Intestinal Helminth Infection Impairs Oral and Parenteral Vaccine Efficacy.

The impact of endemic parasitic infection on vaccine efficacy is an important consideration for vaccine development and deployment. We have examined whether intestinal infection with the natural murine helminth Heligmosomoides polygyrus bakeri alters Ag-specific Ab and cellular immune responses to oral and parenteral vaccination in mice. Oral vaccination of mice with a clinically relevant, live, attenuated, recombinant Salmonella vaccine expressing chicken egg OVA (Salmonella-OVA) induced the accumulation of activated, OVA-specific T effector cells rather than OVA-specific regulatory T cells in the GALT. Intestinal helminth infection significantly reduced Th1-skewed Ab responses to oral vaccination with Salmonella-OVA. Activated, adoptively transferred, OVA-specific CD4+ T cells accumulated in draining mesenteric lymph nodes of vaccinated mice, regardless of their helminth infection status. However, helminth infection increased the frequencies of adoptively transferred OVA-specific CD4+ T cells producing IL-4 and IL-10 in the mesenteric lymph node. Ab responses to the oral Salmonella-OVA vaccine were reduced in helminth-free mice adoptively transferred with OVA-specific CD4+ T cells harvested from mice with intestinal helminth infection. Intestinal helminth infection also significantly reduced Th2-skewed Ab responses to parenteral vaccination with OVA adsorbed to alum. These findings suggest that vaccine-specific CD4+ T cells induced in the context of helminth infection retain durable immunomodulatory properties and may promote blunted Ab responses to vaccination. They also underscore the potential need to treat parasitic infection before mass vaccination campaigns in helminth-endemic areas.

Redox Active Zn@MOFs as Spontaneous Reactive Oxygen Species Releasing Antimicrobials.

The rapid development of antimicrobial resistance (AMR) among infectious pathogens has become a major threat and challenge in healthcare systems globally. A strategy distinct from minimizing the overuse of antimicrobials involves the development of novel antimicrobials with a mode of action that prevents the development of AMR microbial strains. Reactive oxygen species (ROS) are formed as a natural byproduct of the cellular aerobic metabolism. However, it becomes pathological when ROS is produced at excessive levels. Exploiting this phenomenon, research on redox-active bactericides has been demonstrated to be beneficial. Materials that release ROS via photodynamic, thermodynamic, and photocatalytic interventions have been developed as nanomedicines and are used in various applications. However, these materials require external stimuli for ROS release to be effective as biocides. In this paper, we report novel zinc-based metal organic framework (Zn@MOF) particles that promote the spontaneous release of active ROS species. The synthesized Zn@MOF spontaneously releases superoxide anions and hydrogen peroxide, exhibiting a potent antimicrobial efficacy against various microbes. Zn@MOF-incorporated plastic films and coatings show excellent, long-lasting antimicrobial potency even under continuous microbial challenge and an aging process. These disinfecting surfaces maintain their antimicrobial properties even after 500× surface wipes. Zn@MOF is also biocompatible and safe on the skin, illustrating its broad potential applications in medical technology and consumer care applications.

Self-Promoted Hydroxyl Radical Releasing Magnetic Zn@Fe Particles.

Semiconductor photocatalysts, such as TiO2 and ZnO, have garnered significant attention for their ability to generate hydroxyl radicals, offering various practical applications. However, the reliance on UV light to facilitate electron-hole separation for hydroxyl radical production poses limitations. In this study, a novel approach is presented utilizing Zn@Fe core/shell particles capable of generating hydroxyl radicals without external energy input. The generation process involves electron donation from Zn to O2 , resulting in the formation of radical species . O2 - /H2 O2 , followed by Fe-catalyzed conversion of H2 O2 into hydroxyl radicals through the Fenton reaction. The release of . OH imparts good antimicrobial and antiviral properties to the Zn@Fe particles. Furthermore, the inclusion of Fe confers magnetic properties to the material. This dual functionality holds promise for diverse potential applications for the Zn@Fe particles.

Computational design of metal hydrides on a defective metal-organic framework HKUST-1 for ethylene dimerization.

Catalytic ethylene dimerization to 1-butene is a crucial reaction in the chemical industry, as 1-butene is used for the production of most common plastics (e.g., polyethylene). With well-defined tuneable structures and unsaturated active sites, defective metal-organic frameworks have recently emerged as potential catalysts for ethylene dimerization. Herein, we computationally design a series of metal hydrides on defective HKUST-1 namely H-M-DHKUST-1 (M: Co, Ni, Cu, Ru, Rh and Pd), and subsequently assess their catalytic activity for ethylene dimerization by density functional theory calculations. Due to the antiferromagnetic behavior of dimeric metal-based clusters, we comprehensively investigate all possible multiplicity states on H-M-DHKUST-1 and observe multiplicity crossing. The ground-state reaction barriers for four elementary steps (initiation, C-C coupling, ß-hydride elimination and 1-butene desorption) are rationalized and C-C coupling is revealed to be the rate-determining step on H-Co-, H-Ni-, H-Ru-, H-Rh- and H-Pd-DHKUST-1. The energy barrier for ß-hydride elimination is found to be the lowest on H-Ru- and H-Rh-DHKUST-1, attributed to the weak stability of agostic arrangement; however, the energy barrier for 1-butene desorption is the highest on H-Rh-DHKUST-1. Among the designed H-M-DHKUST-1, Co- and Ni-based ones are predicted to exhibit the best overall catalytic performance. The mechanistic insights from this study may facilitate the development of new MOFs toward efficient ethylene dimerization and other industrially important reactions.

Ultra-Microporous and Stable MOFs with Zero-Linker Ligands for Gas Capture and Separation.

Zero-linker ligands have maximized the size coordination efficiency of the metal ions in MOF framework which is important in constructing ultra-microporous MOFs with high stability and density, a bridge between zeolites and traditional MOFs. This article highlighted several recently developed ultra-microporous MOFs with zero-linker ligands for gas capture and separation.

Antiviral activity of human OASL protein is mediated by enhancing signaling of the RIG-I RNA sensor.

Virus infection is sensed in the cytoplasm by retinoic acid-inducible gene I (RIG-I, also known as DDX58), which requires RNA and polyubiquitin binding to induce type I interferon (IFN) and activate cellular innate immunity. We show that the human IFN-inducible oligoadenylate synthetases-like (OASL) protein has antiviral activity and mediates RIG-I activation by mimicking polyubiquitin. Loss of OASL expression reduced RIG-I signaling and enhanced virus replication in human cells. Conversely, OASL expression suppressed replication of a number of viruses in a RIG-I-dependent manner and enhanced RIG-I-mediated IFN induction. OASL interacted and colocalized with RIG-I, and through its C-terminal ubiquitin-like domain specifically enhanced RIG-I signaling. Bone-marrow-derived macrophages from mice deficient for Oasl2 showed that among the two mouse orthologs of human OASL, Oasl2 is functionally similar to human OASL. Our findings show a mechanism by which human OASL contributes to host antiviral responses by enhancing RIG-I activation.

Nanostructured Surfaces with Multimodal Antimicrobial Action.

Self-disinfecting surfaces are a current pressing need for public health and safety in view of the current COVID-19 pandemic, where the keenly felt worldwide repercussions have highlighted the importance of infection control, frequent disinfection, and proper hygiene. Because of its potential impact upon real-world translation into downstream applications, there has been much research interest in multiple disciplines such as materials science, chemistry, biology, and engineering. Various antimicrobial technologies have been developed and currently applied on surfaces in public spaces, such as elevator buttons and escalator handrails. These technologies are mainly based on conventional methods of grafting quaternary ammonium salts (QACs) such as benzalkonium chloride or the immobilization of metal species of silver or copper. However, neither the long-term efficacy nor the fast-killing properties have been proven, and the future repercussions from extended use, such as environmental hazards and the induction of MDR development, is unknown. Nanostructured surfaces with excellent antimicrobial activities have been claimed to be the next generation of self-disinfecting surfaces with various promising applications and passive antimicrobial mechanisms, without the potential repercussions of active ingredient overuse. In this Account, we briefly introduce the concept of mechanobactericidal action realized by these nanostructured surfaces first discovered on cicada wings. The elimination of microbes on the surface was actualized by the physical rupture of the microbe cell wall by nanoprotusions, without any involvement of chemical species. By mimicking the physical features of naturally occurring biocidal surfaces, the fabrication of nanostructures on various substrates such as titania, silicon, and polymers has been well described. Observations of the dependence of their antimicrobial efficacy on physical characteristics such as height, density, and rigidity have also been documented. However, the complex fabrication of such nanostructures remains the main drawback preventing its widespread application. We outline our efforts in fabricating a series of zinc-based nanostructured materials with facile and generally applicable wet chemistry methods, including nanodaggered zeolitic imidazolate frameworks (ZIF-L) and ZnO nanoneedles. In our investigations, we discovered that there were additional modes of action that contributed to the excellent biocidal activities of our materials. The impact of surface chemistry and charge was partially responsible for the selectivity and efficacy of ZIF-L-coated surfaces, where the positively charged surfaces were able to attract and adhere negatively charged bacteria to the surface. The combination of semiconductor ZnO nanoneedles on electron-donating substrates allowed for the generation of reactive oxygen species (ROS), realizing the remote killing of bacteria unadhered to the nanostructured surface. Additionally, we demonstrate several real-life applications of the synthesized materials, underscoring the importance of materials development suited for scale-up and eventual translation to potential applications and commercial end products.

IL-1α Is Essential for Oviduct Pathology during Genital Chlamydial Infection in Mice.

Chlamydia trachomatis infection of the female genital tract can lead to irreversible fallopian tube scarring. In the mouse model of genital infection using Chlamydia muridarum, IL-1R signaling plays a critical role in oviduct tissue damage. In this study, we investigated the pathologic role of IL-1α, one of the two proinflammatory cytokines that bind to IL-1R. Il1a-/- mice infected with C. muridarum cleared infection at their cervix at the same rate as wild-type (WT) mice, but were significantly protected from end point oviduct damage and fibrosis. The contribution of IL-1α to oviduct pathology was more dramatic than observed in mice deficient for IL-1ß. Although chlamydial burden was similar in WT and Il1a-/- oviduct during peak days of infection, levels of IL-1ß, IL-6, CSF3, and CXCL2 were reduced in Il1a-/- oviduct lysates. During infection, Il1a-/- oviducts and uterine horns exhibited reduced neutrophil infiltration, and this reduction persisted after the infection resolved. The absence of IL-1α did not compromise CD4 T cell recruitment or function during primary or secondary chlamydial infection. IL-1α is expressed predominantly by luminal cells of the genital tract in response to infection, and low levels of expression persisted after the infection cleared. Ab-mediated depletion of IL-1α in WT mice prevented infection-induced oviduct damage, further supporting a key role for IL-1α in oviduct pathology.

Soft Surface Nanostructure with Semi-Free Polyionic Components for Sustainable Antimicrobial Plastic.

Surface antimicrobial materials are of interest as they can combat the critical threat of microbial contamination without contributing to issues of environmental contamination and the development drug resistance. Most nanostructured surfaces are prepared by post fabrication modifications and actively release antimicrobial agents. These properties limit the potential applications of nanostructured materials on flexible surfaces. Here, we report on an easily synthesized plastic material with inherent antimicrobial activity, demonstrating excellent microbicidal properties against common bacteria and fungus. The plastic material did not release antimicrobial components as they were anchored to the polymer chains via strong covalent bonds. Time-kill kinetics studies have shown that bactericidal effects take place when bacteria come into contact with a material for a prolonged period, resulting in the deformation and rupture of bacteria cells. A scanning probe microscopy analysis revealed soft nanostructures on the submicron scale, for which the formation is thought to occur via surface phase separation. These soft nanostructures allow for polyionic antimicrobial components to be present on the surface, where they freely interact with and kill microbes. Overall, the new green and sustainable plastic is easily synthesized and demonstrates inherent and long-lasting activity without toxic chemical leaching.

Nitrogen-Linked Hexaazatrinaphthylene Polymer as Cathode Material in Lithium-Ion Battery.

Nitrogen-linked hexaazatrinaphthylene polymer (N2 -HATN) as organic cathode material with low HOMO-LOMO gap was synthesized and was observed to possess reversible high capacity and unexpected long-term cycling stability. The pre-treated N2 -HATN and pRGO combination demonstrated good structure compatibility and the resultant cathode exhibited a constant increment of capacity during the redox cycles. The initial capacity at 0.05 A g-1 was 406 mA h-1 g-1 , and increased to 630 mA h-1 g-1 after 70 cycles. At 0.5 A g-1 discharging rate, the capacity increased from an initial value of 186 mA h-1 g-1 to 588 mA h-1 g-1 after 1600 cycles. The pseudocapacitance-type behavior is postulated to be attributed to the structure compatibility between the active material and pRGO.

Caspase-11 Contributes to Oviduct Pathology during Genital Chlamydia Infection in Mice.

It has been shown that caspase-1, but not its upstream activator, ASC, contributes to oviduct pathology during mouse genital Chlamydia muridarum infection. We hypothesized that this dichotomy is due to the inadvertent absence of caspase-11 in previously used caspase-1-deficient mice. To address this, we studied the independent contributions of caspase-1 and -11 during genital Chlamydia infection. Our results show that caspase-11 deficiency was sufficient to recapitulate the effect of the combined absence of both caspase-1 and caspase-11 on oviduct pathology. Further, mice that were deficient for both caspase-1 and -11 but that expressed caspase-11 as a transgene (essentially, caspase-1-deficient mice) had no significant difference in oviduct pathology from control mice. Caspase-11-deficient mice showed reduced dilation in both the oviducts and uterus. To determine the mechanism by which caspase-11-deficient mice developed reduced pathology, the chlamydial burden and immune cell infiltration were determined in the oviducts. In the caspase-11-deficient mice, we observed increased chlamydial burdens in the upper genital tract, which correlated with increased CD4 T cell recruitment, suggesting a contribution of caspase-11 in infection control. Additionally, there were significantly fewer neutrophils in the oviducts of caspase-11-deficient mice, supporting the observed decrease in the incidence of oviduct pathology. Therefore, caspase-11 activation contributes to pathogen control and oviduct disease independently of caspase-1 activation.

WP1130 reveals USP24 as a novel target in T-cell acute lymphoblastic leukemia.

BACKGROUND: T-cell acute lymphoblastic leukemia (T-ALL) is a lymphoid malignancy caused by the oncogenic transformation of immature T-cell progenitors with poor outcomes. WP1130 has shown potent activity against a variety of cancer but whether WP1130 has anti-T-ALL activity is not clear. USP24, one target of WP1130, is one of the largest deubiquitinases and its detailed mechanism is poorly understood. The aim of this study was to explore whether WP1130 could suppress T-ALL and the role of USP24 in T-ALL. METHODS: Molecular docking and cellular thermal shift assay were performed to determine whether and how WP1130 directly interact with USP24. Mitochondrial transmembrane potential assay was measured via Rhodamine 123 staining. USP24 was reactivated using the deactivated CRISPR-associated protein 9 (dCas9)-synergistic activation mediator (SAM) system. The in vivo results were examined by tumor xenografts in NOD-SCID mice. All statistical analyses were performed with the SPSS software package. RESULTS: WP1130 treatment decreased the viability and induces apoptosis of T-ALL cells both in vitro and in vivo. Furthermore, we demonstrated that knockdown of USP24 but not USP9X could significantly induce growth inhibition and apoptosis of T-ALL cells. Oncomine database showed that USP24 expression was upregulated in T-ALL samples and Kaplan-Meier results indicated that the USP24 was negatively but USP9X was positively associated with survival in T-ALL patients. Additionally, we proposed that WP1130 directly interacts with the activity site pocket of USP24 in T-ALL cells, which leads to the decrease of its substrates Mcl-1. Mechanistically, WP1130 induces apoptosis by accelerating the collapse of mitochondrial transmembrane potential via USP24-Mcl-1 axis. CONCLUSIONS: Altogether, using WP1130 as a chemical probe, we demonstrate that USP24 but not USP9X is a novel target in T-ALL cells. Moreover, we uncovered that WP1130 induces apoptosis by accelerating the collapse of mitochondrial transmembrane potential via USP24-Mcl-1 axis. These results provide that USP24-Mcl-1 axis may represent a novel strategy in the treatment of T-ALL and WP1130 is a promising lead compound for developing anti-T-ALL drugs.

Microbicide surface nano-structures.

The prevention of infectious diseases is a global challenge where multidrug-resistant bacteria or "superbugs" pose a serious threat to worldwide public health. Microtopographic surfaces have attracted much attention as they represent a biomimetic and nontoxic surface antibacterial strategy to replace biocides. The antimicrobial effect of such natural and biomimetic surface nanostructures involves a physical approach which eradicates bacteria via the structural features of the surfaces without any release of biocides or chemicals. These recent developments present a significant proof-of-concept and a powerful tool in which cellular adhesion and death caused by a physical approach, can be controlled by the micro/nanotopology of such surfaces. This represents an innovative direction of development of clean, effective and nonresistant antimicrobial surfaces. The minireview will cover novel approaches for the construction of nanostructures on surfaces in order to create antimicrobial surface in an environmentally friendly, nontoxic manner.

ZnO Nanopillar Coated Surfaces with Substrate-Dependent Superbactericidal Property.

ZnO nanopillars coated on various surfaces are able to kill adhered bacteria and fungi due to their physical structure through a rupturing mechanism. Remarkably, zinc foil and galvanized steel surfaces with ZnO nanopillar coatings demonstrate an excellent remote bacteria-killing property. Their bacterial killing efficacy is several orders higher than ZnO nanopillars coated on other surfaces as well as ZnO nanoparticles themselves. Mechanistic study shows that the nanostructure surface kills adhered microbial cells by rupturing the cell wall, while superoxide (• O2- ) released from the ZnO coating with electrons donated from zinc via the Zn/ZnO interface rather than photoirritation is responsible for the superior remote killing. The results of this study represent a novel mechanism of surface disinfection and its application in water disinfection is also demonstrated.

Poly (I:C) alleviates obesity related pro-inflammatory status and promotes glucose homeostasis.

Obesity associated insulin resistance (IR) is implicated in chronic inflammation that mediated by the immune system. Imbalance between anti-inflammatory and pro-inflammatory response contributes to the origins and drivers of IR. However, cells of innate and adaptive immune system participate in the pathogenesis of IR, while glucose homeostasis related immune tolerance could be compromised high fat diet (HFD) reduced metabolic disorder. Although previous studies have demonstrated that anti-inflammatory therapy has a protective role in alleviating the pro-inflammatory status in HFD induced IR, the precise mechanism is still unclear. Ploy (I:C) is a synthetic double-stranded RNA that activates innate and/or adaptive immune response via retinoic acid-inducible gene-I (RIG-I), toll-like receptor 3 (TLR3) and melanoma differentiation-associated protein 5 (MDA5). In the present study, we initially perform a novel research on the relationship between Poly (I:C) preconditioning and improved glucose metabolism in obesity related IR. Interestingly, Poly (I:C) treatment has alleviated the pro-inflammatory status and promoted glucose homeostasis during a HFD feeding. Improved insulin sensitivity is consistent with enhanced immune tolerance, which accompanied with increased Foxp3+ regulatory T cells (Tregs). Of note, Tregs have a pivotal role in orchestrating the self-balance between autoimmunity and inflammation reaction. Thus, our findings reveal that Ploy (I:C) preconditioning prevents HFD induced glucose intolerance, which may be recognized as vaccination by the host. Overall, selectively targeting precise immune regulators may lead to new classes of potentially meaningful therapies for IR in the clinical trials.

Redox Active Metal- and Covalent Organic Frameworks for Energy Storage: Balancing Porosity and Electrical Conductivity.

Porous redox-active metal-organic frameworks (MOFs) and covalent organic frameworks (COFs) have emerged as electrode materials for energy storage devices. These porous frameworks have different levels of intrinsic properties such as low solubility, high ionic conductivity (porosity) and low electrical conductivity, all of which are critical parameters when utilised as electrode materials. This Minireview focuses on recent developments of using porous MOFs/COFs as redox active electrode materials for energy storage and strategies to improve their electrochemical performance.

Enhanced biomimic bactericidal surfaces by coating with positively-charged ZIF nano-dagger arrays.

Cicada wing surfaces are covered with dense patterns of nano-pillar structure that prevent bacterial growth by rupturing adhered microbial cells. To mimic the natural nano-pillar structure, we developed a general and simple method to grow metal organic framework (MOF) nano-dagger arrays on a wide range of surfaces. These nano-daggers possess high bactericidal activity, with log reduction >7 for Escherichia coli and Staphylococcus aureus. It was hypothesized that the positively-charged ZIF-L nano-dagger surfaces enhance bacterial cell adhesion, facilitating selective and efficient bacteria killing by the rigid and sharp nano-dagger tips. This research provides a safe and clean antimicrobial surface technology which does not require external chemicals and will not cause drug resistance.

Ultrafast Killing and Self-Gelling Antimicrobial Imidazolium Oligomers.

Infectious diseases and the increasing threat of worldwide pandemics have underscored the importance of antibiotics and hygiene. Intensive efforts have been devoted to developing new antibiotics to meet the rapidly growing demand. In particular, advancing the knowledge of the structure-property-activity relationship is critical to expedite the design and development of novel antimicrobial with the needed potential and efficacy. Herein, a series of new antimicrobial imidazolium oligomers are developed with the rational manipulation of terminal group's hydrophobicity. These materials exhibit superior activity, excellent selectivity, ultrafast killing (>99.7% killing within 30 s), and desirable self-gelling properties. Molecular dynamic simulations reveal the delicate effect of structural changes on the translocation motion across the microbial cell membrane. The energy barrier of the translocation process analyzed by free energy calculations provides clear kinetic information to suggest that the spontaneous penetration requires a very short timescale of seconds to minutes for the new imidazolium oligomers.

The DNA sensor, cyclic GMP-AMP synthase, is essential for induction of IFN-ß during Chlamydia trachomatis infection.

IFN-ß has been implicated as an effector of oviduct pathology resulting from genital chlamydial infection in the mouse model. In this study, we investigated the role of cytosolic DNA and engagement of DNA sensors in IFN-ß expression during chlamydial infection. We determined that three-prime repair exonuclease-1, a host 3' to 5' exonuclease, reduced IFN-ß expression significantly during chlamydial infection using small interfering RNA and gene knockout fibroblasts, implicating cytosolic DNA as a ligand for this response. The DNA sensor cyclic GMP-AMP synthase (cGAS) has been shown to bind cytosolic DNA to generate cyclic GMP-AMP, which binds to the signaling adaptor stimulator of IFN genes (STING) to induce IFN-ß expression. We determined that cGAS is required for IFN-ß expression during chlamydial infection in multiple cell types. Interestingly, although infected cells deficient for STING or cGAS alone failed to induce IFN-ß, coculture of cells depleted for either STING or cGAS rescued IFN-ß expression. These data demonstrate that cyclic GMP-AMP produced in infected cGAS(+)STING(-) cells can migrate into adjacent cells via gap junctions to function in trans in cGAS(-)STING(+) cells. Furthermore, we observed cGAS localized in punctate regions on the cytosolic side of the chlamydial inclusion membrane in association with STING, indicating that chlamydial DNA is most likely recognized outside the inclusion as infection progresses. These novel findings provide evidence that cGAS-mediated DNA sensing directs IFN-ß expression during Chlamydia trachomatis infection and suggest that effectors from infected cells can directly upregulate IFN-ß expression in adjacent uninfected cells during in vivo infection, contributing to pathogenesis.

ROS-generating oxidases Nox1 and Nox4 contribute to oncogenic Ras-induced premature senescence.

Activated oncogenes induce premature cellular senescence, a permanent state of proliferative arrest in primary rodent and human fibroblasts. Recent studies suggest that generation of reactive oxygen species (ROS) is involved in oncogenic Ras-induced premature senescence. However, the signaling mechanism controlling this oxidant-mediated irreversible growth arrest is not fully understood. Here, we show that through the Ras/MEK pathway, Ras oncogene up-regulated the expression of superoxide-generating oxidases, Nox1 in rat REF52 cells and Nox4 in primary human lung TIG-3 cells, leading to an increase in intracellular level of ROS. Ablation of Nox1 and Nox4 by small interfering RNAs (siRNAs) blocked the RasV12 senescent phenotype including ß-galactosidase activity, growth arrest and accumulation of tumor suppressors such as p53 and p16Ink4a. This suggests that Nox-generated ROS transduce senescence signals by activating the p53 and p16Ink4a pathway. Furthermore, Nox1 and Nox4 siRNAs inhibited both Ras-induced DNA damage response and p38MAPK activation, whereas overexpression of Nox1 and Nox4 alone was able to induce senescence. The involvement of Nox1 in Ras-induced senescence was also confirmed with embryonic fibroblasts derived from Nox1 knockout mice. Together, these findings suggest that Nox1- and Nox4-generated ROS play an important role in Ras-induced premature senescence, which may involve DNA damage response and p38MAPK signaling pathways.