and efficient peer-to-peer communication. This survey provides an introduction to CXL covering the standards CXL 1.0, CXL 2.0, and CXL 3.0. We further survey CXL implementations, discuss CXL's impact on the datacenter landscape, and future directions.

A read-efficient and write-optimized hash table for Intel Optane DC Persistent Memory

Emerging non-volatile memory technologies are driving the next generation of storage systems and durable data structures. Among them, many hash table proposals employ NVM as the storage layer for both fast access and efficient persistence. Most of them are based on the assumption that NVM has cacheline access granularity, poor write endurance, DRAM-comparable read latency and relatively higher write latency. However, a commercial non-volatile memory product, namely Intel Optane DC Persistent Memory (Optane), has some interesting features that are different from previous assumptions, such as 256-byte OptaneLine access granularity, higher read latency than DRAM and DRAM-comparable write latency, limited read/write bandwidth, and hardware-layer wear-leveling. Confronted with the new challenges brought by Optane, we propose Rewo-Hash, a novel read-efficient and write-optimized persistent hash table. Our incremental contributions over our previous work are summarized as follows. First, provide a more detailed technical description for cached table-inclined read mechanism and log-free atomic write mechanism. Second, we devise a consistent shadowing synchronization scheme to mask the data synchronization overhead. Third, we propose a non-blocking lightweight resizing scheme and elaborate the crash recovery mechanism. Fourth, we conduct a comprehensive analysis of the implications of Intel ceasing the production of Optane, and provide a forward-looking perspective on the future of non-volatile memory. The experimental results show that compared with state-of-the-art NVM-Optimized hash tables, Rewo-Hash gains remarkable performance improvement.

Co-stimulation of CD28/CD40 signaling molecule potentiates CAR-T cell efficacy and stemness

CD19 chimeric antigen receptor T (CD19CAR-T) cells have achieved promising outcomes in relapsed/refractory B-cell malignancies. However, recurrences occur due to the loss of CAR-T cell persistence. We developed dual T/B-cell co-stimulatory molecules (CD28 and CD40) in CAR-T cells to enhance intense tumoricidal activity and persistence. CD19.28.40z CAR-T cells promoted pNF-κB and pRelB downstream signaling while diminishing NFAT signaling upon antigen exposure. CD19.28.40z CAR-T cells demonstrated greater proliferation which translated into effective anti-tumor cytotoxicity in long-term co-culture assay. Repetitive weekly antigen stimulation unveiled continuous CAR-T cell expansion while preserving central memory T-cell subset and lower expression of exhaustion phenotypes. The intrinsic genes underlying CD19.28.40z CAR-T cell responses were compared to conventional CARs and demonstrated the up-regulated genes associated with T-cell proliferation and memory as well as down-regulated genes related to apoptosis, exhaustion, and glycolysis pathway. Enrichment of genes toward T-cell stemness, particularly SELL, IL-7r, TCF7, and KLF2, was observed. Effective and continuing anti-tumor cytotoxicity in vivo was exhibited in both B-ALL and B-NHL xenograft models while demonstrating persistent T-cell memory signatures. The functional enhancement of CD37.28.40z CAR-T cell activities against CD37+ tumor cells was further validated. The modification of dual T/B-cell signaling molecules remarkably maximized the efficacy of CAR-T cell therapy.