Metacognition comprises both the ability to be aware of one’s cognitive processes (metacognitive knowledge) and to regulate them (metacognitive control). Research in educational sciences has amassed a large body of evidence on the importance of metacognition in learning and academic achievement. More recently, metacognition has been studied from experimental and cognitive neuroscience perspectives. This research has started to identify brain regions that encode metacognitive processes. However, the educational and neuroscience disciplines have largely developed separately with little exchange and communication. In this article, we review the literature on metacognition in educational and cognitive neuroscience and identify entry points for synthesis. We argue that to improve our understanding of metacognition, future research needs to (i) investigate the degree to which different protocols relate to the similar or different metacognitive constructs and processes, (ii) implement experiments to identify neural substrates necessary for metacognition based on protocols used in educational sciences, (iii) study the effects of training metacognitive knowledge in the brain, and (iv) perform developmental research in the metacognitive brain and compare it with the existing developmental literature from educational sciences regarding the domain-generality of metacognition. For instance, high performers tend to present better metacognitive abilities  than low performers in diverse educational activities9. Recently, there has been a lot of progress in studying the neural mechanisms of metacognition11, yet it is unclear at this point how these results may inform educational sciences or interventions. Given the potential benefits of metacognition, it is important to get a better understanding of how metacognition works and of how training can be useful.Metacognition is defined as “thinking about thinking” or the ability to monitor and control one’s cognitive processes14. With it, researchers have brought forward issues that are viewed as critical for the discipline to improve education. Recurring issues that may impede the relevance of neural insights for educational practices concern external validity16, theoretical discrepancies17 and differences in terms of the domains of (meta)cognition operationalised 15. This is important because, in recent years, brain research is starting to orient itself towards training metacognitive abilities that would translate into real-life benefits. However, direct links between metacognition in the brain and metacognition in domains such as education have still to be made. As for educational sciences, a large body of literature on metacognitive training is available, yet we still need clear insights about what works and why. While studies suggest that training metacognitive abilities results in higher academic achievement18, other interventions show mixed results20. Moreover, little is known about the long-term effects of, or transfer effects, of these interventions. A better understanding of the cognitive processes involved in metacognition and how they are expressed in the brain may provide insights in these regards.The interest in bridging cognitive neuroscience and educational practices has increased in the past two decades, spanning a large number of studies grouped under the umbrella term of educational neuroscience21. Similar to metacognition, EF shows a positive relationship with learning at school. For instance, performance in laboratory tasks involving error monitoring, inhibition and working memory (i.e. processes that monitor and regulate cognition) are associated with academic achievement in pre-school children22. More recently, researchers have studied metacognition in terms of introspective judgements about performance in a task10. Although the neural correlates of such behaviour are being revealed11, little is known about how behaviour during such tasks relates to academic achievement.Within cognitive neuroscience, there has been a long tradition of studying executive functions (EF), which are closely related to metacognitive processes16. We argue that neurocognitive research on metacognition has a lot of potential to provide insights in mechanisms relevant in educational contexts, and that theoretical and methodological exchange between the two disciplines can benefit neuroscientific research in terms of ecological validity.Educational and cognitive neuroscientists study metacognition in different contexts using different methods. Indeed, while the latter investigate metacognition via behavioural task, the former mainly rely on introspective questionnaires. The extent to which these different operationalisations of metacognition match and reflect the same processes is unclear. As a result, the external validity of methodologies used in cognitive neuroscience is also unclear23  is defined as the knowledge individuals have of their own cognitive processes and their ability to monitor and reflect on them. Second, metacognitive control  consists of someone’s self-regulatory mechanisms, such as planning and adapting behaviour based on outcomes27. Following Nelson and Narens’ definition23, meta-knowledge is characterised as the flow and processing of information from the object level to the meta-level, and meta-control as the flow from the meta-level to the object level30 4, which shares common conceptual roots with the theoretical framework used in cognitive neuroscience but varies from it in several ways31. First, SRL is constrained to learning activities, usually within educational settings. Second, metacognition is merely one of three components, with “motivation to learn” and “behavioural processes”, that enable individuals to learn in a self-directed manner3. In SRL, metacognition is defined as setting goals, planning, organising, self-monitoring and self-evaluating “at various points during the acquisition”3. The distinction between meta-knowledge and meta-control is not formally laid down although reference is often made to a “self-oriented feedback loop” describing the relationship between reflecting and regulating processes that resembles Nelson and Narens’ model , and meta-control with experiments involving cognitive offloading. In these experiments, subjects can perform actions such as set reminders, making notes and delegating tasks34, or report their desire for them35. Some research has investigated how metacognitive judgements can influence subsequent cognitive behaviour , but only one study so far has explored how this relationship is mapped in the brain35. In the other track, researchers investigate EF, also referred to as cognitive control36, which is closely related to metacognition. Note however that EF are often not framed in metacognitive terms in the literature37 (but see ref. 30). For the sake of concision, we limit our review to operational definitions that have been used in neuroscientific studies.In cognitive neuroscience, research in metacognition is split into two tracks10. These judgements are commonly referred to as metacognitive judgements, which can be viewed as a form of meta-knowledge (for reviews see Schwartz38 and Nelson39). Historically, researchers mostly resorted to paradigms known as Feelings of Knowing (FOK)40 and Judgements of Learning (JOL)41. FOK reflect the belief of a subject to knowing the answer to a question or a problem and being able to recognise it from a list of alternatives, despite being unable to explicitly recall it40. Here, metacognitive judgement is thus made after retrieval attempt. In contrast, JOL are prospective judgements during learning of one’s ability to successfully recall an item on subsequent testing41.Cognitive neuroscientists have been using paradigms in which subjects make judgements on how confident they are with regards to their learning of some given material42. In 2-AFCs, subjects are asked to choose which of two presented options has the highest criterion value. Different domains can be involved, such as perception  and memory. For example, subjects may be instructed to visually discriminate which one of two boxes contains more dots43, identify higher contrast Gabor patches44, or recognise novel words from words that were previously learned45 , metacognitive bias , and metacognitive efficiency 47 which allows Type 1 sensitivity, or d’′  to be differentiated from metacognitive sensitivity (a judgement on the correctness of this decision)48. Importantly, only comparing meta-d′ to d′ seems to give reliable assessments metacognitive efficiency49. A ratio of 1 between meta-d’′ and d’′, indicates that a subject was perfectly able to discriminate between their correct and incorrect judgements. A ratio of 0.8 suggests that 80% of the task-related sensory evidence was available for the metacognitive judgements. Table 50. Alternatively, transcranial magnetic stimulation (TMS) can be used to temporarily deactivate chosen brain regions and test whether this affects metacognitive abilities in given tasks52.More recently, cognitive neuroscientists have used paradigms in which subjects make retrospective metacognitive judgements on their performance in a two-alternative Forced Choice task 2-AFC)-AFC42. I11. This network includes the medial and lateral prefrontal cortex , precuneus and insula. In contrast, the right anterior dorsolateral PFC (dlPFC) was specifically involved in decision-making tasks, and the bilateral parahippocampal cortex was specific to memory tasks. In addition, prospective judgements were associated with the posterior mPFC, left dlPFC and right insula, whereas retrospective judgements were associated with bilateral parahippocampal cortex and left inferior frontal gyrus. Finally, emerging evidence suggests a role of the right rostrolateral PFC (rlPFC)54, anterior PFC (aPFC)56, dorsal anterior cingulate cortex (dACC)55 and precuneus55 in metacognitive sensitivity . In addition, several studies suggest that the aPFC relates to metacognition specifically in perception-related 2-AFC tasks, whereas the precuneus is engaged specifically in memory-related 2-AFC tasks56. This may suggest that metacognitive processes engage some regions in a domain-specific manner, while other regions are domain-general. For educational scientists, this could mean that some domains of metacognition may be more relevant for learning and, granted sufficient plasticity of the associated brain regions, that targeting them during interventions may show more substantial benefits. Note that rating one’s confidence and metacognitive sensitivity likely involve additional, peripheral cognitive processes instead of purely metacognitive ones. These regions are therefore associated with metacognition but not uniquely per se. Notably, a recent meta-analysis50 suggests that domain-specific and domain-general signals may rather share common circuitry, but that their neural signature varies depending on the type of task or activity, showing that domain-generality in metacognition is complex and still needs to be better understood.A recent meta-analysis analysed 47 neuroimaging studies on metacognition and identified a domain-general network associated with high vs. low confidence ratings in both decision-making tasks (perception 2-AFC) and memory tasks 35.In terms of the role of metacognitive judgements on future behaviour, one study found that brain patterns associated with the desire for cognitive offloading  partially overlap with those associated with meta-knowledge (metacognitive judgements of confidence), suggesting that meta-control is driven by either non-metacognitive, in addition to metacognitive, processes or by a combination of different domain-specific meta-knowledge processes36. To activate these processes, participants are asked to perform tasks in laboratory settings such as Flanker tasks, Stroop tasks, Demand Selection tasks and Motion Discrimination tasks , and the dlPFC to regulate it59. In particular, activity in the ACC in conflict monitoring (meta-knowledge) seems to contribute to control of cognition (meta-control) in the dlPFC61 and to “bias behavioural decision-making toward cognitively efficient tasks and strategies” (p. 356)62 . In a recent fMRI study, subjects performed a motion discrimination task  and then were asked to rate their confidence in their initial choice. The post-decisional evidence was encoded in the activity of the posterior medial frontal cortex , while lateral aPFC (meta-control) modulated the impact of this evidence on subsequent confidence rating63. Finally, results from a meta-analysis study on cognitive control identified functional connectivity between the pMFC, associated with monitoring and informing other regions about the need for regulation, and the lPFC that would effectively regulate cognition64.In a review article on the neural basis of EF (in which they are defined as meta-control), Shimamura argues that a network of regions composed of the aPFC, ACC, ventrolateral PFC (vlPFC) and dlPFC is involved in the regulations of cognitionask Fig. 63. After66. Indeed, engaging in metacognitive judgements requires subjects to reflect on past or future activities. As such, metacognitive judgements can be considered as offline metacognitive processes. In contrast, high-order processes involved in decision-making tasks such as used in EF research are arguably largely made on the fly, or online, at a rapid pace and subjects do not need to reflect on their actions to perform them. Hence, we propose to explicitly distinguish online and offline processes. Other researchers have shared a similar view and some have proposed models for metacognition that make similar distinctions68. The functional difference between online and offline metacognition is supported by some evidence. For instance, event-related brain potential (ERP) studies suggest that error negativities are associated with error detection in general, whereas an increased error positivity specifically encodes error that subjects could report upon70. Furthermore, brain-imaging studies suggest that the MFC and ACC are involved in online meta-knowledge, while the aPFC and lPFC seem to be activated when subjects engage in more offline meta-knowledge and meta-control, respectively72. An overview of the different tasks can be found in Table While the processes engaged during tasks such as those used in EF research can be considered as metacognitive in the sense that they are higher-order functions that monitor and control lower cognitive processes, scientists have argued that they are not functionally equivalent to metacognitive judgements22. While working memory does not directly reflect metacognitive abilities, its training is often hypothesised to improve general cognitive abilities and academic achievement. However, most meta-analyses found that training methods lead only to weak, non-lasting effects on cognitive control75. One meta-analysis did find evidence of near-transfer following EF training in children , but found no evidence of far-transfer20. According to this study, training on one component leads to improved abilities in that same component but not in other EF components. Regarding adults, however, one meta-analysis suggests that EF training in general and working memory training specifically may both lead to significant near- and far-transfer effects76. On a neural level, a meta-analysis showed that cognitive training resulted in decreased brain activity in brain regions associated with EF77. According to the authors, this indicates that “training interventions reduce demands on externally focused attention” (p. 193)77.There are extensive accounts in the literature of efforts to improve EF components such as inhibitory control, attention shifting and working memory78. Related, Baird and colleagues79 found that a two-week mindfulness meditation training lead to enhanced meta-knowledge in the memory domain, but not the perceptual domain. The authors link these results to evidence of increased grey matter density in the aPFC in meditation practitioners.With regards to meta-knowledge, several studies have reported increased task-related metacognitive abilities after training. For example, researchers found that subjects who received feedback on their metacognitive judgements regarding a perceptual decision-making task displayed better metacognitive accuracy, not only in the trained task but also in an untrained memory taskResearch on metacognition in cognitive science has mainly been studied through the lens of metacognitive judgements and EF . Meta-knowledge is commonly activated in subjects by asking them to rate their confidence in having successfully performed a task. A distinction is made between metacognitive sensitivity, metacognitive bias and metacognitive efficacy. Monitoring and regulating processes in EF are mainly operationalised with behavioural tasks such as Flanker tasks, Stroop tasks, Motion Discrimination tasks and Demand Selection tasks. In addition, metacognitive judgements can be viewed as offline processes in that they require the subject to reflect on her cognition and develop meta-representations. In contrast, EF can be considered as mostly online metacognitive processes because monitoring and regulation mostly happen rapidly without the need for reflective thinking.Although there is some evidence for domain specificity, other studies have suggested that there is a single network of regions involved in all meta-cognitive tasks, but differentially activated in different task contexts. Comparing research on meta-knowledge and meta-control also suggest that some regions play a crucial role in both knowledge and regulation Fig. . We have16. A solution for improving validity may be to compare operationalisations of metacognition in cognitive neuroscience with the ones in educational sciences, which have shown clear links with learning in formal education. This also applies to metacognitive training.One major limitation of current research in metacognition is ecological validity. It is unclear to what extent the operationalisations reviewed above reflect real-life metacognition. For instance, are people who can accurately judge their performance on a behavioural task also able to accurately assess how they performed during an exam? Are people with high levels of error regulation and inhibitory control able to learn more efficiently? Note that criticism on the ecological validity of neurocognitive operationalisations extends beyond metacognition research80. During interviews, subjects are asked to answer questions regarding hypothetical situations81. In learning journals, students write about their learning experience and their thoughts on learning83. In thinking-aloud protocols, subjects are asked to verbalise their thoughts while performing a problem-solving task80. Each of these instruments can be used to study meta-knowledge and meta-control. For instance, one of the most widely used questionnaires, the Metacognitive Awareness Inventory (MAI)42, operationalises “Flavellian” metacognition and has dedicated scales for meta-knowledge and meta-control . The meta-knowledge scale of the MAI operationalises knowledge of strategies  and self-awareness ; the meta-control scale operationalises planning  and use of learning strategies . Learning journals, self-report questionnaires and interviews involve offline metacognition. Thinking aloud, though not engaging the same degree self-reflection, also involves offline metacognition in the sense that online processes are verbalised, which necessitate offline processing . Most of the studied components are related to meta-control and not meta-knowledge. For instance, the BRIEF87 is a questionnaire completed by parents and teachers which assesses different subdomains of EF: (1) inhibition, shifting, and emotional control which can be viewed as online metacognitive control, and (2) planning, organisation of materials, and monitoring, which can be viewed as offline meta-control87.More recently, methodologies borrowed from cognitive neuroscience have been introduced to study EF in educational settings88. Offline meta-knowledge processes operationalised by learning journals were found to be positively associated with academic achievement when related to reflection on learning activities but negatively associated when related to reflection on learning materials, indicating that the type of reflection is important89. EF have been associated with abilities in mathematics (mainly) and reading comprehension86. However, the literature points towards contrary directions as to what specific EF component is involved in academic achievement. This may be due to the different groups that were studied, to different operationalisations or to different theoretical underpinnings for EF86. For instance, online and offline metacognitive processes, which are not systematically distinguished in the literature, may play different roles in academic achievement. Moreover, the bulk of research focussed on young children with few studies on adolescents86 and EF may play a role at varying extents at different stages of life.Assessment of metacognition is usually compared against metrics of academic performance such as grades or scores on designated tasks. A recent meta-analysis reported a weak correlation of self-report questionnaires and interviews with academic performance whereas think-aloud protocols correlated highly90, with evidence for the development of meta-knowledge into adolescence91. Furthermore, current theories propose that meta-knowledge abilities are initially highly domain-dependent and gradually become more domain-independent as knowledge and experience are acquired and linked between domains32. Meta-control is believed to evolve in a similar fashion92.A critical question in educational sciences is that of the nature of the relationship between metacognition and academic achievement to understand whether learning at school can be enhanced by training metacognitive abilities. Does higher metacognition lead to higher academic achievement? Do these features evolve in parallel? Developmental research provides valuable insights into the formation of metacognitive abilities that can inform training designs in terms of what aspect of metacognition should be supported and the age at which interventions may yield the best results. First, meta-knowledge seems to emerge around the age of 5, meta-control around 8, and both develop over the years93. Interestingly, learning journals appear to be used for both assessing and fostering metacognition. Metacognitive instruction consists of teaching learners’ strategies to “activate” their metacognition. Metacognitive prompts most often consist of text pieces that are sent at specific times and that trigger reflection (offline meta-knowledge) on learning behaviour in the form of a question, hint or reminder.Common methods used to train offline metacognition are direct instruction of metacognition, metacognitive prompts and learning journals. In addition, research has been done on the use of (self-directed) feedback as a means to induce self-reflection in students, mainly in computer-supported settings95. Their findings show that metacognitive instruction can have a positive effect on learning abilities and achievement within a population ranging from primary schoolers to university students. In particular, interventions lead to the highest effect sizes when they both (i) instructed a combination of metacognitive strategies with an emphasis on planning strategies (offline meta-control) and (ii) “provided students with knowledge about strategies” (offline meta-knowledge) and “illustrated the benefits of applying the trained strategies, or even stimulated metacognitive reasoning” (p.114)18. The longer the duration of the intervention, the more effective they were. The strongest effects on academic performance were observed in the context of mathematics, followed by reading and writing.Meta-analyses have investigated the effects of direct metacognitive instruction on students’ use of learning strategies and academic outcomes96, meta-analyses that specifically investigate their effectiveness have yet to be performed. Nonetheless, evidence suggests that such interventions can be successful. Researchers found that metacognitive prompts fostered the use of metacognitive strategies (offline meta-control) and that the combination of cognitive and metacognitive prompts improved learning outcomes97. Another experiment showed that students who received metacognitive prompts performed more metacognitive activities inside the learning environment and displayed better transfer performance immediately after the intervention98. A similar study using self-directed prompts showed enhanced transfer performance that was still observable 3 weeks after the intervention99.While metacognitive prompts and learning journals make up the larger part of the literature on metacognitive training102. However, how the learning journal is used seems to be critical; good instructions are crucial103, and subjects who simply summarise their learning activity benefit less from the intervention than subjects who reflect about their knowledge, learning and learning goals104. An overview of studies using learning journals and metacognitive prompts to train metacognition can be found in Supplementary Table Several studies suggest that learning journals can positively enhance metacognition. Subjects who kept a learning journal displayed stronger high meta-control and meta-knowledge on learning tasks and tended to reach higher academic outcomes105. A meta-analysis did not show evidence for a causal relationship between EF and academic achievement19, but suggested that the relationship is bidirectional, meaning that the two are “mutually supportive”106.In recent years, educational neuroscience researchers have tried to determine whether training and improvements in EF can lead to learning facilitation and higher academic achievement. Training may consist of having students continually perform behavioural tasks either in the lab, at home, or at school. Current evidence in favour of training EF is mixed, with only anecdotal evidence for positive effects96. Overall, research in metacognitive training has been mainly invested in developing learners’ meta-control rather than meta-knowledge. Furthermore, most of the interventions were done in the context of science learning. Critically, there appears to be a lack of studies that employed randomised control designs, such that the effects of metacognitive training intervention are often difficult to evaluate. In addition, research overwhelmingly investigated metacognitive prompts and learning journals in adults96, while interventions on EF mainly focused on young children22. Lastly, meta-analyses evaluating the effectiveness of metacognitive training have so far focused on metacognitive instruction on children. There is thus a clear disbalance between the meta-analyses performed and the scope of the literature available.A recent review article has identified several gaps and shortcoming in the literature on metacognitive training86. For instance, Clements and colleagues mention work on SRL to illustrate research in EF in relation to academic achievement but the two spawn from different lines of research, one rooted in metacognition and socio-cognitive theory31 and the other in the cognitive (neuro)science of decision-making. In addition, the MSLQ, as discussed above, assesses offline metacognition along with other components relevant to SRL, whereas EF can be mainly understood as online metacognition  is performed in the lab. Common to all protocols for offline metacognition is that they consist of a form of self-report from the learner, either during the learning activity  or after the learning activity . Questionnaires are popular protocols due to how easy they are to administer but have been criticised to provide biased evaluations of metacognitive abilities. In contrast, learning journals evaluate the degree to which learners engage in reflective thinking and may therefore be less prone to bias. Lastly, it is unclear to what extent thinking-aloud protocols are sensitive to online metacognitive processes, such as on-the-fly error correction and effort regulation. The strength of the relationship between metacognitive abilities and academic achievement varies depending on how metacognition is operationalised. Self-report questionnaires and interviews are weakly related to achievement whereas thinking-aloud protocols and EF are strongly related to it.Based on the well-documented relationship between metacognition and academic achievement, educational scientists hypothesised that fostering metacognition may improve learning and academic achievement, and thus performed metacognitive training interventions. The most prevalent training protocols are direct metacognitive instruction, learning journals, and metacognitive prompts, which aim to induce and foster offline metacognitive processes such as self-reflection, planning and selecting learning strategies. In addition, researchers have investigated whether training EF, either through tasks or embedded in the curriculum, results in higher academic proficiency and achievement. While a large body of evidence suggests that metacognitive instruction, learning journals and metacognitive prompts can successfully improve academic achievement, interventions designed around EF training show mixed results. Future research investigating EF training in different age categories may clarify this situation. These various degrees of success of interventions may indicate that offline metacognition is more easily trainable than online metacognition and plays a more important role in educational settings. Investigating the effects of different methods, offline and online, on the neural level, may provide researchers with insights into the trainability of different metacognitive processes.In this article, we reviewed the literature on metacognition in educational sciences and cognitive neuroscience with the aim to investigate gaps in current research and propose ways to address them through the exchange of insights between the two disciplines and interdisciplinary approaches. The main aspects analysed were operational definitions of metacognition and metacognitive training, through the lens of metacognitive knowledge and metacognitive control. Our review also highlighted an additional construct in the form of the distinction between online metacognition (on the fly and largely automatic) and offline metacognition . In cognitive neuroscience, research has focused on metacognitive judgements (mainly offline) and EF (mainly online). Metacognition is operationalised with tasks carried out in the lab and are mapped onto brain functions. In contrast, research in educational sciences typically measures metacognition in the context of learning activities, mostly in schools and universities. More recently, EF has been studied in educational settings to investigate its role in academic achievement and whether training it may benefit learning. Evidence on the latter is however mixed. Regarding metacognitive training in general, evidence from both disciplines suggests that interventions fostering learners’ self-reflection and knowledge of their learning behaviour  may best benefit them and increase academic achievement.We focused on four aspects of research that could benefit from an interdisciplinary approach between the two areas: (i) validity and reliability of research protocols, (ii) under-researched dimensions of metacognition, (iii) metacognitive training, and (iv) domain-specificity vs. domain generality of metacognitive abilities. To tackle these issue, we propose four avenues for integrated research: (i) investigate the degree to which different protocols relate to similar or different metacognitive constructs, (ii) implement designs and perform experiments to identify neural substrates necessary for offline meta-control by for example borrowing protocols used in educational sciences, (iii) study the effects of (offline) meta-knowledge training on the brain, and (iv) perform developmental research in the metacognitive brain and compare it with the existing developmental literature in educational sciences regarding the domain-generality of metacognitive processes and metacognitive abilities.d′ metacognitive sensitivity in a 2-AFC task and the meta-knowledge subscale of the MAI, would provide external validity to the former. Moreover, educational scientists would be provided with bias-free tools to assess metacognition. These tools may enable researchers to further investigate to what extent metacognitive bias, sensitivity and efficiency each play a role in education settings. In contrast, a low correlation may highlight a difference in domain between the two measures of metacognition. For instance, metacognitive judgements in brain research are made in isolated behaviour, and meta-d’ can thus be viewed to reflect “local” metacognitive sensitivity. It is also unclear to what extent processes involved in these decision-making tasks cover those taking place in a learning environment. When answering self-reported questionnaires, however, subjects make metacognitive judgements on a large set of (learning) activities, and the measures may thus resemble more “global” or domain-general metacognitive sensitivity. In addition, learners in educational settings tend to receive feedback — immediate or delayed — on their learning activities and performance, which is generally not the case for cognitive neuroscience protocols. Therefore, investigating metacognitive judgements in the presence of performance or social feedback may allow researchers to better understand the metacognitive processes at play in educational settings. Devising a global measure of metacognition in the lab by aggregating subjects’ metacognitive abilities in different domains or investigating to what extent local metacognition may affect global metacognition could improve ecological validity significantly. By investigating the neural correlates of educational measures of metacognition, researchers may be able to better understand to what extent the constructs studied in the two disciplines are related. It is indeed possible that, though weakly correlated, the meta-knowledge scale of the MAI and meta-d’ share a common neural basis.First, neurocognitive research on metacognitive judgements has developed robust operationalisations of offline meta-knowledge. However, these operationalisations often consist of specific tasks  carried out in the lab. These tasks are often very narrow and do not resemble the challenges and complexities of behaviours associated with learning in schools and universities. Thus, one may question to what extent they reflect real-life metacognition, and to what extent protocols developed in educational sciences and cognitive neuroscience actually operationalise the same components of metacognition. We propose that comparing different protocols from both disciplines that are, a priori, operationalising the same types of metacognitive processes can help evaluate the ecological validity of protocols used in cognitive neuroscience, and allow for more holistic assessments of metacognition, provided that it is clear which protocol assesses which construct. Degrees of correlation between different protocols, within and between disciplines, may allow researchers to assess to what extent they reflect the same metacognitive constructs and also identify what protocols are most appropriate to study a specific construct. For example, a relation between meta-107), common experimental designs make it hard to disentangle online from offline metacognitive processes. A few studies have implemented subject reports  to pin-point the neural substrates specifically involved in offline meta-control and the current evidence points at a role of the lPFC. More research implementing similar designs may clarify this construct. Alternatively, researchers may exploit educational sciences protocols, such as self-report questionnaires, learning journals, metacognitive prompts and feedback to investigate offline meta-control processes in the brain and their relation to academic proficiency and achievement.Second, our review highlights gaps in the literature of both disciplines regarding the research of certain types of metacognitive processes. There is a lack of research in offline meta-control (or strategic regulation of cognition) in neuroscience, whereas this construct is widely studied in educational sciences. More specifically, while there exists research on EF related to planning  transfer to meta-knowledge in other lab tasks. The case of meditation is particularly interesting since meditation has been demonstrated to beneficiate varied aspects of everyday life108. Given its importance for efficient regulation of cognition, training (offline) meta-knowledge may present the largest benefits to academic achievement. Hence, it is important to investigate development in the brain relative to meta-knowledge training. Evidence on metacognitive training in educational sciences tends to suggest that offline metacognition is more “plastic” and may therefore benefit learning more than online metacognition. Furthermore, it is important to have a good understanding of the developmental trajectory of metacognitive abilities — not only on a behavioural level but also on a neural level — to identify critical periods for successful training. Doing so would also allow researchers to investigate the potential differences in terms of plasticity that we mention above. Currently, the developmental trajectory of metacognition is under-studied in cognitive neuroscience with only one study that found an overlap between the neural correlates of metacognition in adults and children109. On a side note, future research could explore the potential role of genetic factors in metacognitive abilities to better understand to what extent and under what constraints they can be trained.Third, there is only one study known to us on the training of meta-knowledge in the labFourth, domain-specific and domain-general aspects of metacognitive processes should be further investigated. Educational scientists have studied the development of metacognition in learners and have concluded that metacognitive abilities are domain-specific at the beginning  and progressively evolve towards domain-general abilities as knowledge and expertise increase. Similarly, neurocognitive evidence points towards a common network for (offline) metacognitive knowledge which engages the different regions at varying degrees depending on the domain of the activity . Investigating this network from a developmental perspective and comparing findings with the existing behavioural literature may improve our understanding of the metacognitive brain and link the two bodies of evidence. It may also enable researchers to identify stages of life more suitable for certain types of metacognitive intervention.Supplementary materials


Breast cancer represents the most commonly diagnosed cancer while neoadjuvant and adjuvant chemotherapies are extensively used in order to reduce tumor development and improve disease-free survival. However, chemotherapy also leads to severe off-target side-effects resulting, together with the tumor itself, in major skeletal muscle deconditioning. This review first focuses on recent advances in both macroscopic changes and cellular mechanisms implicated in skeletal muscle deconditioning of breast cancer patients, particularly as a consequence of the chemotherapy treatment. To date, only six clinical studies used muscle biopsies in breast cancer patients and highlighted several important aspects of muscle deconditioning such as a decrease in muscle fibers cross-sectional area, a dysregulation of protein turnover balance and mitochondrial alterations. However, in comparison with the knowledge accumulated through decades of intensive research with many different animal and human models of muscle atrophy, more studies are necessary to obtain a comprehensive understanding of the cellular processes implicated in breast cancer-mediated muscle deconditioning. This understanding is indeed essential to ultimately lead to the implementation of efficient preventive strategies such as exercise, nutrition or pharmacological treatments. We therefore also discuss potential mechanisms implicated in muscle deconditioning by drawing a parallel with other cancer cachexia models of muscle wasting, both at the pre-clinical and clinical levels. Cancer represents the leading cause of death worldwide and a substantial barrier to increasing life expectancy. Among the different cancer sites, breast cancer is the most commonly diagnosed cancer, with 11.7% of total cases and 6.9% of cancer deaths . EffectiSkeletal muscle deconditioning is a direct consequence of global muscle homeostasis perturbation, leading to both structural and functional alterations that will translate into a decrease in muscle mass and/or force as well as an increase in fatigability . In the To date, the cellular mechanisms of skeletal muscle deconditioning are of great importance and have been extensively reviewed in healthy people, elderly as well as in relation with many chronic diseases . HoweverThis review focuses on recent advances in both macroscopic changes and cellular mechanisms implicated in skeletal muscle deconditioning of breast cancer patients, specifically as a consequence of chemotherapy treatment. This review also aims to highlight other potential mechanisms by drawing a parallel with cancer cachexia models of muscle wasting, both at the pre-clinical and clinical levels.Two families of chemotherapeutic agents are commonly used in clinical practice for breast cancer patients: anthracyclines  leading to DNA damage, and taxanes  acting as cytoskeletal disruptors . Importavs. post-chemotherapy assessments) and lean body mass measurements , only two studies emerged (N = 221), sarcoma (N = 115) and lymphoma (N = 216) female patients. In breast cancer only, Although it is widely accepted that chemotherapy induces skeletal muscle loss in breast cancer patients, very few studies clearly demonstrated it. Indeed, by excluding all non-longitudinal studies  may explain these contrasting results. Other studies also highlighted a decrease in muscle force of breast cancer patients undergoing chemotherapy in comparison with healthy women , found inconsistent results on chemotherapy-treated breast cancer patients. Indeed, some longitudinal studies  documenthy women , supportThere is a growing body of evidence that the loss of muscle strength and power mostly exceeds the loss of muscle mass observed in many diseases or inactivity experiments, emphasizing that a deterioration in muscle quality could explain the loss in force and lead to functional impairments . Muscle max2) represents the gold standard measurement of exercise tolerance  is the only technique allowing full investigation of the cellular mechanisms of muscle deconditioning . To datevs. aging. Two other longitudinal studies found no reduction in muscle fibers vastus lateralis CSA during chemotherapy including taxanes, cyclophosphamide, doxorubicin, and carboplatin , that are responsible for the degradation of most proteins and organelles in skeletal muscle cells. First, numerous pre-clinical studies observed an increase in skeletal muscle protein breakdown , demonstThe FoxO family of transcription factors (FoxO1 and FoxO3 particularly) and NF-κB are known to be essential transcription factors implicated in the regulation of numerous genes of both UPS and autophagy pathways in various models of skeletal muscle atrophy . These tAside from studies presented in the section of this review dedicated to breast cancer clinical studies , no precAs a critical upstream of protein turnover alteration, inflammation plays a key role in the development of muscle wasting in cancer patients. Indeed, either released by the tumor or immune cells, pro-inflammatory cytokines like TNF-α, TWEAK, IL-6, IL-1β, IL-8, and INFγ have been found to be upregulated at a systemic level in animals  and in cIn addition to pro-inflammatory cytokines, two particular members of the TGF-β family have been particularly explored in cancer cachexia: myostatin (MSTN) and Activin A. MSTN clearly represents one of the most potent negative regulator of muscle growth and is known to act through its receptor ActRIIB and the subsequent activation of the SMAD2/SMAD3 cascade . MSTN anMitochondrial alterations represent a major aspect of muscle deconditioning that have been already associated with skeletal muscle atrophy in breast cancer patients , and in 2O2). Unanimously, several studies reported that doxorubicin administration in rodents led to an increase in H2O2 production (in vitro (C2C12) and found increased levels of caspase 3 (both its activity and cleaved form of caspase 3 protein expression) and of Bax . Indeed, many different studies found an increase in ROS , more spoduction , while toduction , 2018 anoduction . Three od of Bax . Finallyd of Bax .Increased levels in unfolded or misfolded proteins and oxidative stress  will lead to endoplasmic reticulum stress and trigger the unfolded protein response (UPR) that might represent another major maladaptation taking place during cancer cachexia. Acting through three pathways  the UPR contributes to skeletal muscle atrophy by decreasing protein synthesis, increasing protein breakdown and, ultimately, inducing apoptosis . The UPRper se would inhibit myogenic differentiation process, the combination of both the disease and chemotherapeutic drugs administration might lead to global SCs dysfunction and loss in breast cancer patients. However, as highlighted in our section dedicated to clinical studies in breast cancer patients, only +-labeled SCs and found no change in their number. Therefore, more studies are necessary to clarify SCs fate and implication in breast cancer patients and/or pre-clinical models.The capacity of skeletal muscle to regenerate is another key parameter of its functionality. After injury, successful skeletal muscle regeneration appears to be driven by complex and precisely orchestrated processes involving multiple cell types. Of these cell types, satellite cells (SCs), localized between the sarcolemma and the basal lamina of myofibers , represeThe abnormal development of fibrotic and/or IMAT deposits within skeletal muscle is a strong marker of regenerative failure. As documented above, breast cancer patients exhibit an increase in IMAT , a resulOther than their important role in muscle regeneration and abnormal development of IMAT, FAPs have been recently shown to promote skeletal muscle atrophy. Indeed, the study of Breast cancer patients undergoing chemotherapy definitively experience skeletal muscle deconditioning, mainly characterized by both a decrease in muscle mass and function. Despite the fact that mechanisms of muscle deconditioning are well known in many other muscle wasting models, including in other pre-clinical or clinical models of cancers, they still remain relatively unknown in breast cancer patients. In fact, some studies using muscle biopsies highlighted protein turnover and mitochondrial alterations in breast cancer patients, but other studies are clearly needed to obtain a more precise understanding of the cellular processes implicated in breast cancer-mediated muscle deconditioning. This lack of knowledge inevitably leads to difficulties for the implementation of efficient preventive strategies such as exercise, nutrition or pharmacological treatments.JM, EH, TH, and AP contributed to writing or editing the manuscript and approved the final version of the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Reliable and responsive tools for monitoring disease activity and treatment outcomes in patients with neuropathies are lacking. With the emergence of ultrasensitive blood bioassays, proteins released with nerve damage are potentially useful response biomarkers for many neurological disorders, including polyneuropathies. In this review, we provide an overview of the existing literature focusing on potential applications in polyneuropathy clinical care and trials. Whilst several promising candidates have been identified, no studies have investigated if any of these proteins can serve as response biomarkers of longitudinal disease activity, except for neurofilament light (NfL). For NfL, limited evidence exists supporting a role as a response biomarker in Guillain-Barré syndrome, vasculitic neuropathy, and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Most evidence exists for NfL as a response biomarker in hereditary transthyretin-related amyloidosis (hATTR). At the present time, the role of NfL is therefore limited to a supporting clinical tool or exploratory endpoint in trials. Future developments will need to focus on the discovery of additional biomarkers for anatomically specific and other forms of nerve damage using high-throughput technologies and highly sensitive analytical platforms in adequality powered studies of appropriate design. For NfL, a better understanding of cut-off values, the relation to clinical symptoms and long-term disability as well as dynamics in serum on and off treatment is needed to further expand and proceed towards implementation.The online version contains supplementary material available at 10.1007/s13311-021-01136-0. Polyneuropathies have a total prevalence of about 1% in the unselected population, and up to 7% in elderly . TypicalArguably, the most important unmet need in the field is the monitoring of disease activity and treatment response in patients with treatable neuropathies such as chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), hereditary transthyretin-related amyloidosis (hATTR), and anti-MAG neuropathy. Nerve conduction studies can be poorly tolerated by patients and are also poorly responsive to change, especially in patients with severe axonal damage. Nerve imaging with ultrasound or MRI in the twenty-first century has improved resolution, but with low specificity and inconsistent reliability when used as a response biomarker limits utility . TherefoThe recent development of high-sensitivity techniques to measure fluid biomarkers has accelerated biomarker research in polyneuropathies. There have recently been several reports on how biomarkers could potentially improve and accelerate diagnosis but also allow for assessment of disease activity. Most have focused on non-specific biomarkers of disease activity reflecting nerve damage. In this review, we will provide an overview of biomarker candidates that reflect structural damage across different types of neuropathies, with a focus on diagnostic and response biomarkers . In partAt least three important challenges exist for damage biomarkers in neuropathies. Firstly, peripheral nerve tissue is of low volume and nerve-specific proteins are usually only present in very low concentrations in blood. Secondly, the tempo of damage can be acute or more importantly very prolonged, which when combined with biomarker pharmacokinetics means levels can be even lower. Therefore, assays need to have sufficient sensitivity to detect very low circulating levels. Thirdly, nerve structures, like myelin, axon, or paranode, may be preferentially or even exclusively damaged in different disorders. Therefore, it is likely that different biomarkers reflecting different nerve components are needed. While one would prefer high specificity for a diagnostic biomarker, in general response biomarkers do not need to be so specific as long as they have sufficient sensitivity and responsiveness . Below, we have summarized biomarkers reflecting damage to different nerve structures Table .While the numerous lipids and proteins within Schwann cells and the myelin sheath are now well-characterized , there aNeural cell adhesion molecule (NCAM) is a member of the immunoglobulin superfamily expressed on several different neural cell types including Schwann cells. In one study, the mean serum NCAM levels were higher in demyelinating neuropathies (both inflammatory and Charcot-Marie-Tooth disease (CMT) type 1A) than in healthy controls and axonal neuropathies, and there was a positive correlation with the Overall Neuropathy Limitations Score . NCAM leSerum levels of p75 neurotrophin receptor, a transmembrane protein expressed on Schwann cells and some CNS neurons, were raised in inflammatory demyelinating neuropathies but not in CMT1A, whereas NCAM levels were raised in both, indicating that there may be potential to use the levels of NCAM and p75 to differentiate CIDP from CMT in difficult cases, with a raised p75 differentiating CIDP from CMT1A with both high sensitivity and specificity . The higTransmembrane protease serine 5 (TMPRSS5), a transmembrane protein expressed on Schwann cells, was identified in one study as capable of discriminating between CMT subtypes, with CMT1A patients showing increased serum levels whereas other forms of CMT did not have elevated levels .The axonal cytoskeleton is made from a small number of repeating co-associating proteins, and these can be released to the extracellular space by axonal damage. By far, the best studied axonal damage markers in neurological diseases is NfL. NfL is a ubiquitous cytoskeletal protein and released into the CSF and blood in numerous CNS disorders and peripheral neuropathies (see further below). Although neurofilament heavy (NfH) was described as an axonal biomarker well before NfL and early studies of small numbers of patients showed that higher CSF levels predict axonal involvement and poor outcome in GBS –13, it hThe neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) have been studied in diabetic neuropathy and chemotherapy-induced peripheral neuropathy (CIPN), with higher levels postulated to have a neuroprotective effect. While most studies found that lower levels of neurotrophins correlated with neuropathy and its severity –23, the Glial fibrillary acidic protein (GFAP) is an intermediate filament expressed by astrocytes in the CNS and by non-myelinating Schwann cells in the PNS. GFAP is thought to be upregulated in Schwann cells after axonal injury, and thus may be an indirect marker of axonal damage . One resS-100B is another glial protein expressed in CNS glial cells and Schwann cells, though unlike GFAP it is found in both myelinating and non-myelinating Schwann cells . S-100B Osteopontin is a widely expressed protein also found in Schwann cells, and is involved in inflammation and possibly axonal regeneration . One stutau may be used as markers for neuronal damage [Tau and neuron-specific enolase (NSE), another neuronal protein, have both been studied in GBS, with CSF levels of tau associated with worse short- and medium-term outcome [tau levels in COVID-19-positive CINM patients and other critically unwell COVID-19 patients at different timepoints [For disorders such as sensory neuronopathies, and infectious and inflammatory polyradiculopathies, damage to the neuronal cell body may occur at an early stage of disease. Although the axon and neuron are a continuum, and neuronal damage subsequently leads to axonal damage, some authors have advocated that neuronal proteins such as total l damage . Tau and outcome , 13, and outcome  correlat outcome . In a remepoints .In summary, for most of the molecules above, variations of study design and overlap between groups make it difficult to say whether any of them are reliable disease overarching diagnostic biomarkers , their degree of automation , and the platform costs. Standardization across labs and platforms is the subject of several initiatives, such as the Alzheimer’s Association Quality Control Program and Blood-Based Biomarker Working Interest Group. The development of reference material and methods is an important unmet need, to allow comparison between different platforms and assay formats and the development of unified cut-offs. There is a strong relationship between NfL levels and age, which means that cross-sectional results should always be compared against reference values obtained in the same age groups .NfL levels can increase rapidly (within 12 h after hypoxic cardiac arrest ) and decAn overview of studies investigating NfL in neuropathies is provided in Table Taken together, only a handful of candidates of nerve tissue biomarkers have been explored in neuropathies. NfL has been studied most and has potential uses in clinical practice and trials. Although there is some way to go in development, we are now at an important juncture for exploring clinical applications.tau) and are not specific enough to be diagnostic for particular disorders, as raised levels occur in many diseases including ALS, adrenoleukodystrophy, frontotemporal dementia, and autoimmune encephalitis. In clinical scenarios where the differential diagnosis includes disorders with differing degrees of axonal degeneration, NfL may be of diagnostic help, especially early after disease onset when clinical symptoms can be limited. In a memory clinic, normal serum or CSF NfL in the ‘worried well’ can be reassuring of the lack of a neurodegenerative process [NfL is released in measurable amounts in any disorder where axonal degeneration occurs fast enough to exceed clearance. Where this occurs in a large tissue mass, released into a small volume of fluid and the axon loss is rapidly occurring, this is straightforward; for example, in prion disease and other rapidly progressive dementias, CSF NfL levels are in nanogrammes per millilitre . Signifi process . Convers process . The perAs with CNS disease, there are many potential applications such as assessing treatment efficacy and prognosis, identifying relapses of relapsing and remitting diseases such as CIDP, and differentiating the worried well from those with active disease. However, NfL has not yet found a place in clinical use despite potential in GBS, CIDP, and very promising findings in hATTR . ArguablClinical trials are geared towards measuring clinically significant changes in outcome measures directly relating the therapeutic effect of an intervention to patient benefit in a reliable, reproducible, and unequivocal manner. In neuromuscular disease, measures of disability are favoured as meaningful to patients, and impairments as quantitatively measurable. However, neither relates directly to disease pathogenesis; quantifiable change may take time to develop; and as these measures are indirectly related to the pathology, they can be influenced by patient and measurement errors.Some biological biomarkers have proven utility as outcomes in trials, such as muscle fat fraction MRI measurement in CMT1A which has excellent responsiveness and reliability in much shorter term assessments compared to clinical measures . As NfL Other biomarkers of Schwann cell or cell body damage, or perhaps immune activation, may be developed, possibly as compound measures in the future, and these may eventually become favoured for their directness. Until then, their inclusion as exploratory outcomes to prove their utility, explore responsiveness, correlate them to clinical change, and develop cut-off values will be important steps to them becoming accepted by regulatory authorities alongside traditional scales.Now that we have the technologies and analytical platforms, as well as increasing molecular knowledge, there is huge potential for biomarkers to become significant tools in diagnosis, therapeutics, and prognosis.For biomarker identification, peripheral nerve diseases perhaps have some advantages over CNS diseases. Firstly, the lesser tissue mass and greater volume of distribution into which NfL is released might more reliably identify severe and acute damage. And arguably, more easily quantifiable clinical outcome measures of neuromuscular disease compared to CNS pathologies may correlate better with measured levels of a blood biomarker. Changes may occur more rapidly and reliably than clinical outputs resulting in better signal to noise in outcome measurement and possibly shorter trials, at least in early phases. However, the lack of a readily available tissue correlate and limitations of disability and impairment measures in discerning ongoing or residual axonal degeneration may form challenges to accurately anchor NfL levels and define meaningful changes in polyneuropathies.Other protein biomarkers of damage to specific cell types, which differentiate CNS from PNS disease, that quantify blood-nerve barrier dysfunction and identify different pathway perturbations need to be identified and assays developed employing the novel technologies. It is likely that compound biomarkers utilizing two or more biomarkers in panels will be useful. Reaching from single protein measures into more complex pathway biomarkers has been explored in recent novel metabolomic –65 and eBesides more biomarkers, the best fluid compartment for measurement also needs to be explored. Blood-based analysis of molecules using ultrasensitive technologies offers advantages over CSF as sampling is atraumatic and repeated samples are easily accessible giving better time resolution and more granular results. Urine and tears might also possible sources of measurable biomarkers in some cases.Recently initiated international registries and biobanks, such as the International Guillain-Barré Syndrome Outcome Study (IGOS) , InflammSupplementary file1 (PDF 595 KB)Supplementary file2 (PDF 356 KB)Supplementary file3 (PDF 373 KB)Supplementary file4 (PDF 356 KB)Below is the link to the electronic supplementary material.


Kaposi’s sarcoma-associated herpesvirus (KSHV) is an oncogenic gammaherpesvirus associated with several human cancers. KSHV infection and KSHV-induced anabolic cell proliferation and cellular transformation depend on reprogramming of cellular metabolic pathways, which provide the building blocks and energy for the growth of both the virus and the infected cells. Furthermore, KSHV dysregulates numerous metabolic sensors including mTOR, AMPK, CASTOR1 and sirtuins to maintain cellular energetic homeostasis during infection and in KSHV-induced cancers. In this review, we summarize the recent advances in the understanding of KSHV hijacking of metabolic pathways and sensors, providing insights into the molecular basis of KSHV infection and KSHV-induced oncogenesis. In addition, we highlight the critical metabolic targets and sensors for developing potential new therapies against KSHV infection and KSHV-induced cancers. Cancer is recognized as a metabolic disease since a defining hallmark of cancer is uncontrolled proliferation that demands surplus bioenergetics and biosynthetic precursors . To meetAccording to the assessment of the International Agency for Research on Cancer, viral infection accounts for at least 11% of human cancer worldwide . OncogenThe recent resurgence of research in cancer metabolism has arisen as a result of advances in newly developed biomedical and biological tools, which expands our understanding of the underpinning mechanisms and functional consequences of altered metabolism in cancer. Cancer cells often show increased consumption of glucose, accompanied by a switch of energy metabolism from oxidative phosphorylation to aerobic glycolysis even in the presence of ambient oxygen, the so-called Warburg effect . AlthougKaposi’s sarcoma-associated herpesvirus (KSHV), discovered in 1994 by Chang and Moore , is one KS tumors are spindle-shaped cells expressing vascular endothelial, lymphatic endothelial, precursor and mesenchymal markers . Most KS18F-fluorodeoxyglucose (18F-FDG), has been successfully applied to diagnose and stage tumors. The combination of PET with 18F-FDG and computed tomography (18F-FDG PET/CT) provides valuable functional information regarding the uptake of glucose and glycolytic processes of cancer cells, which benefits cancer recurrence detection and treatments [The first characterization of metabolic changes in tumors cells dated back to more than six decades ago when the Germany physiologist Otto Warburg observed that cancer cells consume a large amount of glucose and secrete excessive lactate even in the presence of oxygen yielding only 2 ATP per glucose . In conteatments .Fig. 1ThTo examine the effect of KSHV infection on glucose catabolism, Delgado et al. infected telomerase-immortalized microvascular endothelial cells (TIME cells) and primary human dermal microvascular endothelial cells (hDMVECs) with KSHV for 48 h, and observed the induction of Warburg effect in KSHV-infected cells, which had increased glucose uptake and increased lactate secretion but decreased oxygen consumption in KSHV- versus mock-infected cells . InhibitThe above studies rely on the use of short-term KSHV infection systems or overexpression of KSHV-encoded miRNAs without taking into consideration of KSHV infection that doesn’t lead to cellular transformation. It is unclear how these systems might recapitulate the in vivo metabolic characteristics of KS tumors. In 2012 Jones et al. successfully infected, immortalized and transformed primary rat metanephric mesenchymal precursor cells (MM) with KSHV . KSHV-trGlutamine is a very versatile amino acid, acting as energy fueling as well as a precursor for synthesizing many biological macromolecules. GLS and GLS2 hydrolyze glutamine to glutamate, which is exported by antiporter xCT coupled with cysteine import , 33. InhVeettil et al. observed an increased secretion of glutamate into medium following KSHV latent infection, which was essential for the proliferation of KSHV-infected cells . MechaniZhu et al. found that KSHV-transformed cells were addicted to glutamine but not glucose to sustain cell proliferation, survival and transformation . CompareCancer cells have a high demand for fatty acids used for membrane synthesis. Acetyl-CoA is the obligate substrate for fatty acid synthesis (FAS), which is derived from the catabolism of glucose and glutamine. Bhatt et al. reported that KSHV-infected PEL cells upregulated fatty acid synthase and FAS compared to KSHV-negative primary B lymphocytes, which was essential for PEL cell proliferation and survival . AdditioSphingosine is a class of cell membrane lipids and can be phosphorylated by sphingosine kinases (SphK) to form a signaling lipid called sphingosine-1-phosphate (S1P) to elicit pro-proliferative and pro-survival signaling. Qin et al. showed that the inhibition of SphK1 specifically induced the apoptosis of PEL and KSHV-infected endothelial cells, hinting the important role of lipid metabolism . MoreoveConsidering the cellular environments that support KSHV latent and lytic replications are different, the metabolic activities during these two stages could differ. KSHV relies on cellular metabolites and energy for viral replication. Studies regarding the host metabolism during KSHV reactivation are limited. Sanchez et al. reported that glycolysis, glutaminolysis, and FAS are required for KSHV virion production and these metabolic pathways participate in distinct stages of viral life cycle . InhibitAlthough cancer cells are addicted to uptake of glucose and amino acids, they often encounter the nutrient scarcity because of the imbalance between increased consumption and limited supplies of nutrients. The aberrantly activated growth and survival signaling pathways play a major role in tumorigenesis at least by partially reprogramming the metabolism of cancer cells, allowing them to survive in nutrition-stressed conditions. Conversely, the reprogrammed metabolic pathways as well as the altered balance in metabolites in cancer cells also impact the metabolic sensors that sustain the uncontrolled proliferation of cancer cells. The most understood metabolite-sensing and signaling pathways are AMPK, sirtuins (SIRTs) and mTOR . Many grAMPK is another evolutionarily conserved metabolic sensor and is activated when energy supply is insufficient, resulting in an increase in the intracellular ratio of AMP/ATP or glucose shortage. Anabolism is inhibited by the activated AMPK leading to catabolism of glucose and lipids for ATP restoration. As a result, gluconeogenesis is inhibited, glucose uptake is increased and the mitochondrial biogenesis is prompted . Elevate+ and NADH. Catabolism of one glucose requires two molecules of NAD+, producing two NADH in addition to two hydrogen ions and two molecules of water. The sirtuin family is composed of seven members from 1 to 7, which use NAD+ a co-substrate for enzymatic activities, are class III histone deacetylases (HDACs) functionally linked to cellular metabolism, and hence are regarded as metabolic sensors. Among them, SIRT1 is the most well-studied, and has a critical role in cancer because it inhibits glycolysis and stimulates fatty acids [2O2), leading to SIRT1 downregulation and hence KSHV reactivation [NAD is a cofactor central to cellular metabolism and is composed of two forms: oxidized and reduced forms, abbreviated for NADty acids . In PEL ty acids , 71. Addty acids . Consisttivation  Fig. 4)+ and NADThe notion that KSHV hijacks the metabolic sensors including mTOR, AMPK, SIRT1 and CASTOR1 has been established. Nevertheless, whether KSHV hijacks these sensors to regulate host cell metabolism during latent and lytic infection remains unclear. Moreover, how KSHV-infected cells integrate the signals sensed by mTOR, AMPK, SIRT1 and CASTOR1 to sustain anabolic proliferation and survival is of great interest for understanding the mechanisms of viral persistence and KSHV-induced oncogenesis.18F-FDG PET/CT technique to monitor the glycolytic efflux might reveal the true glucose metabolism in KS and PEL patients. However, it is also important to keep in mind that cancer cells and their microenvironment might have different metabolic demands, which could confound these assessments. Several KSHV-encoded products might be involved in reprogramming the glycolysis, glutaminolysis and FAS by activating specific cellular pathways. However, there is so far no experimental evidence to indicate the direct involvement of viral genes except miRNAs in regulating the host metabolic enzymes and remodeling the metabolic pathways. Most studies so far have only demonstrated the regulation of host cell signaling pathways by viral products and hence potential involvement in rewiring the cellular metabolic profiles [Cancer cells sustain their uncontrolled proliferation in nutrients- and oxygen-deficient tumor microenvironments through reprogramming cellular metabolic pathways and sensors, which optimize their responses to environmental inputs and stress. While most studies concentrate on the glucose and glutamine metabolism, cancer cells usurp a great variety of other nutrients, for example, cysteines, vitamins, trace metals, and proline. The diversity of nutrients and the complexity of cellular responding circuits complicate our understanding how nutrients contribute to tumorigenesis. Viruses are absolute parasites that depend on the energy and macromolecules of host cells for their infection and spread. Oncogenic KSHV infection induces cellular transformation by altering host cell metabolism, which is essential for maintaining cell survival and viral persistence. However, the delineation of the underpinning mechanisms is instead confounded by the multiple stages of KSHV infection. A simple example is the differential glucose catabolism observed by two groups in short-term KSHV-infected endothelial and persistent KSHV-transformed cells, respectively. The application of profiles . Hence, Numerous studies have investigated how KSHV evolves to usurp the host metabolic resources, funneling them towards reproducing virion progeny and transforming host cells. However, how cells utilize the metabolic countermeasures to sense and antagonize viral infections and how the host cell metabolic pathways impact KSHV infection and replication are less studied. It has been reported that high glucose could induce KSHV reactivation and KS is clinically correlated with diabetes mellitus –77. It i


With few exceptions, humans are incapable of fully recovering from severe physical trauma. Due to these limitations, the field of regenerative medicine seeks to find clinically viable ways to repair permanently damaged tissue. There are two main approaches to regenerative medicine: promoting endogenous repair of the wound, or transplanting a material to replace the injured tissue. In recent years, these two methods have fused with the development of biomaterials that act as a scaffold and mobilize the body’s natural healing capabilities. This process involves not only promoting stem cell behavior, but by also inducing activity of the immune system. Through understanding the immune interactions with biomaterials, we can understand how the immune system participates in regeneration and wound healing. In this review, we will focus on biomaterials that promote endogenous tissue repair, with discussion on their interactions with the immune system. ImmediaActivated platelets release platelet-derived growth factor (PDGF), CXCL8, TNF-α, and other immune mediators . This envia release of immune mediators and breakdown of ECM   . Hui et  (TGF-B) . Additio (TGF-B) . The comvia apoptosis/or by other unestablished mechanisms  . The actIt is estimated that the conservative failure rate of implants due to foreign body response is around 10%, and the cost of solving this need is around $10 billion per year . There aTissue-derived ECM scaffolds have long been used due to its natural role in promoting endogenous repair and proving to be well suited for the clinic . DespitePlant-derived alginates (a polysaccharide block co-polymer of β-D-mannuronate and α-L-guluronate) also elicit a severe foreign body response . Since iIn addition to changing the shape and size of the biomaterial, alginates are extremely easy to chemically modify. Papers such as that of Regardless of chemical composition, however, the size and morphology of the biomaterial itself could lead to a foreign body response. Muscle tissue is highly structured and composed largely of long, multinucleated muscle fibers that are enclosed into bundles by extracellular matrix protein. Muscle precursor cells, named satellite cells, the resulting tissue is strong but dynamic, and able to meet evolving physical demands.According to the World Health Organization, there are 1.71 billion people in the world suffering from musculoskeletal disorders . PrevaleCourtesy of the regenerative nature of muscle tissue, healthy muscle is often able to heal in response to minor trauma. Significant issues come, however, when the extent of muscle trauma exceeds the regenerative capacity of the muscle. This triggers a dysregulated immune and regenerative response that involves scarring, deteriorated muscle function, and long-term health issues . A commoThe process of muscle healing is extensively reviewed elsewhere  and brie9 leukocytes per liter in adult, rodent limb muscles  and derivatives are a well-established class of biomaterials and have already shown great clinical success . At its Extracellular matrix (ECM) and derivatives have already shown great clinical success in treating muscular injury . Cheap, While Type I collagen is not immunogenic, it is the various smaller components of ECM that succeed in triggering desirable cell stimulation, activation, or migration. This includes growth factors, ECM degradation products, or cell adhesion molecules .Porcine ECM scaffolds have been shown to promote muscle wound healing in mice and humans . Deeper Release of IGF-1 by ECM scaffolds also aids in M1 to M2 macrophage polarization during the transition from the inflammatory to repair phase in muscle wound healing . As mentIn addition to M2 macrophages, myoblasts and neurogenic precursor cells were found to infiltrate to the center of the implanted ECM. Researchers previously demonstrated that degradation products from ECM scaffolds promote M2 macrophage phenotype similarly to IL-4 . M2 macr+ transfer, but not with transfer of Rictr- T cells -linked β-D-mannuronic acid (M) and α-L-guluronic acid (G) monomers . AlginatUnlike other biomaterials for muscle healing, alginate is unique because it does not degrade easily in the body . Howeverin vivo function of silk biomaterials for muscle healing. However, reports indicate that there are certain derivatives of silk that are able to not trigger an adverse immune response and are able to be degraded by macrophages in vivo  fiber mesh successfully formed unidirectional myofibers in vivo . HoweverPolyethylene glycol (PEG) is a common synthetic biomaterial, largely because it was believed to not be as immunogenic as other synthetic biomaterials and has many physical characteristics that make it a desirable biomaterial . PEG hydMethacrylic Acid (MAA) has shown great efficacy as a biomaterial in other tissues, and has recently been applied to skeletal muscle. Methacrylic acid promotes IGF-1 signaling and increases presence of Fizz-1+ macrophages in skeletal muscle . MAA alsApplying electrospinning techniques to synthetic biomaterials has significantly increased the feasibility of synthetic scaffolds for tissue engineering by making them less immunogenic. This technique allows for easy and tunable manipulation of synthetic biomaterials to create scaffolds with similar properties as the natural extracellular matrix . ElectroElectrospinning has greatly improved efficacy of synthetic biomaterials for muscle healing. PLGA fiber scaffolds laden with myoblasts showed aligned myofiber growth and development, indicating that PLGA was a suitable biomaterial to promote muscle formation . PLGA isAs previously mentioned, each biomaterial type has its limitations. However, significant progress has been made in combining various materials to create a superior scaffold. While synthetic biomaterials may provide the best scaffolds for myoblasts to attach and differentiate upon, foreign body response to most of these materials is virtually unavoidable. While synthetic scaffolds have been used in the clinic for decades, permanent implantation of these materials alone to treat an area where fibrosis is likely to trigger adverse effects in many patients. As a result, combinatorial materials made of both immunomodulatory and synthetic scaffolds are an emerging field.To combat the M1 macrophage-mediated response against polypropylene mesh, Using ECM scaffolds to combat the foreign body response to synthetic biomaterials has also shown success with PCL scaffolds. + tissue-resident memory T cells, while the dermis contains dendritic cells, macrophages, innate lymphoid cells, natural killer (NK) cells CD8+ tissue-resident memory T cells, fibroblasts, and pericytes  and dermis (lower layer), that are separated by the basement membrane. These layers are in turn composed of sublayers with different cell types and structures . The epiericytes . The immericytes .Detailed reviews of skin composition and the wound healing process have been written by others . In brieThe proliferative phase is characterized by fibroblast, keratinocyte, and endothelial cell migration and proliferation . KeratinStem cells play an important role throughout the skin wound healing process, with involvement of both stem cell proliferation and signaling in healing . StudiesThe applications of skin wound healing include treatment of diabetic wounds, burn wounds, and full-thickness skin wounds. Traditional biomaterial-based approaches to skin wound healing typically focus on providing flexible mechanical properties while protecting the wound from infection. In this section, however, we will focus on biomaterial-based approaches that seek to modulate the body’s immune response to aid in the healing process. Many skin wound healing studies include the use of polymeric nanofibers [reviewed by Many skin healing studies have been undertaken with naturally-derived biomaterials , but fewvia mediation by proteins that bind with the Pro-Hyp-Gly unit, those that bind with the Phe-Hyp-Gly sequence, receptors for collagen’s cryptic binding sites, and receptors for non-collagenous domains  seeded on the nanofiber membranes were favorable. The collagen nanofibers were also found to lead to upregulation of involucrin, filaggrin, and TGase1 genes, indicating keratinocyte differentiation. In vivo placement of the collagen nanofibers in Sprague Dawley rat full-thickness skin wound models demonstrated an improvement in wound healing rate and reduced inflammation compared to Kaltostat and untreated controls. Other studies have primarily focused on the use of commercially-available collagen-based wound dressings such as Aplifraf, Dermagraft, Graftjacket, Integra, and others in human trials, for example for use in treating diabetic foot ulcers  is a non-sulfated glycosaminoglycan and extracellular matrix component that acts as an immune regulator in physiological and pathological conditions . HA accuin vivo in acute and chronic inflammation models , as well as immunosuppressive factors (COX-2 and TSG-6). Additionally, macrophages treated with media that had been conditioned by adipose-derived mesenchymal stromal cells (ASCs) exposed to the coaxial scaffolds had a greater M2/M1 ratio than those treated with PLGA scaffolds or PLGA scaffolds with only fibrinogen or only collagen I incorporated. When applied to an in vivo diabetic rat wound model, coaxial scaffolds were found to accelerate diabetic wound healing by resolving inflammation.A major concern with diabetic wounds is that they are persistently open due to slow healing, which can increase the potential for the development of infections. Acceleration of wound healing can reduce the opportunity for wound infection. In the context of diabetic wounds, even scarred healing would be an improved outcome compared to wound infection. PLGA is an FDA approved polymer that is biocompatible and biodegradable . While nvia sonic hedgehog signaling and promote M2 macrophage polarization via an IGF-1 mediated pathway  and loaded with mangiferin liposomes (MF-Lip@PEG), with the goal of combining mangiferin’s cytoprotective properties with the antimicrobial activity of Ag+. When injected in a mouse skin flap injury model, the MF-Lip@PEG hydrogel was found to reduce tissue necrosis and increase microvessel density in the skin flaps. Furthermore, although PEG itself led to high macrophage recruitment, the MF-Lip@PEG hydrogel was able to reduce macrophage recruitment in a concentration-dependent manner.in vivo than those crosslinked with L-amino acids. This faster degradation was a result of enhanced immune cell recruitment, and was found to lead to tissue regeneration, in contrast to the formation of semi-fibrous dermal scar tissue when MAP hydrogels crosslinked with L-amino acids were used. These results suggest that the adaptive immune response can be exploited for skin wound healing.In contrast to approaches that seek to dampen the immune response, via the immune system plays a crucial part in our understanding of how endogenous repair works. Countless papers highlight the role that various immune cells, particularly macrophages, play in mediating adult stem cell replication and differentiation into the target cell. By modulating the immune cell infiltrate into the injury site, it is possible to effectively modulate stem cell behavior. Hybrid biomaterials are a promising next step in regenerative medicine and will likely be able to combine the benefits of different materials. With hybrid materials come an exciting next step in understanding the healing process, creating more space for optimization. To achieve this goal, more research must be done on understanding all steps of the immune response to biomaterials, particularly in vivo.The fields of regenerative medicine and bioengineering have made great advances in developing biocompatible and regenerative scaffolds using biomaterials. As discussed, numerous biomaterials developed incorporate the immune system to naturally mediate regeneration and prevent scarring. Each of these approaches have their pros and cons, and it is likely that the best scaffold for regeneration will involve a combination of these materials. Understanding how these biomaterials promote regeneration


Brazil is among the countries hit hardest by COVID-19, and older adults are among the vulnerable groups. Intergenerational coresidence and interdependence among family members, both prevalent in Brazil, likely increase social and physical contact. Using nationally representative data from the COVID-19 module of the Brazilian National Household Sample Survey, collected from July to November of 2020, we examined the association between living arrangements and exposure to and testing for COVID-19 among 63,816 Brazilians 60+. Our multivariate analyses utilize multilevel mixed-effects Poisson regression to examine the association between living arrangements and the COVID-19 outcome measures. Results show that those living alone were more likely to report having symptoms and having had a test for COVID-19. However, older adults in multigenerational  and skipped generation households  were more likely than solo-dwellers to test positive for COVID-19. Those with symptoms were more likely to test, regardless of their living arrangement. Among older adults without symptoms, those living alone had a higher probability of testing than those living in multigenerational or skipped-generation households. Overall, our findings suggest that coresidence with younger family members is a risk factor for older adults’ health due to the higher COVID-19 positivity. As younger Brazilians are increasingly vulnerable to COVID-19 and experiencing severe outcomes, policy makers need to be more attentive to the health needs of households that comprise older and younger cohorts, which are also more prevalent in poor and marginalized segments of the population.


Post-traumatic stress disorder (PTSD) is a devastating illness with treatment that is effective in only approximately half of the population. This limited rate of response highlights the necessity for research into underlying individual biological mechanisms that mediate development and progression of this disease, allowing for identification of patient-specific treatments. PTSD has clear sex differences in both risk and symptom patterns. Thus, one approach is to characterize trauma-related changes between men and women who exhibit differences in treatment efficacy and response to trauma. Recent technological advances in sequencing have identified several genomic loci and transcriptional changes that are associated with post-trauma symptomatology. However, although the diagnosis of PTSD is more prevalent in women, the genetic factors underlying sex differences remain poorly understood. Here, we review recent work that highlights current understanding and limitations in the field of sex differences in PTSD and related symptomatology. It is often accompanied by significant comorbid syndromes including depression, substance abuse, and elevated suicide risk. According to the National Comorbidity Survey Replication, a large-scale assessment of the epidemiology of mental illness in the United States conducted between February 2001 and April 2003, the lifetime prevalence of PTSD in adult Americans was 6.8% , with woSex differences in PTSD prevalence are not fully explained by the type of incident trauma, although women appear to be more vulnerable to experiencing sexual trauma, such as rape, molestation and physical abuse, while men are more likely to experience events related to combat, threat with a weapon, or being a witness to trauma . When coDespite emerging evidence of the role of sex on development of trauma-related disorders and on treatment, few human studies have examined the role of genetic factors in this dichotomy. More literature is available from studies of transcriptional changes in depressive disorders and in pre-clinical work with rodents, which suggest a sex difference in pathways involved in immune function and neuronal structure . Work coThese observations have led to increased focus on sex as a risk factor for PTSD, with recent findings of the initial response to trauma, role of neurosteroids, environmental and genetic factors . Further2Genome wide association studies (GWAS) are a useful tool for the study of genetic variables with inherent differences in common DNA sequence variants  that may contribute to disease pathology. GWAS scan the entire genome for associations of genetic elements (SNPs) with a trait of interest. Large-scale GWAS have begun to elucidate the correlations of genetic variants with PTSD symptomatology, although few studies have reported the results stratified by sex .Recent GWAS conducted in military veterans with PTSD identified several loci, including those corresponding to genes in the corticosteroid and steroid function, however, they did not report effects stratified by sex . In a GWAlthough the field of PTSD has only recently started to gain insights from large-scale GWAS, studies that include stratification by sex suggest underlying genetic differences may contribute to variability of PTSD prevalence in males and females. Of note, many sexually dimorphic genes in the human genome are located on X and Y chromosomes, which have not been included in most GWAS analyses to date. Insights from human studies could also be complemented with work in animal models; however, recent rodent GWAS and large-scale transcription studies exploring changes in gene-expression in circuitry related to PTSD-symptomatology included only male animals .3Drosophila show sexual dimorphism, and sexually dimorphic genes are involved in the majority of changes in adult gene expression during recent evolution , as upregulated in the dorsolateral prefrontal cortex of females with PTSD.A better powered recent publication provided the largest transcriptomic study of human brain tissue to date, with a transcriptome-wide analysis of 143 subjects from four subregions of the prefrontal cortex in males and females . The resFKBP5 and dendritic spine morphology  that has been implicated in the pathophysiology of PTSD, with several identified SNPs exhibiting a gene × environment interaction with PTSD symptoms . When borphology . These rrphology . In addirphology . Recent rphology . Work int in men . The samAnother recent study using postmortem brain tissue provides evidence for a differential regulation of microglia-associated marker in the orbitofrontal cortex of women with PTSD – an effect that was not observed in tissue collected from male subjects . InteresIn the absence or readily-available brain tissue for genetic studies, peripheral blood biomarkers have been used to study the contribution of inflammatory markers to PTSD development, including impaired glucocorticoid signaling; however, most of these studies have focused on male subjects . One stu2 receptor signaling and glucose homeostasis. In the periphery, blood markers of inflammation were upregulated in the resilient group, whereas a sexually dimorphic dysregulation of inflammatory pathways was found in animals more susceptible to stress  receptor variants identified in prior GWAS studies, recent work by McCullough and colleagues examined transcription in CRH-expressing cells in the central amygdala of male and female mice after fear conditioning and extinction . In male4Circulating gonadal hormone levels regulate response to environmental stressors, with multiple studies demonstrating modulatory effects of estrogen, testosterone, and progesterone . Note thPerhaps the best-characterized example of one such pathway in the stress response is signaling through pituitary adenylate cyclase-activating polypeptide (PACAP), a member of the secretin/vasoactive intestinal polypeptide family. Together with its receptor, PAC1R, PACAP is expressed in brain regions involved in stress response, and shows an increase in expression after acute and chronic stress exposure . In humaPACAP is a known paracrine mediator of the hypothalamic-pituitary-adrenal (HPA) axis , and alsADCYAP1R1) has several estrogen response elements (ERE), consensus sequences to which estrogen binds to regulate downstream transcription  receptors and an antagonist at N-methyl-D-aspartate (NMDA) receptors, exerting an anxiolytic effect on behavior . Women iew, see .Testosterone regulates genomic expression through its metabolites, dihydrotestosterone (DHT), which binds to the androgen receptor, and estradiol, which binds to the estrogen receptor . Little A few clinical studies have examined the role of testosterone on differential gene expression after exposure to a traumatic stressor, with inconsistent results. Circulating serum levels of testosterone were found to be elevated in patients with PTSD, although this change was not observed in patients with comorbid MDD or alcohol dependence . AnotherCombined, these studies suggest a mechanism by which naturally-cycling gonadal hormones can exert a sexually dimorphic transcriptional response to a stressor; however, further work on the role of downstream signaling and potential modulation of these signaling pathways is warranted. Notably, a recent analysis suggests that the progesterone/estrogen ratio, rather than individual hormone levels, may be a more useful biomarker for the study of PTSD symptomatology in both humans and rodent models .5HDAC4). Validation of this observation was suggested by finding, in mice, that increased Hdac4 transcription was associated with low estrogen levels after fear conditioning in naturally cycling females , after previously demonstrating a role of targeted histone acetylation of this gene in fear-memory retrieval in male mice . Using tl stress . The grol stress . Cdk5 mR cascade .Another recent study found a sex-specific effect of a histone variant, H2A.Z on fear learning in female mice . A condi6Recent data from large-scale RNA sequencing of human tissues  project) suggest that over one third of genes examined exhibit a tissue-specific, sex-biased gene expression . IncreasIn addition to large scale genetic studies in humans, there are multiple approaches to aid in the mechanistic study of genetic factors of sex differences using rodents. For example, the Four-Core-Genotypes model is a transgenic mouse in which the testis-determining gene, Sry, is moved from the Y chromosome to an autosomal chromosome, producing XX mice that have testes, and XY mice that develop ovaries. This animal model is useful to differentiate between sexual dimorphism produced by the presence of the sex chromosomes, or by circulating gonadal hormones . AnotherFuture studies should also consider the role of naturally-circulating hormone levels on fear response and symptom development, as some phenotypes are not evident until after puberty, highlighting importance of controlling for naturally-cycling menstrual phase, as well as role of elevated testosterone, on transcription. Because cyclic binding of estrogen to EREs induces a feedback loop by which estrogen regulates levels of estrogen receptors, use of exogenous sources of estrogen may result in supranormal levels and downregulate receptor levels, hindering further exploration of estrogen effects . Where pAs noted in In summary, recent and emerging work in the field of PTSD research suggests that multiple genomic mechanisms, including pathways involved in glucocorticoid signaling, HPA axis regulation, immune response, and epigenetic regulation, exhibit sex differences in signaling underlying the pathophysiology of this disease; however, current treatment options do not account for these underlying changes. Future work will help to identify specific targets for a more personalized and biologically-informed approach to the treatment of PTSD and other devastating stress-related conditions.Olga Y. Ponomareva: Conceptualization, Methodology, Writing – original draft. Kerry J. Ressler: Conceptualization, Writing – review & editing.KJR has received consulting income from Alkermes and Bioxcel, and is on scientific advisory boards for Janssen, Verily, and Resilience Therapeutics. He has also received sponsored research support from Takeda and Brainsway. None of these are related to the work presented here.