Lactate and lactylation in cardiovascular diseases: current progress and future perspectives.

Cardiovascular diseases (CVDs) are often linked to structural and functional impairments, such as heart defects and circulatory dysfunction, leading to compromised peripheral perfusion and heightened morbidity risks. Metabolic remodeling, particularly in the context of cardiac fibrosis and inflammation, is increasingly recognized as a pivotal factor in the pathogenesis of CVDs. Metabolic syndromes further predispose individuals to these conditions, underscoring the need to elucidate the metabolic underpinnings of CVDs. Lactate, a byproduct of glycolysis, is now recognized as a key molecule that connects cellular metabolism with the regulation of cellular activity. The transport of lactate between different cells is essential for metabolic homeostasis and signal transduction. Disruptions to lactate dynamics are implicated in various CVDs. Furthermore, lactylation, a novel post-translational modification, has been identified in cardiac cells, where it influences protein function and gene expression, thereby playing a significant role in CVD pathogenesis. In this review, we summarized recent advancements in understanding the role of lactate and lactylation in CVDs, offering fresh insights that could guide future research directions and therapeutic interventions. The potential of lactate metabolism and lactylation as innovative therapeutic targets for CVD is a promising avenue for exploration.

Contrasting philosophical and scientific views in the long history of studying the generation of form in development.

Focusing on the opposing ways of thinking of philosophers and scientists to explain the generation of form in biological development, I show that today's controversies over explanations of early development bear fundamental similarities to the dichotomy of preformation theory versus epigenesis in Greek antiquity. They are related to the acceptance or rejection of the idea of a physical form of what today would be called information for the generating of the embryo as a necessary pre-requisite for specific development and heredity. As a recent example, I scrutinize the dichotomy of genomic causality versus self-organization in 20th and 21st century theories of the generation of form. On the one hand, the generation of patterns and form, as well as the constant outcome in development, are proposed to be causally related to something that is "preformed" in the germ cells, the nucleus of germ cells, or the genome. On the other hand, it is proposed that there is no pre-existing form or information, and development is seen as a process where genuinely new characters emerge from formless matter, either by immaterial "forces of life," or by physical-chemical processes of self-organization. I also argue that these different ways of thinking and the research practices associated with them are not equivalent, and maintain that it is impossible to explain the generation of form and constant outcome of development without the assumption of the transmission of pre-existing information in the form of DNA sequences in the genome. Only in this framework of "preformed" information can "epigenesis" in the form of physical and chemical processes of self-organization play an important role.

Metabolic Reprogramming: A Byproduct or a Driver of Cardiomyocyte Proliferation?

Defining mechanisms of cardiomyocyte proliferation should guide the understanding of endogenous cardiac regeneration and could lead to novel treatments for diseases such as myocardial infarction. In the neonatal heart, energy metabolic reprogramming (phenotypic alteration of glucose, fatty acid, and amino acid metabolism) parallels cell cycle arrest of cardiomyocytes. The metabolic reprogramming occurring shortly after birth is associated with alterations in blood oxygen levels, metabolic substrate availability, hemodynamic stress, and hormone release. In the adult heart, myocardial infarction causes metabolic reprogramming but these changes cannot stimulate sufficient cardiomyocyte proliferation to replace those lost by the ischemic injury. Some putative pro-proliferative interventions can induce the metabolic reprogramming. Recent data show that altering the metabolic enzymes PKM2 [pyruvate kinase 2], LDHA [lactate dehydrogenase A], PDK4 [pyruvate dehydrogenase kinase 4], SDH [succinate dehydrogenase], CPT1b [carnitine palmitoyl transferase 1b], or HMGCS2 [3-hydroxy-3-methylglutaryl-CoA synthase 2] is sufficient to partially reverse metabolic reprogramming and promotes adult cardiomyocyte proliferation. How metabolic reprogramming regulates cardiomyocyte proliferation is not clearly defined. The possible mechanisms involve biosynthetic pathways from the glycolysis shunts and the epigenetic regulation induced by metabolic intermediates. Metabolic manipulation could represent a new approach to stimulate cardiac regeneration; however, the efficacy of these manipulations requires optimization, and novel molecular targets need to be defined. In this review, we summarize the features, triggers, and molecular regulatory networks responsible for metabolic reprogramming and discuss the current understanding of metabolic reprogramming as a critical determinant of cardiomyocyte proliferation.

Targeting NPM1 Epigenetically Promotes Postinfarction Cardiac Repair by Reprogramming Reparative Macrophage Metabolism.

BACKGROUND: Reparative macrophages play a crucial role in limiting excessive fibrosis and promoting cardiac repair after myocardial infarction (MI), highlighting the significance of enhancing their reparative phenotype for wound healing. Metabolic adaptation orchestrates the phenotypic transition of macrophages; however, the precise mechanisms governing metabolic reprogramming of cardiac reparative macrophages remain poorly understood. In this study, we investigated the role of NPM1 (nucleophosmin 1) in the metabolic and phenotypic shift of cardiac macrophages in the context of MI and explored the therapeutic effect of targeting NPM1 for ischemic tissue repair. METHODS: Peripheral blood mononuclear cells were obtained from healthy individuals and patients with MI to explore NPM1 expression and its correlation with prognostic indicators. Through RNA sequencing, metabolite profiling, histology, and phenotype analyses, we investigated the role of NPM1 in postinfarct cardiac repair using macrophage-specific NPM1 knockout mice. Epigenetic experiments were conducted to study the mechanisms underlying metabolic reprogramming and phenotype transition of NPM1-deficient cardiac macrophages. The therapeutic efficacy of antisense oligonucleotide and inhibitor targeting NPM1 was then assessed in wild-type mice with MI. RESULTS: NPM1 expression was upregulated in the peripheral blood mononuclear cells from patients with MI that closely correlated with adverse prognostic indicators of MI. Macrophage-specific NPM1 deletion reduced infarct size, promoted angiogenesis, and suppressed tissue fibrosis, in turn improving cardiac function and protecting against adverse cardiac remodeling after MI. Furthermore, NPM1 deficiency boosted the reparative function of cardiac macrophages by shifting macrophage metabolism from the inflammatory glycolytic system to oxygen-driven mitochondrial energy production. The oligomeric NPM1 recruited histone demethylase KDM5b to the promoter of Tsc1 (TSC complex subunit 1), the mTOR (mechanistic target of rapamycin kinase) complex inhibitor, reduced histone H3K4me3 modification, and inhibited TSC1 expression, which then facilitated mTOR-related inflammatory glycolysis and antagonized the reparative function of cardiac macrophages. The in vivo administration of antisense oligonucleotide targeting NPM1 or oligomerization inhibitor NSC348884 substantially ameliorated tissue injury and enhanced cardiac recovery in mice after MI. CONCLUSIONS: Our findings uncover the key role of epigenetic factor NPM1 in impeding postinfarction cardiac repair by remodeling metabolism pattern and impairing the reparative function of cardiac macrophages. NPM1 may serve as a promising prognostic biomarker and a valuable therapeutic target for heart failure after MI.

Early developmental risks for tobacco addiction: A probabilistic epigenesis framework.

Considerable progress has been made in elucidating the relationships between early life psychobiological and environmental risk factors and the development of tobacco addiction. However, a comprehensive understanding of the heterogeneity in tobacco addiction phenotypes requires integrating research findings. The probabilistic epigenesis meta-theory offers a valuable framework for this integration, considering systemic, multilevel, developmental, and evolutionary perspectives. In this paper, we critically review relevant research on early developmental risks associated with tobacco addiction and highlight the integrative heuristic value of the probabilistic epigenesis framework for this research. For this, we propose a four-level systems approach as an initial step towards integration, analyzing complex interactions among different levels of influence. Additionally, we explore a coaction approach to examine key interactions between early risk factors. Moreover, we introduce developmental pathways to understand interindividual differences in tobacco addiction risk during development. This integrative approach holds promise for advancing our understanding of tobacco addiction etiology and informing potentially effective intervention strategies.

Effects of valproic acid on wound healing of the abdominal wall musculoaponeurotic layer: an experimental study in rats / Os efeitos do ácido valpróico na cicatrização do plano músculoaponeurótico da parede abdominal: estudo experimental em ratos

ABSTRACT Introduction: valproic acid (VPA), an epigenetic drug, has potential for the treatment of neoplasms. Its effects on the healing of the peritoneal-musculo-aponeurotic plane (PMA) of the abdominal wall are studied. Method: sixty Wistar rats were allocated into two groups: experimental (VPA) and control (0.9% sodium chloride), treated daily, starting three days before the intervention and until euthanasia. Under anesthesia, a median laparotomy was performed and repaired with two synthetic layers. Assessments took place 3, 7 and 14 days after surgery. The integrity of the wounds, the quality of the inflammatory reaction, the intensity of the leukocyte infiltrate, collagen synthesis, the intensity of angiogenesis and the presence of myofibroblasts were studied. Results: there was dehiscence of the PMA plane in 11 of the 30 animals (p=0.001) in the experimental group. There was no difference in the quality and intensity of the inflammatory reaction. Immunohistochemistry revealed, in the experimental group, less collagen I (p3=0.003, p7=0.013 and p14=0.001) and more collagen III (p3=0.003, p7=0.013 and p14= 0.001). Collagen evaluated by Sirus Supra Red F3BA showed, in the experimental group, less collagen at all three times (p<0.001) with less collagen I and collagen III (p<0.001). A lower number of vessels was found on the 3rd day (p<0.001) and on the 7th day (p=0.001) and did not affect the number of myofibroblasts. Conclusion: VPA showed dehiscence of the PMA plane, with less deposition of total collagen and collagen I, less angiogenic activity, without interfering with the number of myofibroblasts.

RESUMO Introdução: o ácido valpróico (VPA), droga epigenética, apresenta-se com potencial para o tratamento de neoplasias. Estudam-se seus efeitos sobre a cicatrização do plano peritônio-músculo-aponeurótico (PMA) da parede abdominal. Método: sessenta ratos Wistar, foram alocados em dois grupos: o experimental (VPA) e o controle (cloreto de sódio 0,9%), tratados diariamente, iniciando três dias antes da intervenção e até a eutanásia. Sob anestesia, fez-se uma laparotomia mediana que foi reparada com dois planos de síntese. As avaliações aconteceram 3, 7 e 14 dias após a cirurgia. Estudou-se a integridade das feridas, a qualidade da reação inflamatória, a intensidade do infiltrado de leucócitos, a síntese do colágeno, a intensidade da angiogênese e a presença de miofibroblastos. Resultados: o plano PMA mostrou-se deiscente em 11 dos 30 animais (p=0,001) do grupo experimento. Não houve diferença na qualidade da reação inflamatória e nem no infiltrado de leucócitos. A imuno-histoquímica revelou, no grupo experimento, menos colágeno I (p3=0,003, p7=0,013 e p14=0,001) e mais colágeno III (p3=0,003, p7=0,013 e p14= 0,001). Colágeno avaliado pelo Sirus Supra Red F3BA mostrou, no grupo experimento,menos colágeno nos três tempo (p<0,001) com menos colágeno I e colágeno III (p<0,001). Constatou-se menor número de vasos no 3º dia (p<0,001) e no 7º dia (p=0,001) e não afetou a quantidade de miofibroblastos. Conclusão: o VPA mostrou deiscências do plano PMA, com reação inflamatória semelhante.ao controle, menor deposição de colágeno total e de colágeno I, menor atividade angiogênica, sem interferir na quantidade de miofibroblastos.

KMT2A maintains stemness of gastric cancer cells through regulating Wnt/ß-catenin signaling-activated transcriptional factor KLF11.

The molecular mechanisms of epigenetic regulation in gastric cancer development are not yet well established. In this study, we demonstrated that KMT2A was highly expressed in gastric cancer and associated with poor outcomes of patients and revealed that KMT2A was significantly associated with stemness and increased nuclear ß-catenin in gastric cancer. Mechanistically, KMT2A activated the translocation of ß-catenin into the nucleus of gastric cancer cells, and then, ß-catenin served as a coactivator of KLF11, which promoted the expression of specific gastric cancer stemness-related molecules, including SOX2 and FOXM1. Together, KMT2A is an important epigenetic regulator of gastric cancer stemness, which provides a novel insight to the potential application of targeting against KMT2A in treating gastric cancer.

Disulfiram ameliorates bleomycin induced pulmonary inflammation and fibrosis in rats.

Bleomycin (BL) is a widely used anticancer drug that can cause pulmonary fibrosis due to increased fibroblast proliferation and increased secretion of extracellular matrix. RASSF1A is a tumor suppressor gene that is down-regulated by DNA methylation during fibrosis. Disulfiram (DSF), a noncytosine DNA methyltransferase inhibitor, can revert epigenetic biomarkers and re-express silenced genes. We investigated anti-inflammatory and anti-fibrotic effects of DSF on regulation of epigenetic molecules and histopathology in a rat model of BL induced pulmonary fibrosis. We used six groups of rats: sesame oil (SO) control (Co) group, BL group, BL + SO group and three BL + DSF groups administered 1 mg/kg DSF (BL + DSF), 10 mg/kg DSF (BL + DSF10) or 100 mg/kg DSF (BL + DSF100), respectively. BL was administered intratracheally to induce pulmonary fibrosis. DSF and SO were injected intraperitoneally (i.p.) 2 days before BL administration; these injections were continued for 3 weeks. At the end of the study, lung tissues were removed for molecular and histopathologic studies. Administration of 10 or 100 mg/kg DSF after BL induced pulmonary inflammation and fibrosis, and up-regulated RASSF1A and down-regulated TNF-α and IL-1 ß compared to the BL and BL + SO groups. A RASSF1A unmethylated band was observed using the methylation-specific PCR technique in rats that had been administered 10 and 100 mg/kg DSF, which indicated partial DNA demethylation. Histopathologic evaluation revealed that fibrosis and all inflammatory scores were decreased significantly in the BL + DSF10 and BL + DSF100 groups compared to the BL group. Our findings indicate that DSF modified DNA methylation by up-regulating RASSF1A, which reduced inflammation and fibrosis in BL induced pulmonary inflammation and fibrosis.

Epigenetic regulation of Parkinson's disease risk variant GPNMB cg17274742 methylation by sex and exercise from Taiwan Biobank.

Background: Parkinson's disease (PD) is a complex neurodegenerative disease with an elusive etiology that involves the interaction between genetic, behavioral, and environmental factors. Recently, epigenetic modifications, particularly DNA methylation, have been recognized to play an important role in the onset of PD. Glycoprotein non-metastatic melanoma protein B (GPNMB), a type I transmembrane protein crucial for immune cell activation and maturation, has emerged as a potential biomarker for the risk of PD. This research aims to investigate the influence of exercise and gender on the regulation of methylation levels of GPNMB cg17274742 in individuals. Methods: We analyze data from 2,474 participants in the Taiwan Biobank, collected from 2008 and 2016. Methylation levels at the GPNMB cg17274742 CpG site were measured using Illumina Infinium MethylationEPIC beads. After excluding individuals with incomplete data or missing information on possible risk factors, our final analysis included 1,442 participants. We used multiple linear regression models to assess the association between sex and exercise with adjusted levels of GPNMB cg17274742 for age, BMI, smoking, drinking, coffee consumption, serum uric acid levels, and hypertension. Results: Our results demonstrated that exercise significantly influenced the methylation levels of GPNMB cg17274742 in males (ß = -0.00242; p = 0.0026), but not in females (ß = -0.00002362; p = 0.9785). Furthermore, male participants who exercised showed significantly lower levels of methylation compared to the reference groups of the female and non-exercising reference groups (ß = -0.00357; p = 0.0079). The effect of the interaction between gender and exercise on the methylation of GPNMB cg17274742 was statistically significant (p = 0.0078). Conclusion: This study suggests that gender and exercise can modulate GPNMB cg17274742, with hypomethylation observed in exercise men. More research is needed to understand the underlying mechanisms and implications of these epigenetic changes in the context of risk and prevention strategies.

Novel insights of EZH2-mediated epigenetic modifications in degenerative musculoskeletal diseases.

Degenerative musculoskeletal diseases (Osteoporosis, Osteoarthritis, Degenerative Spinal Disease and Sarcopenia) are pathological conditions that affect the function and pain of tissues such as bone, cartilage, and muscles, and are closely associated with ageing and long-term degeneration. Enhancer of zeste homolog 2 (EZH2), an important epigenetic regulator, regulates gene expression mainly through the PRC2-dependent trimethylation of histone H3 at lysine 27 (H3K27me3). Increasing evidence suggests that EZH2 is involved in several biological processes closely related to degenerative musculoskeletal diseases, such as osteogenic-adipogenic differentiation of bone marrow mesenchymal stem cells, osteoclast activation, chondrocyte functional status, and satellite cell proliferation and differentiation, mainly through epigenetic regulation (H3K27me3). Therefore, the synthesis and elucidation of the role of EZH2 in degenerative musculoskeletal diseases have attracted increasing attention. In addition, although EZH2 inhibitors have been approved for clinical use, whether they can be repurposed for the treatment of degenerative musculoskeletal diseases needs to be considered. Here, we reviewed the role of EZH2 in the development of degenerative musculoskeletal diseases and brought forward prospects of its pharmacological inhibitors in the improvement of the treatment of the diseases.

METTL3 enhances dentinogenesis differentiation of dental pulp stem cells via increasing GDF6 and STC1 mRNA stability.

BACKGROUND: The dentinogenesis differentiation of dental pulp stem cells (DPSCs) is controlled by the spatio-temporal expression of differentiation related genes. RNA N6-methyladenosine (m6A) methylation, one of the most abundant internal epigenetic modification in mRNA, influences various events in RNA processing, stem cell pluripotency and differentiation. Methyltransferase like 3 (METTL3), one of the essential regulators, involves in the process of dentin formation and root development, while mechanism of METTL3-mediated RNA m6A methylation in DPSC dentinogenesis differentiation is still unclear. METHODS: Immunofluorescence staining and MeRIP-seq were performed to establish m6A modification profile in dentinogenesis differentiation. Lentivirus were used to knockdown or overexpression of METTL3. The dentinogenesis differentiation was analyzed by alkaline phosphatase, alizarin red staining and real time RT-PCR. RNA stability assay was determined by actinomycin D. A direct pulp capping model was established with rat molars to reveal the role of METTL3 in tertiary dentin formation. RESULTS: Dynamic characteristics of RNA m6A methylation in dentinogenesis differentiation were demonstrated by MeRIP-seq. Methyltransferases (METTL3 and METTL14) and demethylases (FTO and ALKBH5) were gradually up-regulated during dentinogenesis process. Methyltransferase METTL3 was selected for further study. Knockdown of METTL3 impaired the DPSCs dentinogenesis differentiation, and overexpression of METTL3 promoted the differentiation. METTL3-mediated m6A regulated the mRNA stabiliy of GDF6 and STC1. Furthermore, overexpression of METTL3 promoted tertiary dentin formation in direct pulp capping model. CONCLUSION: The modification of m6A showed dynamic characteristics during DPSCs dentinogenesis differentiation. METTL3-mediated m6A regulated in dentinogenesis differentiation through affecting the mRNA stability of GDF6 and STC1. METTL3 overexpression promoted tertiary dentin formation in vitro, suggesting its promising application in vital pulp therapy (VPT).

Lactate, histone lactylation and cancer hallmarks.

Histone lactylation, an indicator of lactate level and glycolysis, has intrinsic connections with cell metabolism that represents a novel epigenetic code affecting the fate of cells including carcinogenesis. Through delineating the relationship between histone lactylation and cancer hallmarks, we propose histone lactylation as a novel epigenetic code priming cells toward the malignant state, and advocate the importance of identifying novel therapeutic strategies or dual-targeting modalities against lactylation toward effective cancer control. This review underpins important yet less-studied area in histone lactylation, and sheds insights on its clinical impact as well as possible therapeutic tools targeting lactylation.

The evolutionary consequences of epigenesis and neutral change: A conceptual approach at the organismal level.

Living beings are autopoietic systems with highly context-dependent structural dynamics and interactions, that determine whether a disturbance in the genotype or environment will lead or not to phenotypic change. The concept of epigenesis entails how a change in the phenotype may not correspond to a change in the structure of an earlier developmental stage, including the genome. Disturbances of embryonic structure may fail to change the phenotype, as in regulated development, or when different genotypes are associated to a single phenotype. Likewise, the same genotype or early embryonic structure may develop different phenotypes, as in phenotypic plasticity. Disturbances that fail to trigger phenotypic change are considered neutral, but even so, they can alter unexpressed developmental potential. Here, we present conceptual diagrams of the "epigenic field": similar to Waddington's epigenetic landscapes, but including the ontogenic niche (organism/environment interactional dynamics during ontogeny) as a factor in defining epigenic fields, rather than just selecting among possible pathways. Our diagrams illustrate transgenerational changes of genotype, ontogenic niche, and their correspondence (or lack thereof) with changes of phenotype. Epigenic fields provide a simple way to understand developmental constraints on evolution, for instance: how constraints evolve as a result of developmental system drift; how neutral changes can be involved in genetic assimilation and de-assimilation; and how constraints can evolve as a result of neutral changes in the ontogenic niche (not only the genotype). We argue that evolutionary thinking can benefit from a framework for evolution with conceptual foundations at the organismal level.

The Ratio of Second and Fourth Digit Length: A Biomarker for Methamphetamine Dependence?

Objective: The ratio of 2nd and 4th digit length (2D:4D) is considered to be a sexually dimorphic trait. Low 2D:4D is implicated in alcohol dependence and heroin dependence and correlated with psychological traits such as aggression, physical aggression, and sensation. The purpose of this study is to compare the 2D:4D between methamphetamine (METH) dependence and controls and the 2D:4D ratio that is a potential biomarker for METH dependence. Methods: In this study, 40 patients diagnosed with METH dependence in Eulji University Gangnam Eulji Hospital and 50 healthy volunteers were all employees in the same hospital. Images of participants' hands were created using a scanning device. The images contained both the right and left hands; computer software was used to measure the 2D:4D ratio for both hands. We compared the ratios, analyzed by t test, between the METH dependence group and the control group. Results: The mean 2D:4D values were 0.941 (right hand) and 0.943 (left hand) for the patients with METH dependence; in contrast, they were 0.961 (right hand) and 0.961 (left hand) for the control group. These values were significantly smaller than the control in patients' right hands (p = 0.003) and left hands (p = 0.012). Conclusion: Patients with METH dependence had smaller 2D:4D ratios than those in the control group, which is similar to the results from the previous substance use disorder studies. Thus, elevated prenatal testosterone levels during the gonadal period could be related to future METH problems. Furthermore, the 2D:4D ratio is a potential marker for the prediction of METH dependence.

The reversibility of cellular determination: An evolutive pattern of epigenetic plasticity.

Until the middle of the 20th century, embryogenesis patterns were considered as based on a rigid, unidirectional ontogenetic development, whose nuclear programming yields an irreversibility feature for cellular determination. Further empirical pieces of evidence have provided new insights about a certain reversibility to cellular determination, finding new biomolecular mechanisms (nuclear reprogramming, dedifferentiation, transdifferentiation) which have clearly shown that such a reversibility exists, warranting a certain cellular plasticity inside cell cycle; moreover, they seem mainly ruled by epigenetic factors. In this framework, evolution can be viewed as a systemic transformation of the spatiotemporal epigenetic organization, and the maintenance of the stable final adult stage includes a possibility of dedifferentiation at the particular points of ontogenetic development leading to the achievement of the final stage though the alternate sets of epigenetic trajectories. This paper is aimed to briefly outline historically the main aspects which have led to define the mechanisms of cellular plasticity, highlighting the chief empirical facts supporting it and the related still unresolved problematic issues.

Multilevel development of cognitive abilities in an artificial neural network.

Several neuronal mechanisms have been proposed to account for the formation of cognitive abilities through postnatal interactions with the physical and sociocultural environment. Here, we introduce a three-level computational model of information processing and acquisition of cognitive abilities. We propose minimal architectural requirements to build these levels, and how the parameters affect their performance and relationships. The first sensorimotor level handles local nonconscious processing, here during a visual classification task. The second level or cognitive level globally integrates the information from multiple local processors via long-ranged connections and synthesizes it in a global, but still nonconscious, manner. The third and cognitively highest level handles the information globally and consciously. It is based on the global neuronal workspace (GNW) theory and is referred to as the conscious level. We use the trace and delay conditioning tasks to, respectively, challenge the second and third levels. Results first highlight the necessity of epigenesis through the selection and stabilization of synapses at both local and global scales to allow the network to solve the first two tasks. At the global scale, dopamine appears necessary to properly provide credit assignment despite the temporal delay between perception and reward. At the third level, the presence of interneurons becomes necessary to maintain a self-sustained representation within the GNW in the absence of sensory input. Finally, while balanced spontaneous intrinsic activity facilitates epigenesis at both local and global scales, the balanced excitatory/inhibitory ratio increases performance. We discuss the plausibility of the model in both neurodevelopmental and artificial intelligence terms.