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Senescence is a state of indefinite cell-cycle arrest associated with aging, cancer, and age-related diseases. Here, we find that translational deregulation, together with a corresponding maladaptive integrated stress response (ISR), is a hallmark of senescence that desensitizes senescent cells to stress. We present evidence that senescent cells maintain high levels of eIF2α phosphorylation, typical of ISR activation, but translationally repress production of the stress response activating transcription factor 4 (ATF4) by ineffective bypass of the inhibitory upstream open reading frames (uORFs). Surprisingly, ATF4 translation remains inhibited even after acute proteotoxic and amino acid starvation stressors, resulting in a highly diminished stress response. We also find that stress augments the senescence-associated secretory phenotype with sustained remodeling of inflammatory factors expression that is suppressed by non-uORF carrying ATF4 mRNA expression. Our results thus show that senescent cells possess a unique response to stress, which entails an increase in their inflammatory profile. [Display omitted] • Senescent cells have basal levels of eIF2α phosphorylation without ATF4 expression • Senescence is accompanied by a global decrease in ribosome content • Reduced ribosome content suppresses the ability of stress to activate the ISR • Acute stress modulates the SASP up to days after the stress has been removed Payea et al. find that ribosome depletion associated with senescence suppresses the integrated stress response (ISR) and leads to transcriptional remodeling of the senescence secretome. Stress-induced secretory remodeling (SSR) lasts days after the initial stress is removed and is suppressed by reactivation of the ISR. [ABSTRACT FROM AUTHOR]

Aging is usually accompanied by excessive body fat gain, leading to increased susceptibility to comorbidities. This study aimed to explore an unexpected function for the eukaryotic initiation factor‐2α (eIF2α) during aging. Reducing the eIF2α dose led to a reconfiguration of the metabolic equilibrium, promoting catabolism, facilitating lipolysis, and decreasing body fat accumulation while maintaining healthy glucose and lipid metabolism during aging. Specifically, eIF2α enhanced the expression of distinct messenger RNAs encoding mitochondrial electron transport chain proteins at the translation level. The mitochondrial respiration increased in eIF2α heterozygotes, even during aging. Deceleration of translation was demonstrated as a conserved mechanism for promoting longevity across various species. Our findings demonstrated that the restriction of translation by reducing eIF2α expression could fend off multiple tissue damage and improve metabolic homeostasis during aging. Hence, eIF2α was a crucial target for benefiting mammalian aging achieving delayed mammalian aging. [ABSTRACT FROM AUTHOR]

The function of General Control Nonderepressible 2 (GCN2), an evolutionaryconserved component of the integrated stress response (ISR), has been welldocumented across organisms from yeast to mammals. Recently GCN2 has also gained attention for its role in health and disease states. In this review, we provide a brief overview of GCN2, including its structure, activation mechanisms and interacting partners, and explore its potential significance as a therapeutic target in various age-related diseases including neurodegeneration, inflammatory disorders and cancer. Finally, we summarize the barriers to effectively targeting GCN2 for the treatment of disease and to promote a healthier aging process. [ABSTRACT FROM AUTHOR]

The Magic Touch sirolimus-coated balloon (SCB) was recently introduced in Europe and features robust clinical technology different from other devices on the market. This device is able to deliver a sufficient sirolimus dose to the target segment to reduce neointimal proliferation with very little exposure downstream and no apparent adverse effects at sustained high drug concentrations. The SCB represents a promising novelty within the drug-coated balloon arena due to its mid-term efficacy and safety in the treatment of coronary artery disease, especially in de novo and small-vessel coronary lesions. The purpose of this article is to provide an up-to-date overview of the currently available animal and clinical trial results, as well as to highlight ongoing trials on the Magic Touch SCB. Tweetable Abstract Among modern drug-coated balloons, Magic Touch features Nanolutè technology, which allows effective and rapid sirolimus release and retention for 8–12 weeks. Previous and ongoing trials are showing good clinical performance with sustained safety. Graphical Abstract In the EASTBOURNE section of the graphical abstract, the statistical data, including numbers and percentages, were taken from the EASTBOURNE trial [1] to create the graphs. Article Highlights Background The development of drug-coated balloons (DCBs) has improved the management of coronary artery disease (CAD), the leading cause of death worldwide. The Magic Touch Sirolimus DCB was recently introduced in Europe and features Nanolutè technology to deliver sirolimus to the vessel wall, ensuring that it is sustained for the duration required to achieve therapeutic effects. The objective of this review is to provide an up-to-date overview and summary of the most recent animal and clinical trial data on the Magic Touch sirolimus DCB, as well as to highlight ongoing investigations analyzing the role of this sirolimus-coated balloon (SCB) in various clinical settings. Pre-clinical & clinical data of Magic Touch SCB This article demonstrates that the SCB is a promising novelty within the DCB arena due to its mid-term efficacy and safety in the treatment of CAD, particularly in de novo and small-vessel coronary lesions, at least from the Magic Touch perspective, as the other two SCBs on the market lack clinical evidence. In addition, preclinical studies have demonstrated that this device is capable of delivering sirolimus to the target segment in a sufficient amount to reduce neointima proliferation in a vascular model with minimal exposure to downstream organs, with no apparent adverse effects when sustained high drug concentrations in the target vessel are maintained. Conclusion In conclusion, SCBs represent a new option in the treatment of CAD, especially in patients with in-stent restenosis, de novo artery disease, and small coronary arteries, in addition to a few well-known and effective paclitaxel-coated balloons. Currently, ongoing trials will have to clarify the performance of this device compared with drug-eluting stents. [ABSTRACT FROM AUTHOR]

Given the inherent complexities of bioanalysis, the role of incurred sample reanalysis (ISR) is increasingly appreciated in regulatory bioanalysis. Incurred sample reanalysis has evolved as an integral part of an assay to ensure method reproducibility. The current regulatory ISR guidelines do not provide clarity regarding ISR assessment for chiral drugs comprising enantiomers. Because chiral assays evaluate two enantiomers, there are additional complexities associated with the ISR data generation and interpretation. Based on the current literature, the practices for conducting ISR in chiral methods were reviewed and assessed. While ISR was conducted in chiral methods for both enantiomers using the acceptance criteria prescribed for non‐chiral methods, there may be a need to streamline the nuances of ISR data interpretation and define the ISR requirements for chiral methods. The article provides perspectives on the ISR of enantiomeric drugs, including strategy development, by providing various hypothetical scenarios and possible considerations for defining ISR evaluation for chiral assays. [ABSTRACT FROM AUTHOR]

The circadian timing system and integrated stress response (ISR) systems are fundamental regulatory mechanisms that maintain body homeostasis. The central circadian pacemaker in the suprachiasmatic nucleus (SCN) governs daily rhythms through interactions with peripheral oscillators via the hypothalamus-pituitary-adrenal (HPA) axis. On the other hand, ISR signaling is pivotal for preserving cellular homeostasis in response to physiological changes. Notably, disrupted circadian rhythms are observed in cases of impaired ISR signaling. In this work, we examine the potential interplay between the central circadian system and the ISR, mainly through the SCN and HPA axis. We introduce a semimechanistic mathematical model to delineate SCN's capacity for indirectly perceiving physiological stress through glucocorticoid-mediated feedback from the HPA axis and orchestrating a cellular response via the ISR mechanism. Key components of our investigation include evaluating general control nonderepressible 2 (GCN2) expression in the SCN, the effect of physiological stress stimuli on the HPA axis, and the interconnected feedback between the HPA and SCN. Simulation revealed a critical role for GCN2 in linking ISR with circadian rhythms. Experimental findings have demonstrated that a Gcn2 deletion in mice leads to rapid re-entrainment of the circadian clock following jetlag as well as to an elongation of the circadian period. These phenomena are well replicated by our model, which suggests that both the swift re-entrainment and prolonged period can be ascribed to a reduced robustness in neuronal oscillators. Our model also offers insights into phase shifts induced by acute physiological stress and the alignment/misalignment of physiological stress with external light-dark cues. Such understanding aids in strategizing responses to stressful events, such as nutritional status changes and jetlag. NEW & NOTEWORTHY: This study is the first theoretical work to investigate the complex interaction between integrated stress response (ISR) sensing and central circadian rhythm regulation, encompassing the suprachiasmatic nucleus (SCN) and hypothalamus-pituitary-adrenal (HPA) axis. The findings carry implications for the development of dietary or pharmacological interventions aimed at facilitating recovery from stressful events, such as jetlag. Moreover, they provide promising prospects for potential therapeutic interventions that target circadian rhythm disruption and various stress-related disorders. [ABSTRACT FROM AUTHOR]

ABSTRACTThis experiment is to investigate whether interspecies differences exist in the effects of leucine (Leu) on digestive enzyme secretion in pancreatic tissues through in vitro. Five healthy Simmental cattle and Duroc × Landrace × Yorkshire growing-finishing pigs were selected, and pancreatic tissues were taken for culture after slaughter. Leu levels of 0, 2.62, 5.24, 10.48 mg/mL. Leu levels of 0, 5.24 mg/mL were selected to determine the expression of mRNA and proteins in the signaling pathways. The results showed that Leu increased the activity of digestive enzyme in cattle and pig, and there was an interaction was found on trypsin and chymotrypsin (P

The European "Green Deal" policies are shifting toward more sustainable and environmentally conscious agricultural practices, reducing the use of chemical fertilizer and pesticides. This implies exploring alternative strategies. One promising alternative to improve plant nutrition and reinforce plant defenses is the use of beneficial microorganisms in the rhizosphere, such as "Plant-growth-promoting rhizobacteria and fungi". Despite the great abundance of iron (Fe) in the Earth's crust, its poor solubility in calcareous soil makes Fe deficiency a major agricultural issue worldwide. Among plant promoting microorganisms, the yeast Debaryomyces hansenii has been very recently incorporated, for its ability to induce morphological and physiological key responses to Fe deficiency in plants, under hydroponic culture conditions. The present work takes it a step further and explores the potential of D. hansenii to improve plant nutrition and stimulate growth in cucumber plants grown in calcareous soil, where ferric chlorosis is common. Additionally, the study examines D. hansenii's ability to induce systemic resistance (ISR) through a comparative relative expression study by qRT-PCR of ethylene (ET) biosynthesis (ACO1), or ET signaling (EIN2 and EIN3), and salicylic acid (SA) biosynthesis (PAL)-related genes. The results mark a significant milestone since D. hansenii not only enhances nutrient uptake and stimulates plant growth and flower development but could also amplify induced systemic resistance (ISR). Although there is still much work ahead, these findings make D. hansenii a promising candidate to be used for sustainable and environmentally friendly integrated crop management. [ABSTRACT FROM AUTHOR]

Radiata pine is one of the most commonly planted tree species in Chile due to its fast growth and desirable wood and pulp properties. However, its productivity is hampered by several diseases. Pitch canker disease (PCC) caused by Fusarium circinatum, is considered the most damaging disease to the pine forest industry. Several control measures have been established, with biological control emerging as an environmentally friendly and effective way for F. circinatum control. Previous studies support the value of Clonostachys rosea in reducing PCC damage, with evidence suggesting a potential induced systemic resistance (ISR) triggered in radiata pines by this agent. Ten-month-old radiata pine plants were pre-treated with C. rosea on a substrate at 8 and 1 days before inoculation with F. circinatum on the stem tip, and expression levels were determined for DXS1, LOX, PAL, and PR3 genes 24 h later. Lesion length was 45% lower on plants pre-treated with C. rosea and infected with F. circinatum compared to non-pre-treated and infected plants. Additionally, LOX and PR3 were induced 23 and 62 times more, respectively, in comparison to untreated plants. Our results indicate that C. rosea causes an ISR response in pre-treated plants, significantly increasing the expression of resistance genes and reducing lesion length. [ABSTRACT FROM AUTHOR]

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Regeneration and repair are prerequisites for maintaining effective function of skeletal muscle under high energy demands, and myogenic differentiation is one of the key steps in the regeneration and repair process. A striking feature of the process of myogenic differentiation is the alteration of mitochondria in number and function. Mitochondrial dysfunction can activate a number of transcriptional, translational and post-translational programmes and pathways to maintain cellular homeostasis under different types and degrees of stress, either through its own signaling or through constant signaling interactions with the nucleus and cytoplasm, a process known as the mitochondrial stress responses (MSRs). It is now believed that mitochondrial dysfunction is closely associated with a variety of muscle diseases caused by reduced levels of myogenic differentiation, suggesting the possibility that MSRs are involved in messaging during myogenic differentiation. Also, MSRs may be involved in myogenesis by promoting bioenergetic remodeling and assisting myoblast survival during myogenic differentiation. In this review, we will take MSRs as an entry point to explore its concrete regulatory mechanisms during myogenic differentiation, with a perspective to provide a theoretical basis for the treatment and repair of related muscle diseases. [ABSTRACT FROM AUTHOR]

In T-cell acute lymphoblastic leukemia (T-ALL), more than 50% of cases display autoactivation of Notch1 signaling, leading to oncogenic transformation. We have previously identified a specific chemovar of Cannabis that induces apoptosis by preventing Notch1 maturation in leukemia cells. Here, we isolated three cannabinoids from this chemovar that synergistically mimic the effects of the whole extract. Two were previously known, cannabidiol (CBD) and cannabidivarin (CBDV), whereas the third cannabinoid, which we termed 331-18A, was identified and fully characterized in this study. We demonstrated that these cannabinoids act through cannabinoid receptor type 2 and TRPV1 to activate the integrated stress response pathway by depleting intracellular Ca2+. This is followed by increased mRNA and protein expression of ATF4, CHOP, and CHAC1, which is hindered by inhibiting the upstream initiation factor eIF2α. The increased abundance of CHAC1 prevents Notch1 maturation, thereby reducing the levels of the active Notch1 intracellular domain, and consequently decreasing cell viability and increasing apoptosis. Treatment with the three isolated molecules resulted in reduced tumor size and weight in vivo and slowed leukemia progression in mice models. Altogether, this study elucidated the mechanism of action of three distinct cannabinoids in modulating the Notch1 pathway, and constitutes an important step in the establishment of a new therapy for treating NOTCH1-mutated diseases and cancers such as T-ALL.

The function of General Control Nonderepressible 2 (GCN2), an evolutionary-conserved component of the integrated stress response (ISR), has been well-documented across organisms from yeast to mammals. Recently GCN2 has also gained attention for its role in health and disease states. In this review, we provide a brief overview of GCN2, including its structure, activation mechanisms and interacting partners, and explore its potential significance as a therapeutic target in various age-related diseases including neurodegeneration, inflammatory disorders and cancer. Finally, we summarize the barriers to effectively targeting GCN2 for the treatment of disease and to promote a healthier aging process.

ObjectiveThe mitochondrial fission protein Drp1 was proposed to promote NAFLD, as inhibition of hepatocyte Drp1 early in life prevents liver steatosis induced by high-fat diet in mice. However, whether Drp1-knockdown in older mice can reverse established NASH is unknown.MethodsN-acetylgalactosamine-siRNA conjugates, an FDA approved method to deliver siRNA selectively to hepatocytes, were used to knockdown hepatocyte-Drp1 in mice (NAG-Drp1si). NASH was induced in C57BL/6NTac mice by Gubra-Amylin-NASH diet (D09100310, 40% fat, 22% fructose and 2% cholesterol) and treatment with NAG-Drp1si was started at week 24 of diet. Circulating transaminases, liver histology, gene expression of fibrosis and inflammation markers, and hydroxyproline synthesis determined NASH severity. Liver NEFA and triglycerides were quantified by GC/MS. Mitochondrial function was determined by respirometry. Western blots of Oma1, Opa1, p-eIf2α, as well as transcriptional analyses of Atf4-regulated genes determined ISR engagement.ResultsNAG-Drp1si treatment decreased body weight and induced liver inflammation in adult healthy mice. Increased hepatic Gdf15 production was the major contributor to body-weight loss caused by NAG-Drp1si treatment, as Gdf15 receptor deletion (Gfral KO) prevented the decrease in food intake and mitigated weight loss. NAG-Drp1si activated the Atf4-controlled integrated stress response (ISR) to increase hepatic Gdf15 expression. NAG-Drp1si in healthy mice caused ER stress and activated the mitochondrial protease Oma1, which are the ER and mitochondrial triggers that activate the Atf4-controlled ISR. Remarkably, induction of NASH was not sufficient to activate Oma1 in liver. However, NAG-Drp1si treatment was sufficient to activate Oma1 in adult mice with NASH, as well as exacerbating NASH-induced ER stress. Consequently, NAG-Drp1si treatment in mice with NASH led to higher ISR activation, exacerbated inflammation, fibrosis and necrosis.ConclusionDrp1 mitigates NASH by decreasing ER stress, preventing Oma1 activation and ISR exacerbation. The elevation in Gdf15 actions induced by NAG-Drp1si might represent an adaptive response decreasing the nutrient load to liver when mitochondria are misfunctional. Our study argues against blocking Drp1 in hepatocytes to combat NASH.

Simple Summary: Activating transcription factor 4 (ATF4) is a transcription factor known to regulate genes associated with the sensing of cellular stress such as amino acid deprival, protein misfolding, growth arrest, and cell death. Despite its key role at the crossroads of immune and stress responses, the precise impact of ATF4 during viral infections remains unclear. Thus, ATF4 has a dual role in promoting cell survival or cell death, but also in limiting infection or participating in viral replication. In this review, we focus specifically on ATF4-mediated signaling during human immunodeficiency virus 1 (HIV-1) infection and examine the multifaceted role of ATF4 in this context. We also explore the potential role of its paralogue ATF5. This review also discusses the possible hijacking of ATF4 activation by viruses to modulate host immune responses. By highlighting the involvement of ATF4 in viral infections, this study gives valuable insights that could be used for further strategies to tackle viral infections, providing a deeper understanding of host–pathogen interactions. Cellular integrated stress response (ISR), the mitochondrial unfolded protein response (UPRmt), and IFN signaling are associated with viral infections. Activating transcription factor 4 (ATF4) plays a pivotal role in these pathways and controls the expression of many genes involved in redox processes, amino acid metabolism, protein misfolding, autophagy, and apoptosis. The precise role of ATF4 during viral infection is unclear and depends on cell hosts, viral agents, and models. Furthermore, ATF4 signaling can be hijacked by pathogens to favor viral infection and replication. In this review, we summarize the ATF4-mediated signaling pathways in response to viral infections, focusing on human immunodeficiency virus 1 (HIV-1). We examine the consequences of ATF4 activation for HIV-1 replication and reactivation. The role of ATF4 in autophagy and apoptosis is explored as in the context of HIV-1 infection programmed cell deaths contribute to the depletion of CD4 T cells. Furthermore, ATF4 can also participate in the establishment of innate and adaptive immunity that is essential for the host to control viral infections. We finally discuss the putative role of the ATF4 paralogue, named ATF5, in HIV-1 infection. This review underlines the role of ATF4 at the crossroads of multiple processes reflecting host–pathogen interactions. [ABSTRACT FROM AUTHOR]

Aims The study aimed to determine the pathogenicity of Fusarium species currently prevalent in tomato fields having history of chemical fungicide applications and determine the bio-efficacy of Bacillus subtilis NBRI-W9 as a potent biological control agent. Methods and results Fusarium was isolated from surface-sterilized infected tomato plants collected from fields. Pathogenicity of 30 Fusarium isolates was determined by in vitro and in vivo assays. Following Koch's postulates, F. chlamydosporum (FOL7) was identified as a virulent pathogen. The biological control of FOL 7 by B. subtilis NBRI-W9 (W9) and the colonization potential of W9 were established using spontaneous rifampicin-resistant mutants. W9 showed 82% inhibition of FOL7 on a dual-culture plate and colonization levels in tomato plants of ∼5.5, ∼3.3, and ∼2.2 log10 CFU/g in root, stem, and leaf tissue, respectively. Antagonistic activity was shown by scanning electron microscopy (SEM) and cell-wall-degradative enzymes. W9 reduced FOL7 infection in net-house and field experiments by 60% and 41%, respectively. Biochemical investigation, defence enzymes, defence gene expression analysis, SEM, and field studies provide evidence of hyperparasitism and induced resistance as the mode of biological control. The study also demonstrates that the potent biocontrol agent W9, isolated from Piper, can colonize tomato plants, control fungal disease by inducing induced systemic resistance (ISR) and systemic acquired resistance (SAR) simultaneously, and increase crop yield by 21.58% under field conditions. Conclusions This study concludes that F. chlamydosporum (NBRI-FOL7) is a potent, fungicide-resistant pathogen causing wilt in tomatoes. NBRI-W9 controlled FOL7 through mycoparasitism and simultaneously activated ISR and SAR in plants, providing an attractive tool for disease control that acts at multiple levels. [ABSTRACT FROM AUTHOR]

This article argues that India–Israel cooperation in space-based imagery originated under a realist logic but has been developing under an increasingly strong value-based commitment in countering terrorism. In this regard, the relationship is somewhat like the UK-US signals intelligence sharing arrangement that was originally formed to defeat the Axis powers but strengthened over shared values in countering communism and then international terrorism. To establish this, the article provides the first detailed account of the evolution of the Indo-Israel spy satellites cooperation and offers fresh insights into the future trajectory considering the recent security developments affecting India and Israel. [ABSTRACT FROM AUTHOR]

Aim: Characterize Growth Differentiation Factor 15 (GDF15) as a secreted biomarker of the integrated stress response (ISR) within the central nervous system (CNS). Methods: We determined GDF15 levels utilizing in vitro and in vivo neuronal systems wherein the ISR was activated. Primarily, we used the murine model of vanishing white matter disease (VWMD), a neurological disease driven by persistent ISR in the CNS, to establish a link between levels of GDF15 in the cerebrospinal fluid (CSF) and ISR gene expression signature in the CNS. GDF15 was also determined in the CSF of VWM patients. Results: GDF15 expression was increased concomitant to ISR activation in stress‐induced primary astrocytes as well as in retinal ganglion cells following optic nerve crush, while treatment with 2Bact, a specific eIF2B activator, suppressed both the ISR and GDF15. In the VWMD model, CSF GDF15 levels corresponded with the magnitude of the ISR and were reduced by 2BAct. In VWM patients, mean CSF GDF15 was elevated >20‐fold as compared to healthy controls, whereas plasma GDF15 was undifferentiated. Conclusions: These data suggest that CSF GDF15 is a dynamic marker of ISR activation in the CNS and may serve as a pharmacodynamic biomarker for ISR‐modulating therapies. [ABSTRACT FROM AUTHOR]

The stem rot caused by Sclerotium hydrophilum and false smut caused by Ustilaginoidea virens are two of the major production constraints in rice cultivation in India and other countries. Stem rot and false smut can be effectively controlled with synthetic fungicides. However, the indiscriminate use of chemical fungicides may cause development of resistance among the pathogens. In addition to this, synthetic fungicides also exhibit harmful impacts on the environment. Exploiting microbe-based alternatives for managing plant diseases diminishes public concerns about the ill effects of pesticide usage in crops. In this regard, the present study was designed to investigate the potential of native microbial biocontrol agents (BCAs) from rice rhizosphere for the sustainable management of stem rot and false smut diseases in rice. Potential BCAs and pathogens were identified and characterized through morphological, biochemical, and sanger sequencing techniques. Bio-efficacy tests of potential BCAs against stem rot and false smut diseases on rice under glasshouse conditions indicated higher seed vigour index of the treated seeds, significant improvement in the growth of the seedling, increased dry weight, reduction in percentage disease index viz., 70.03% (stem rot) and 69.24% (false smut) over the control plants. Phytohormones indole acetic acid (IAA), abscisic acid (ABA), gibberellic acid (GA), salicylic acid (SA), and zeatin (tZ) were detected and quantified in the four potential BCAs using liquid chromatography- tandem mass spectrometry (LC–MS/MS). Scanning electron microscopy (SEM) studies revealed the endophytic nature of the strains in rice. The study indicated a positive correlation between the diversity and concentration of phytohormones released by the bioagents and enhanced plant growth promotion and disease suppression in rice. [ABSTRACT FROM AUTHOR]

In eukaryotic cells, stressors reprogram the cellular proteome by activating the integrated stress response (ISR). In its canonical form, stress-sensing kinases phosphorylate the eukaryotic translation initiation factor eIF2 (eIF2-P), which ultimately leads to reduced levels of ternary complex required for initiation of mRNA translation. Previously we showed that translational control is primarily exerted through a conformational switch in eIF2's nucleotide exchange factor, eIF2B, which shifts from its active A-State conformation to its inhibited I-State conformation upon eIF2-P binding, resulting in reduced nucleotide exchange on eIF2 (Schoof et al. 2021). Here, we show functionally and structurally how a single histidine to aspartate point mutation in eIF2B's β subunit (H160D) mimics the effects of eIF2-P binding by promoting an I-State like conformation, resulting in eIF2-P independent activation of the ISR. These findings corroborate our previously proposed A/I-State model of allosteric ISR regulation.

Ling Hou,1 Ke Su,2 Jinbo Zhao,2 Yuanhong Li2 1Department of Central Hospital of Tujia and Miao Autonomous Prefecture, Hubei University of Medicine, Shiyan, Hubei Province, People’s Republic of China; 2Cardiovascular Disease Center, Central Hospital of Tujia and Miao Autonomous Prefecture, Hubei University of Medicine, Enshi, Hubei Province, People’s Republic of ChinaCorrespondence: Yuanhong Li, Email lyh0101@vip.comObjective: Chronic obstructive pulmonary disease (COPD) is a prevalent chronic respiratory disease that poses a significant health risk to individuals. Patients with COPD are predisposed to a higher incidence of coronary artery disease (CAD) than the general population. This study aims to investigate the correlation between COPD and the incidence of in-stent restenosis (ISR) after percutaneous coronary intervention (PCI).Methods: This study retrospectively analyzed the clinical data and laboratory test results of patients who underwent PCI at our hospital between January 2018 and December 2021 to investigate the relationship between COPD and drug-Eluting Stents (DES) postoperative ISR. We employed the best subset method to select the most suitable combination of predictive factors, utilizing the data, and verified the precision of the model by means of internal validation. We ultimately assessed the performance of the prediction model using an ROC curve.Results: The research indicates that COPD is an independent risk factor for ISR after PCI (OR=2.437, 95% CI [1.336, 4.495], P=0.004). The analysis revealed an area under the receiver operating characteristic (ROC) curve of 0.783 for the training group and 0.705 for the testing group, indicating a model fitting for both groups (both > 0.5).Conclusion: COPD history is a dependable predictor of stent restenosis post percutaneous coronary intervention.Keywords: percutaneous coronary intervention, PCI, chronic obstructive pulmonary disease, COPD, in-stent restenosis, ISR, drug-eluting stents, DES, optimal subset regression

Biotic stress affects economically important crop species and leads to quality and yield losses. Plants exhibit the ability of responding to the pathogen attack by synthesizing compounds which leads to either the inhibition or reduction of disease incidence. Plants live in close association with microbial communities. Microbes and their metabolites impact the health of the plants by supplying mineral nutrients, hormonal modulation and protection from the pathogenic organisms. Induced systemic response is one of the major mechanisms employed by the microbes in biocontrol. Beneficial microbes release certain compounds as elicitors in the rhizospheric region which are perceived by the plant roots as signals that increase the defense and resistance of the plants against the phytopathogens. The phytohormones such as ethylene, jasmonic acid, and salicylic acid are involved in regulation of the induced defense responses. The present review highlights the negative impact of the biotic stress on the plants and how induced systemic response is induced in the plants further discussing the role of the microbial elicitors in induced systemic response, their molecular mechanisms and hormonal regulation and draws the attention of the scientific community to explore new microbial elicitors as disease control alternatives.

Bacteria from the Pantoea genus are regularly found to interact with a variety of plants, as pathogens or as beneficial bacteria, depending on the strain and the host plant. Despite increasing interest in this bacterial genus, the mechanisms by which it interacts with pathogens and host plants remain to be deciphered. This review addresses the current knowledge about the various types of interactions and metabolic traits of Pantoea spp. in protecting plants against pathogens, from direct antagonism to stimulation of plant innate immunity. The biocontrol capacity of Pantoea species mainly relies on the production of a diversity of natural metabolites. In this review, we also discuss the identity and the potential role of these metabolites in Pantoea-driven plant protection.

The sigma 2 receptor (σ2R) was described pharmacologically more than three decades ago, but its molecular identity remained obscure until recently when it was identified as transmembrane protein 97 (TMEM97). We and others have shown that σ2R/TMEM97 ligands alleviate mechanical hypersensitivity in mouse neuropathic pain models with a time course wherein maximal antinociceptive effect is approximately 24 h following dosing. We sought to understand this unique antineuropathic pain effect by addressing two key questions: do these σ2R/TMEM97 compounds act selectively via the receptor, and what is their downstream mechanism on nociceptive neurons? Using male and female conventional knockout mice for Tmem97, we find that a σ2R/TMEM97 binding compound, FEM-1689, requires the presence of the gene to produce antinociception in the spared nerve injury model in mice. Using primary mouse dorsal root ganglion neurons, we demonstrate that FEM-1689 inhibits the integrated stress response (ISR) and promotes neurite outgrowth via a σ2R/TMEM97-specific action. We extend the clinical translational value of these findings by showing that FEM-1689 reduces ISR and p-eIF2α levels in human sensory neurons and that it alleviates the pathogenic engagement of ISR by methylglyoxal. We also demonstrate that σ2R/TMEM97 is expressed in human nociceptors and satellite glial cells. These results validate σ2R/TMEM97 as a promising target for further development for the treatment of neuropathic pain. [ABSTRACT FROM AUTHOR]

Cellular senescence is a complex process characterized by irreversible cell cycle arrest. Senescent cells accumulate with age, promoting disease development, yet the absence of specific markers hampers the development of selective anti-senescence drugs. The integrated stress response (ISR), an evolutionarily highly conserved signaling network activated in response to stress, globally downregulates protein translation while initiating the translation of specific protein sets including transcription factors. We propose that ISR signaling plays a central role in controlling senescence, given that senescence is considered a form of cellular stress. Exploring the intricate relationship between the ISR pathway and cellular senescence, we emphasize its potential as a regulatory mechanism in senescence and cellular metabolism. The ISR emerges as a master regulator of cellular metabolism during stress, activating autophagy and the mitochondrial unfolded protein response, crucial for maintaining mitochondrial quality and efficiency. Our review comprehensively examines ISR molecular mechanisms, focusing on ATF4-interacting partners, ISR modulators, and their impact on senescence-related conditions. By shedding light on the intricate relationship between ISR and cellular senescence, we aim to inspire future research directions and advance the development of targeted anti-senescence therapies based on ISR modulation. [ABSTRACT FROM AUTHOR]

Trichoderma, widely distributed all over the world, is commonly found in soil and root ecosystems. It is a group comprising beneficial fungi that improve plant disease resistance and promote plant growth. Studies have shown that Trichoderma cellulases can also improve plant disease resistance. Based on previous studies, we reported that a C6 zinc finger protein (Thc6) regulates two cellulase genes, thph1 and thph2, to induce ISR responses in plants. Therefore, in this study, we focused on the role of thph2 in the colonization of maize roots by T. harzianum and the induction of systemic resistance against southern leaf blight. The results showed that thph2 had a positive regulatory effect on the Trichoderma colonization of maize roots. After the root was treated with Trichoderma, the leaf defense genes AOS, LOX5, HPL, and OPR1 were expressed to resist the attack of Cochliobolus heterostrophus. The pure Thph2 protein also resulted in a similar induction activity of the AOS, LOX5, HPL, and OPR1 expression in maize roots, further demonstrating that thph2 can induce plant defense responses and that signal transduction occurs mainly through the JA signaling pathway. [ABSTRACT FROM AUTHOR]

In‑stent restenosis (ISR) is the leading cause of the need for reintervention after per‑ cutaneous coronary intervention (PCI). Lumen diameter reduction may occur due to early elastic return, vascular remodelling, or aggressive neointimal hyperplasia in the luminal surface of the stent. Recent data also suggest that a newly occurring atherosclerotic process called „neoatherosclerosis“ can play an essential role in the development of ISR. Numerous studies have shown a high incidence of acute coronary syndrome (ACS) as a clinical manifestation of ISR and its association with increased mortality and morbidity. Stent improvements, novel drug regimens, and technological advances have expanded the scope of treatment for ISR. Intracoronary imaging is also beneficial in guiding the intervention. The development of DES has been shown to reduce the incidence of ISR. However, target lesion revascularisation still exists and may occur within 5 years and 10 years (in 10% and 20%, respectively). Thus, it is necessary to consider the strategy to prevent and manage ISR optimally in order to avoid the possibility of another episode of restenosis. In this paper, we sys‑ tematically reviewed ISR and its various treatments based on recent literature reviews. [ABSTRACT FROM AUTHOR]

• The accuracy of different formulas for h m F2 estimation is investigated using Millstone Hill ISR data. • SHU-2015 model performs better in any condition even compared to the formulas fed by validated data. • BSE-1979 provided reasonably good results, while AMTB-2013 does not work satisfactory during night. • SHI-1955 and BSE-1979 formulas fed by validated data can be used for trend analyses at night. Several empirical formulations used over time to estimate the fundamental ionospheric parameter h m F2 have been compared in this study. These are the first formulation proposed by Shimazaki (1955) (SHI-1955) as a function of the propagation parameter M(3000)F2, the more accurate BSE-1979 formula proposed by Bilitza et al. (1979) and firstly adopted by the International Reference Ionosphere (IRI) model, and the newest Altadill-Magdaleno-Torta-Blanch (AMTB-2013) (Altadill et al., 2013) and SHU-2015 (Shubin, 2015) models, obtained with a different approach with no explicit dependence on any ionospheric parameter and added as alternative options in the IRI-2016. The evaluation of the accuracy of the available formulation is performed by comparing the modeled values of h m F2 with those simultaneously obtained with independent measurements from the Incoherent Scatter Radar (ISR) installed at the Millstone Hill ionospheric station. The database considered consists of 3626 measurements, thus allowing the evaluation of the results for different heliogeophysical conditions. SHI-1955 and BSE-1979 formulations are evaluated also using input data manually scaled from ionograms recorded at the same location, with the aim of evaluating their accuracy when updated with validated data rather than modeled ones. The SHU-2015 is confirmed the best option in any condition, while AMTB-2013 turns out to perform poorly during night, when SHI-1955 and BSE-1979 fed by validated data can be used for trend analyses due to the high correlation with ISR data. Despite this, BSE-1979 performs better with modeled parameters as input, in terms of RMSE and mean deviation from ISR data. The use of SHI-1955 with CCIR-modeled M(3000)F2 is discouraged under daytime conditions even for long trend analyses. [ABSTRACT FROM AUTHOR]

The purpose of this study is to analyze the implementation of corporate social responsibility (CSR) as measured by the ISR index in Islamic banks in Indonesia using the content analysis method. The population and samples used include BRI Syariah Bank, BNI Syariah, Muamalat Bank and BCA Syariah Bank. The results showed that not all Islamic Banks which include BRIS, BM, BNIS, and BBCAS disclose ISR in a formative manner. Only Bank BRI Syariah and Bank Muamalat disclosed ISR informatively in the period 2018-2021. Bank BCA Syariah did not disclose ISR formatively for the period 2018 - 2021. Meanwhile, Bank BNI Syariah only disclosed its ISR informatively for the 2020 and 2021 periods, while the 2018 and 2019 periods were not disclosed informatively. The conclusion shows that informative ISR disclosures are only made by Bank BRI Syariah and Bank Muamalat

This study aims to show how the influence of zakat funds, non-halal funds, and Islamic social reporting (ISR) on the performance and reputation of Islamic commercial banks. This type of research uses a quantitative approach. The research population is Islamic commercial banks (ICB) in Indonesia registered with the financial services authority (FSA) for the 2016-2020 period; 14 ICB samples were obtained using the saturated sample technique. The data used is secondary data derived from the annual report of each bank. Data analysis techniques using structural equation modelling (SEM) with the help of AMOS 26 software include classic assumption tests, model feasibility, and hypotheses. The results of this study indicate that zakat funds and ISR do not affect bank performance as a proxy for return on assets (ROA). However, non-halal funds significantly negatively affect ROA. Zakat funds do not affect the company's reputation proxied by market share. However, non-halal funds significantly negatively affect market share, and ISR significantly positively affects market share. This research can contribute to proving whether signalling theory, stakeholder theory, and sharia enterprise theory can strengthen or weaken the influence of zakat funds, non-halal funds, and ISR on the performance and reputation of ICB and can become reference material for Islamic banks to improve their performance and reputation.

Unmanned aerial vehicle (UAV), which is one of the significant means of maritime and aviation reconnaissance, is recognized as the main reconnaissance force to obtain information control and air control in the future sea battlefield. By combing the models and attribute characteristics of foreign small and medium-sized UAVs on the sea, this paper studies the application mode and application advantages of small and medium-sized ISR UAVs in the sea battlefield, and discusses their problems faced by the application, then analyzes the key technologies, such as launch and recovery, autonomous control, mission load, communication link, platform design, finally looks forward to their development trend. This paper provides reference and ideas for the popularization, application and planning development of small and medium-sized ISR UAVs in the field of maritime.

The integrated stress response (ISR) is activated by phosphorylation of the translation initiation factor eIF2 in response to various stress conditions. Phosphorylated eIF2 (eIF2-P) inhibits eIF2's nucleotide exchange factor eIF2B, a twofold symmetric heterodecamer assembled from subcomplexes. Here, we monitor and manipulate eIF2B assembly in vitro and in vivo. In the absence of eIF2B's α-subunit, the ISR is induced because unassembled eIF2B tetramer subcomplexes accumulate in cells. Upon addition of the small-molecule ISR inhibitor ISRIB, eIF2B tetramers assemble into active octamers. Surprisingly, ISRIB inhibits the ISR even in the context of fully assembled eIF2B decamers, revealing allosteric communication between the physically distant eIF2, eIF2-P, and ISRIB binding sites. Cryo-electron microscopy structures suggest a rocking motion in eIF2B that couples these binding sites. eIF2-P binding converts eIF2B decamers into 'conjoined tetramers' with diminished substrate binding and enzymatic activity. Canonical eIF2-P-driven ISR activation thus arises due to this change in eIF2B's conformational state.

Plant diseases caused by pathogens pose significant threats to agricultural productivity and food security worldwide. The traditional approach of relying on chemical pesticides for disease management has proven to be unsustainable, emphasizing the urgent need for sustainable and environmentally friendly alternatives. One promising strategy is to enhance plant resistance against pathogens through various methods. This review aims to unveil and explore effective methods for stimulating plant resistance, transforming vulnerable plants into vigilant defenders against pathogens. We discuss both conventional and innovative approaches, including genetic engineering, induced systemic resistance (ISR), priming, and the use of natural compounds. Furthermore, we analyze the underlying mechanisms involved in these methods, highlighting their potential advantages and limitations. Through an understanding of these methods, scientists and agronomists can develop novel strategies to combat plant diseases effectively while minimizing the environmental impact. Ultimately, this research offers valuable insights into harnessing the plant’s innate defense mechanisms and paves the way for sustainable disease management practices in agriculture.

Entomopathogenic fungi (EPF) exhibit direct and indirect mechanisms to increase plant resistance against biotic and abiotic stresses. Plant responses to these stresses are interconnected by common regulators such as ethylene (ET), which is involved in both iron (Fe) deficiency and induced systemic resistance responses. In this work, the roots of cucurbit seedlings were primed with Metarhizium brunneum (EAMa 01/58-Su strain), and relative expression levels of 18 genes related to ethylene (ET), jasmonic acid (JA), and salicylic acid (SA) synthesis, as well as pathogen-related (PR) protein genes, were studied by reverse transcription-quantitative PCR (qRT-PCR). Effects of priming on Spodoptera littoralis were studied by feeding larvae for 15 days with primed and control plants. Genes showed upregulation in studied species; however, the highest relative expression was observed in roots and shoots of plants with Fe deficiency, demonstrating the complexity and the overlapping degree of the regulatory network. EIN2 and EIN3 should be highlighted; both are key genes of the ET transduction pathway that enhanced their expression levels up to eight and four times, respectively, in shoots of primed cucumber. Also, JA and SA synthesis and PR genes showed significant upregulation during the observation period (e.g., the JA gene LOX1 increased 506 times). Survival and fitness of S. littoralis were affected with significant effects on mortality of larvae fed on primed plants versus controls, length of the larval stage, pupal weight, and the percentage of abnormal pupae. These results highlight the role of the EAMa 01/58-Su strain in the induction of resistance, which could be translated into direct benefits for plant development. IMPORTANCE Entomopathogenic fungi are multipurpose microorganisms with direct and indirect effects on insect pests. Also, EPF provide multiple benefits to plants by solubilizing minerals and facilitating nutrient acquisition. A very interesting and novel effect of these fungi is the enhancement of plant defense systems by inducing systematic and acquired resistance. However, little is known about this function. This study sheds light on the molecular mechanisms involved in cucurbits plants’ defense activation after being primed by the EPF M. brunneum. Furthermore, the subsequent effects on the fitness of the lepidopteran pest S. littoralis are shown. In this regard, a significant upregulation was recorded for the genes that regulate JA, SA, and ET pathways. This increased expression of defense genes caused lethal and sublethal effects on S. littoralis. This could be considered an added value for the implementation of EPF in integrated pest management programs. [ABSTRACT FROM AUTHOR]

With increased life expectancy, age-associated cognitive decline becomes a growing concern, even in the absence of recognizable neurodegenerative disease. The integrated stress response (ISR) is activated during aging and contributes to age-related brain phenotypes. We demonstrate that treatment with the drug-like small-molecule ISR inhibitor ISRIB reverses ISR activation in the brain, as indicated by decreased levels of activating transcription factor 4 (ATF4) and phosphorylated eukaryotic translation initiation factor eIF2. Furthermore, ISRIB treatment reverses spatial memory deficits and ameliorates working memory in old mice. At the cellular level in the hippocampus, ISR inhibition (i) rescues intrinsic neuronal electrophysiological properties, (ii) restores spine density and (iii) reduces immune profiles, specifically interferon and T cell-mediated responses. Thus, pharmacological interference with the ISR emerges as a promising intervention strategy for combating age-related cognitive decline in otherwise healthy individuals.

Jinbo Zhao,1,* Ling Hou,2,* Ni Zhu,3,* Rui Huang,1 Ke Su,1 Yuhua Lei,1 Yuanhong Li1 1Cardiovascular Disease Center, Central Hospital of Tujia and Miao Autonomous Prefecture, Hubei University of Medicine, Enshi Prefecture, Hubei Province, 445000, People’s Republic of China; 2Department of Central Hospital of Tujia and Miao Autonomous Prefecture, Hubei University of Medicine, Shiyan, Hubei Province, 442000, People’s Republic of China; 3Department of Pathology, Central Hospital of Tujia and Miao Autonomous Prefecture, Hubei University of Medicine, Enshi Prefecture, Hubei Province, 445000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yuanhong Li, Email lyh0101@vip.comObjective: The CHA2DS2-VASc score, a system which has been initially recommended for the assessment of thromboembolic risk in patients with atrial fibrillation (AF), arouses attention in the field of adverse coronary events. The purpose of this study was to explore the predictive value of preprocedural CHA2DS2-VASc score on ISR in patients after drug-eluting stent (DES) implantation.Methods: To further investigate the relationship between CHA2DS2-VASc scores and ISR after DES, a retrospective study of DES was carried on. Additionally, the preoperative variables for the ISR and control groups were contrasted. Predictive factors were chosen using the optimal subset regression. We validate the model using internal validation. The prediction model was evaluated using the receiver operator characteristic (ROC) analysis.Results: We used a 3:7 ratio to create an experimental group and a validation group, and then ran a stepwise regression with the data from each of the two groups. The results showed that CHA2DS2-VASc score was an independent risk factor for ISR in both the experimental (p = 0.0139) and validation groups (p = 0.0014), and both had significant predictive value for ISR. The area of the ROC curve was greater than 0.5 in both groups (AUC = 0.78, 0.719, respectively) indicating that the model fit was good in both groups.Conclusion: The CHA2DS2-VASc score is a reliable predictor of in-stent restenosis (ISR) after DES implantation.Keywords: CHA2DS2-VASc score, drug-eluting stents, DES, percutaneous coronary intervention, PCI, in-stent restenosis, ISR

Cells of metazoans respond to internal and external stressors by activating stress response pathways that aim for re-establishing cellular homoeostasis or, if this cannot be achieved, triggering programmed cell death. Problems during translation, arising from defective mRNAs, tRNAs, ribosomes or protein misfolding, can activate stress response pathways as well as mRNA surveillance and ribosome quality control programs. Recently, ribosome collisions have emerged as a central signal for translational stress and shown to elicit different stress responses. Here, we review our current knowledge about the intricate mutual connections between ribosome collisions, stress response pathways and mRNA surveillance. A central factor connecting the sensing of collided ribosomes with degradation of the nascent polypeptides, dissociation of the stalled ribosomes and degradation of the mRNA by no-go or non-stop decay is the E3-ligase ZNF598. We tested whether ZNF598 also plays a role in nonsense-mediated mRNA decay (NMD) but found that it is dispensable for this translation termination-associated mRNA surveillance pathway, which in combination with other recent data argues against stable ribosome stalling at termination codons being the NMD-triggering signal.

Abstract The integrated stress response (ISR) facilitates cellular adaptation to unfavorable conditions by reprogramming the cellular response. ISR activation was reported in neurological disorders and solid tumors; however, the function of ISR and its role as a possible therapeutic target in hematological malignancies still remain largely unexplored. Previously, we showed that the ISR is activated in chronic myeloid leukemia (CML) cells and correlates with blastic transformation and tyrosine kinase inhibitor (TKI) resistance. Moreover, the ISR was additionally activated in response to imatinib as a type of protective internal signaling. Here, we show that ISR inhibition combined with imatinib treatment sensitized and more effectively eradicated leukemic cells both in vitro and in vivo compared to treatment with single agents. The combined treatment specifically inhibited the STAT5 and RAS/RAF/MEK/ERK pathways, which are recognized as drivers of resistance. Mechanistically, this drug combination attenuated both interacting signaling networks, leading to BCR-ABL1- and ISR-dependent STAT5 activation. Consequently, leukemia engraftment in patient-derived xenograft mice bearing CD34+ TKI-resistant CML blasts carrying PTPN11 mutation responsible for hyperactivation of the RAS/RAF/MAPK and JAK/STAT5 pathways was decreased upon double treatment. This correlated with the downregulation of genes related to the RAS/RAF/MAPK, JAK/STAT5 and stress response pathways and was associated with lower expression of STAT5-target genes regulating proliferation, viability and the stress response. Collectively, these findings highlight the effect of imatinib plus ISRIB in the eradication of leukemic cells resistant to TKIs and suggest potential clinical benefits for leukemia patients with TKI resistance related to RAS/RAF/MAPK or STAT5 signaling. We propose that personalized treatment based on the genetic selection of patients carrying mutations that cause overactivation of the targeted pathways and therefore make their sensitivity to such treatment probable should be considered as a possible future direction in leukemia treatment.