Memory Protection Research Articles

Software-Based Security Approach for Networked Embedded Devices

As the Internet of Things (IoT) continues to expand, data security has become increasingly important for ensuring privacy and safety, especially given the sensitive and, sometimes, critical nature of the data handled by IoT devices. There exist hardware-based trusted execution environments used to protect data, but they are not compatible with low-cost devices that lack hardware-assisted security features. The research in this paper presents software-based protection and encryption mechanisms explicitly designed for embedded devices. The proposed architecture consists of two parts: the Agent, which is designed to work with low-cost, low-end devices without requiring modifications to the underlying hardware, and the Computing Module, which is designed for slightly more computationally powerful devices. The Computing Module enables devices to write data in protected memory and continuously verifies its integrity to provide protection. Additionally, it utilizes the Agents located on the device to safeguard device applications against attacks by requesting the Agent to generate an application code signature and validating it. The proposed solution is an alternative data security approach for low-cost IoT devices without compromising performance or functionality. Our work underscores the importance of developing secure and cost-effective solutions for protecting data in the context of IoT.

Characterizing and Improving Resilience of Accelerators to Memory Errors in Autonomous Robots

Motion planning is a computationally intensive and well-studied problem in autonomous robots. However, motion planning hardware accelerators (MPA) must be soft-error resilient for deployment in safety-critical applications, and blanket application of traditional mitigation techniques is ill-suited due to cost, power, and performance overheads. We propose Collision Exposure Factor (CEF), a novel metric to assess the failure vulnerability of circuits processing spatial relationships, including motion planning. CEF is based on the insight that the safety violation probability increases with the surface area of the physical space exposed by a bit-flip. We evaluate CEF on four MPAs. We demonstrate empirically that CEF is correlated with safety violation probability, and that CEF-aware selective error mitigation provides 12.3 ×, 9.6 ×, and 4.2 × lower dangerous Failures-In-Time rate on average for the same amount of protected memory compared to uniform, bit-position, and access-frequency-aware selection of critical data. Furthermore, we show how to employ CEF to enable fault characterization using 23, 000 × fewer fault injection (FI) experiments than exhaustive FI, and evaluate our FI approach on different robots and MPAs. We demonstrate that CEF-aware FI can provide insights on vulnerable bits in an MPA while taking the same amount of time as uniform statistical FI. Finally, we use the CEF to formulate guidelines for designing soft-error resilient MPAs.

Reactive Oxygen Species-Sensitive Biodegradable Mesoporous Silica Nanoparticles Harboring TheraVac Elicit Tumor-Specific Immunity for Colon Tumor Treatment.

Immunotherapy has revolutionized the field of cancer treatment through invigorating robust antitumor immune response. Here, we report the development of a therapeutic vaccine [consisting of high mobility group nucleosome-binding protein 1 (HMGN1), resiquimod/R848, and anti-PD-L1 (αPD-L1)]-loaded reactive oxygen species (ROS)-responsive mesoporous silica nanoparticle (MSN@TheraVac) for curative therapy of colon cancer. In MSN@TheraVac, αPD-L1 conjugated onto the surface of MSNs via a diselenide bond, which can be rapidly released under the oxidative condition of the tumor microenvironment to avert immunosuppression and effector T cell exhaustion while coloaded HMGN1 and R848 would cooperatively trigger robust tumor-infiltrating dendritic cell (TiDC) maturation and elicitation of antitumor immune responses. Indeed, MSN@TheraVac induced the maturation and activation of dendritic cells (DCs) by promoting the surface expression of CD80, CD86, and CD103 as well as the production of pro-inflammatory cytokines, including TNFα, IL-12, and IL-1β. Importantly, treatment with intravenous MSN@TheraVac led to a complete cure of 100% of BALB/c mice bearing large colon tumors and induced the generation of tumor-specific protective memory without apparent toxicity. Thus, MSN@TheraVac provides a timely release of TheraVac for the curative treatment of colon tumors and holds potential for translation into a clinical therapy for patients with immunologically "cold" colorectal cancers. This ROS-responsive MSN platform may also be tailored for the selective delivery of other cancer vaccines for effective immunotherapy.

SARS-CoV-2 spike-specific TFH cells exhibit unique responses in infected and vaccinated individuals

Long-term humoral immunity to SARS-CoV-2 is essential for preventing reinfection. The production of neutralizing antibody (nAb) and B cell differentiation are tightly regulated by T follicular help (TFH) cells. However, the longevity and functional role of TFH cell subsets in COVID-19 convalescents and vaccine recipients remain poorly defined. Here, we show that SARS-CoV-2 infection and inactivated vaccine elicited both spike-specific CXCR3+ TFH cell and CXCR3− TFH cell responses, which showed distinct response patterns. Spike-specific CXCR3+ TFH cells exhibit a dominant and more durable response than CXCR3− TFH cells that positively correlated with antibody responses. A third booster dose preferentially expands the spike-specific CXCR3+ TFH cell subset induced by two doses of inactivated vaccine, contributing to antibody maturation and potency. Functionally, spike-specific CXCR3+ TFH cells have a greater ability to induce spike-specific antibody secreting cells (ASCs) differentiation compared to spike-specific CXCR3− TFH cells. In conclusion, the persistent and functional role of spike-specific CXCR3+ TFH cells following SARS-CoV-2 infection and vaccination may play an important role in antibody maintenance and recall response, thereby conferring long-term protection. The findings from this study will inform the development of SARS-CoV-2 vaccines aiming to induce long-term protective immune memory.

Pivotal role of tissue-resident memory lymphocytes in the control of mucosal infections: can mucosal vaccination induce protective tissue-resident memory T and B cells?

Pivotal role of tissue-resident memory lymphocytes in the control of mucosal infections: can mucosal vaccination induce protective tissue-resident memory T and B cells?

Cancer immunotherapy with enveloped self-amplifying mRNA CARG-2020 that modulates IL-12, IL-17 and PD-L1 pathways to prevent tumor recurrence

Targeting multiple immune mechanisms may overcome therapy resistance and further improve cancer immunotherapy for humans. Here, we describe the application of virus-like vesicles (VLV) for delivery of three immunomodulators alone and in combination, as a promising approach for cancer immunotherapy. VLV vectors were designed to deliver single chain interleukin (IL)-12, short-hairpin RNA (shRNA) targeting programmed death ligand 1 (PD-L1), and a dominant-negative form of IL-17 receptor A (dn-IL17RA) as a single payload or as a combination payload. Intralesional delivery of the VLV vector expressing IL-12 alone, as well as the trivalent vector (designated CARG-2020) eradicated large established tumors. However, only CARG-2020 prevented tumor recurrence and provided long-term survival benefit to the tumor-bearing mice, indicating a benefit of the combined immunomodulation. The abscopal effects of CARG-2020 on the non-injected contralateral tumors, as well as protection from the tumor cell re-challenge, suggest immune-mediated mechanism of protection and establishment of immunological memory. Mechanistically, CARG-2020 potently activates Th1 immune mechanisms and inhibits expression of genes related to T cell exhaustion and cancer-promoting inflammation. The ability of CARG-2020 to prevent tumor recurrence and to provide survival benefit makes it a promising candidate for its development for human cancer immunotherapy.

Bartonella infections are prevalent in rodents despite efficient immune responses

BackgroundPathogens face strong selection from host immune responses, yet many host populations support pervasive pathogen populations. We investigated this puzzle in a model system of Bartonella and rodents from Israel’s northwestern Negev Desert. We chose to study this system because, in this region, 75–100% of rodents are infected with Bartonella at any given time, despite an efficient immunological response. In this region, Bartonella species circulate in three rodent species, and we tested the hypothesis that at least one of these hosts exhibits a waning immune response to Bartonella, which allows reinfections.MethodsWe inoculated captive animals of all three rodent species with the same Bartonella strain, and we quantified the bacterial dynamics and Bartonella-specific immunoglobulin G antibody kinetics over a period of 139 days after the primary inoculation, and then for 60 days following reinoculation with the same strain.ResultsContrary to our hypothesis, we found a strong, long-lasting immunoglobulin G antibody response, with protective immunological memory in all three rodent species. That response prevented reinfection upon exposure of the rodents to the same Bartonella strain.ConclusionsThis study constitutes an initial step toward understanding how the interplay between traits of Bartonella and their hosts influences the epidemiological dynamics of these pathogens in nature.Graphical

Implicit Hammer: Cross-Privilege-Boundary Rowhammer Through Implicit Accesses

Rowhammer is a hardware vulnerability in DRAM memory, where repeated access to <italic xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">hammer rows</i> can induce bit flips in neighboring <italic xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">victim rows</i> . Being a hardware vulnerability, rowhammer bypasses all the system memory protection, allowing adversaries to compromise the integrity and confidentiality of data. Rowhammer attacks have shown to enable privilege escalation, sandbox escape, and cryptographic key disclosures. A key requirement of <italic xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">all</i> existing rowhammer attacks is that an attacker must have access to at least part of an exploitable hammer row. We term such rowhammer attacks as Explicit Hammer. Recently, several proposals suggest leveraging the spatial proximity between the accessed hammer rows and the location of the victim rows for a defense against rowhammer. These all aim to deny the attacker's permission to access hammer rows near sensitive data, thus defeating explicit hammer-based attacks. In this paper, we question the core assumption underlying these defenses. We present Implicit Hammer, a confused-deputy attack that causes accesses to hammer rows that the attacker is not allowed to access. It is a paradigm shift in rowhammer attacks since it crosses privilege boundary to stealthily rowhammer an inaccessible row by implicit DRAM accesses. Such accesses are achieved by abusing inherent features of modern hardware and/or software. We propose a generic model to rigorously formalize the necessary conditions to initiate implicit hammer and explicit hammer, respectively. Compared to explicit hammer, implicit hammer can defeat the advanced software-only defenses, stealthy in hiding itself and hard to be mitigated. To demonstrate the practicality of implicit hammer, we have created two implicit hammer's instances, called PThammer and SyscallHammer. Specifically, PThammer exploits the page-table-walk process of modern processors, inducing the processor to generate frequent accesses to protected memory locations. SyscallHammer exploits system call handler routine of OS kernels to implicitly access kernel memory.

Retro-cue effect: The retro-cue is effective when and only when working memory consolidation is inadequate.

The retro-cue effect (RCE) describes the finding that participants' working memory performance is enhanced when their attention is directed to the to-be-tested position by a spatial cue during the retention interval. Here, we explore the relationship between RCE and working memory consolidation. A sequential display retro-cue paradigm is used for the present study. In Experiments 1A and 1B, longer consolidation time (CT) completely erased the standard RCE. In Experiment 2, longer CT diminished the RCE in a standard simultaneous display retro-cue paradigm. In Experiment 3, the post-cue time was used by participants to further consolidate memory traces. In Experiment 4, longer CT protected memory representations from invalid cue costs. Our results support a consolidation account of the RCE: the retro-cue is effective when and only when the working memory consolidation is inadequate. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Biodegradable scaffolds for enhancing vaccine delivery.

Sustained release of vaccine components is a potential method to boost efficacy compared with traditional bolus injection. Here, we show that a biodegradable hyaluronic acid (HA)-scaffold, termed HA cryogel, mediates sustained antigen and adjuvant release in vivo leading to a durable immune response. Delivery from subcutaneously injected HA cryogels was assessed and a formulation which enhanced the immune response while minimizing the inflammation associated with the foreign body response was identified, termed CpG-OVA-HAC2. Dose escalation studies with CpG-OVA-HAC2 demonstrated that both the antibody and T cell responses were dose-dependent and influenced by thecompetency of neutrophils to perform oxidative burst. In immunodeficient post-hematopoietic stem cell transplanted mice, immunization with CpG-OVA-HAC2 elicited a strong antibody response, three orders of magnitude higher than dose-matched bolus injection. In a melanoma model, CpG-OVA-HAC2 induced dose-responsive prophylactic protection, slowing the tumor growth rate and enhancing overall survival. Upon rechallenge, none of the mice developed new tumors suggesting the development of robust immunological memory and long-lasting protection against repeat infections. CpG-OVA-HAC2 also enhanced survival in mice with established tumors. The results from this work support the potential for CpG-OVA-HAC2 to enhance vaccine delivery.

Targeted Reprogramming of Vitamin B3 Metabolism as a Nanotherapeutic Strategy towards Chemoresistant Cancers.

Cancer-associated fibroblasts (CAFs) promote cancer stem cell (CSC)-mediated chemoresistance and immunosuppressive tumor microenvironment. However, direct depletion of CAFs may increase cancer invasiveness and metastasis. As a generalized strategy against chemoresistant cancers, Gemini-like homotypic targeting nanoparticles (NPs) are designed for two-pronged CAF transformation and cancer cell elimination. The CAF-targeted NPs couple vitamin B3 metabolic reprogramming to epigenetic modulation of secreted pro-stemness and immunosuppressive factors, thereby diminishing CSC and suppressive immune cell populations to enhance cancer cell drug susceptibility and cytotoxic T cell infiltration. In mouse models of breast, liver, pancreatic and colorectal cancers that are resistant to their respective first-line chemotherapeutics, a single dose of hydrogel co-delivering the Gemini-like NPs can rehabilitate chemosensitivity, induce immune activation, and achieve tumor regression. Moreover, it stimulates robust T cell memory for long-term protection against tumor rechallenge. This study thus represents an innovative approach with broad applicability for overcoming cancer chemoresistance.

Increased innate immune activation induces protective RSV-specific lung-resident memory T cells in neonatal mice

Young infants frequently experience respiratory tract infections, yet vaccines designed to provide mucosal protection are lacking. Localizing pathogen-specific cellular and humoral immune responses to the lung could provide improved immune protection. We used a well-characterized murine model of respiratory syncytial virus (RSV) to study the development of lung-resident memory T cells (TRM) in neonatal compared to adult mice. We demonstrated that priming with RSV during the neonatal period failed to retain RSV-specific clusters of differentiation (CD8) TRM 6weeks post infection, in contrast to priming during adulthood. The reduced development of RSV-specific TRM was associated with poor acquisition of two key markers of tissue residence: CD69 and CD103. However, by augmenting both innate immune activation and antigen exposure, neonatal RSV-specific CD8 T cells increased expression of tissue-residence markers and were maintained in the lung at memory time points. Establishment of TRM correlated with more rapid control of the virus in the lungs upon reinfection. This is the first strategy to effectively establish RSV-specific TRM in neonates providing new insight into neonatal memory T cell development and vaccine strategies.

HPV16 E6/E7 -based mRNA vaccine is therapeutic in mice bearing aggressive HPV-positive lesions.

HPV (Human papillomavirus) affects 600,000 people worldwide each year. Almost all cervical cancers are associated with a past HPV infection. In particular, the positivity to the high-risk type HPV16 is detected in most of the invasive cervical cancers. FDA has approved prophylactic vaccines that protect against new HPV16 infections, but do not induce immunity in those patients with established infections or neoplasms. To date, no therapeutic vaccine targeting HPV16-associated lesions has been authorized. We have developed an mRNA-based vaccine against the HPV16 late oncoproteins E6 and E7, which are abundantly and exclusively expressed in high-grade squamous intraepithelial lesions (HSILs), a stage of the cervical disease that precedes the progression to carcinoma. Our in vitro and in vivo studies demonstrated that the translated mRNA is functional and elicits an antigen-specific adaptive immune response. Upon immunization with the vaccine, mice with HPV16+ lesions exhibited tumor growth inhibition, extension of lifespan, and development of a protective immune memory. In light of these results and the remarkable clinical success of mRNA vaccines against SARS-CoV2, we believe that our mRNA-based therapeutic vaccine has the potential to offer a non-invasive treatment alternative to the current standard of care for HPV16+ HSILs.

Distant antimetastatic effect of enterotropic colon cancer–derived α4β7 + CD8 + T cells

Despite the high prognostic value of immune infiltrates in colorectal cancer (CRC), metastatic disease remains resistant to immunotherapy by immune checkpoint blockade (ICB). Here, we show, in metastatic CRC preclinical models, that orthotopically implanted primary colon tumors exert a colon-specific antimetastatic effect on distant hepatic lesions. Enterotropic α4β7 integrin–expressing neoantigen-specific CD8 T cells were key components of the antimetastatic effect. Accordingly, the presence of concomitant colon tumors improved control of liver lesions by anti–PD-L1 proof-of-concept immunotherapy and generated protective immune memory, whereas partial depletion of α4β7 + cells abrogated control of metastases. Last, in patients with metastatic CRC, response to ICB was associated with expression of α4β7 integrin in metastases and with circulating α4β7 + CD8 T cells. Our findings identify a systemic cancer immunosurveillance role for gut-primed tumor-specific α4β7 + CD8 T cells.

How Flexible is CXL's Memory Protection?

CXL, a new interconnect standard for cache-coherent memory sharing, is becoming a reality - but its security leaves something to be desired. Decentralized capabilities are flexible and resilient against malicious actors, and should be considered while CXL is under active development.

The role of sleep for memory consolidation: does sleep protect memories from retroactive interference?

Numerous studies suggest that sleep benefits memory. A major theoretical question in this area is however if sleep does so by passively shielding memories from interference that arises during wakefulness or by actively stabilizing and strengthening memories. A key finding by Ellenbogen et al. Current Biology, 16, 1290–1294 (2006a) indicates that sleep can protect memories from retroactive interference, which suggests that sleep plays more than a passive role for memory consolidation. Sample size in this study was however small and subsequent reports in the literature provided mixed results. We therefore conducted an online study via Zoom to replicate Ellenbogen et al. Current Biology, 16, 1290–1294 (2006a). Subjects were asked to study paired associates. After a 12-h delay that included either nocturnal sleep or daytime wakefulness, half of all subjects were asked to study an additional list to elicit retroactive interference. All participants were then asked to complete a memory test for the studied list(s). The results were fully consistent with those reported by Ellenbogen et al. Current Biology, 16, 1290–1294 (2006a). We discuss this successful replication against the background of the mixed literature, with a focus on the possibly critical role of study-design features, like the use of high learning criteria that resulted in performance being at ceiling, or a confound between interference and the length of the retention interval. A collaborative replication effort may be needed to reach a straightfoward answer to the question if sleep protects memories from interference (and under what conditions).

Cost-effective memory protection and reliability evaluation based on machine error-tolerance: A case study on no-accuracy-loss YOLOv4 object detection model

In this paper, we investigate and present a cost-effective memory protection and reliability evaluation methodology for machine learning systems based on machine error-tolerance. We show that by well exploiting the inherent error-tolerability, the incurred cost of the typical memory protection methods including ECC (Error Correction Code) and TMR (Triple Modular Redundancy) can be greatly reduced, making these methods attractive to be adopted to implement a reliable machine learning system. In particular, we also target the up-to-date powerful object detection machine learning model YOLOv4 as a case study. To the best of our knowledge, there is no work in the literature addressing reliability evaluation and enhancement for YOLOv4. Based on identifying the set of error-sensitive (critical) memory blocks and protecting only this set, we develop more efficient ECC and TMR methods. Our ECC method does not require any additional memory cost, while the area cost of our TMR method can be reduced from 200 % to only 47.5 %. The reliability evaluation results show that the Mean Time to Failure (MTTF) of the YOLOv4 object detection system can be extended by about 12 times by the proposed ECC method, while the TMR method can even achieve 108 times longer than that of ECC. We also present a generic methodology to exploit machine error-tolerance for developing a cost-effective memory protection method.

Biapenem, a Carbapenem Antibiotic, Elicits Mycobacteria Specific Immune Responses and Reduces the Recurrence of Tuberculosis.

Tuberculosis (TB) still tops the list of global health burdens even after COVID-19. However, it will sooner transcend the current pandemic due to the prevailing risk of reactivation of latent TB in immunocompromised individuals. The indiscriminate misuse and overuse of antibiotics have resulted in the emergence of deadly drug-resistant variants of Mycobacterium tuberculosis (M.tb). This study aims to characterize the functionality of the carbapenem antibiotic-Biapenem (BPM) in generating long-lasting immunity against TB. BPM treatment significantly boosted the activation status of the innate immune arm-macrophages by augmenting p38 signaling. Macrophages further primed and activated the adaptive immune cells CD4+ and CD8+ T-cells in the lung and spleen of the infected mice model. Furthermore, BPM treatment significantly amplified the polarization of T lymphocytes toward inflammatory subsets, such as Th1 and Th17. The treatment also helped generate a long-lived central memory T-cell subset. The generation of central memory T lymphocyte subset upon BPM treatment in the murine model led to a significant curtailing in the recurrence of TB due to reactivation and reinfection. These results suggest the potentiality of BPM as a potent adjunct immunomodulator to improve host defense against M.tb by enriching long-term protective memory cells. IMPORTANCE Tuberculosis (TB) caused by Mycobacterium tuberculosis (M.tb) tops the list of infectious killers around the globe. The emergence of drug-resistant variants of M.tb has been a major hindrance toward realizing the "END TB" goal. Drug resistance has amplified the global burden toward the quest for novel drug molecules targeting M.tb. Host-directed therapy (HDT) offers a lucrative alternative to tackle emerging drug resistance and disease relapse by strengthening the host's immunity. Through our present study, we have tried to characterize the functionality of the carbapenem antibiotic-Biapenem (BPM). BPM treatment significantly augmented long-lasting immunity against TB by boosting the innate and adaptive immune arms. The generation of long-lived central memory T lymphocyte subset significantly improved the disease outcome and provided sterilizing immunity in the murine model of TB. The present investigation's encouraging results have helped us depict BPM as a potent adjunct immunomodulator for treating TB.

Bystander activation in memory and antigen-inexperienced memory-like CD8 T cells.

Antigen-induced memory T cells undergo counterintuitive activation in an antigen-independent manner, which is called bystander response. Although it is well documented that memory CD8+ T cells produce IFNγ and upregulate the cytotoxic program upon the stimulation with inflammatory cytokines, there is only rare evidence that this provides an actual protection against pathogens in immunocompetent individuals. One of the reasons might be numerous antigen-inexperienced memory-like T cells that are also capable of the bystander response. Little is known about the bystander protection of memory and memory-like T cells and their redundancies with innate-like lymphocytes in humans because of the interspecies differences and the lack of controlled experiments. However, it has been proposed that IL-15/NKG2D-driven bystander activation of memory T cells drives protection or immunopathology in particular human diseases.

Tissue-resident memory T cells mediate mucosal immunity to recurrent urinary tract infection.

Urinary tract infection (UTI) is one of the most prevalent human bacterial infections. New therapeutic approaches, including vaccination and immunotherapy, are urgently needed to combat the rapid global dissemination of multidrug-resistant uropathogens. Development of therapies is impeded by an incomplete understanding of memory development during UTI. Here, we found that reducing bacterial load early in infection, by reducing the inoculum or with antibiotics after infection, completely abrogated the protective memory response. We observed a mixed T helper (TH) cell polarization, composed of TH1, TH2, and TH17 T cells, among T cells infiltrating the bladder during primary infection. Thus, we hypothesized that reducing antigen load altered TH cell polarization, leading to poor memory. Unexpectedly, however, TH cell polarization was unchanged in these scenarios. Instead, we uncovered a population of tissue-resident memory (TRM) T cells that was significantly reduced in the absence of sufficient antigen. Demonstrating that TRM cells are necessary for immune memory, transfer of lymph node- or spleen-derived infection-experienced T cells to naïve animals did not confer protection against infection. Supporting that TRM cells are sufficient to protect against recurrent UTI, animals depleted of systemic T cells, or treated with FTY720 to block memory lymphocyte migration from lymph nodes to infected tissue, were equally protected compared with unmanipulated mice against a second UTI. Thus, we uncovered an unappreciated key role for TRM cells in the memory response to bacterial infection in the bladder mucosa, providing a target for non-antibiotic-based immunotherapy and/or new vaccine strategies to prevent recurrent UTI.