Adolescent Brain and Alcohol” have summarized recent developments in the field that further advance our understanding of the neurobiology of adult psychopathology after adolescent alcohol exposure.Binge drinking is prevalent during adolescence and has been shown to increase the susceptibility to adult psychiatric and substance use disorders . AdolescMay et al., provided several interesting findings. First, 24% of 9–10-year-olds in the community sample reported having had at least one sip of alcohol, and had done so 4 times on average, with some as many as 260 times, and had their first sip typically at age 7 (SD = 1.91). Most (76%) alcohol sipping was outside of religious ceremony contexts. Second, support vector machine learning determined that neural activity in brain reward and cognitive control areas  was no better than chance at identifying which youth reported alcohol sipping at Time one but was reasonably accurate (76%) when combined with baseline sipping behavior to predict drinking status at Time 2, even after controlling for demographic factors. These studies suggest that improving our understanding of the neural and behavioral factors that convey propensity for future substance use is crucial for identifying at-risk youth and targets for prevention. The second clinical study, presented by Lorkiewicz et al., found that 16% in a community cohort of adolescents and young adults had at least one alcohol-related blackout, and most who did had more than one, with durations exceeding 1 h. Latent growth curve modeling found that having had one or more alcohol-related blackouts was linked to attenuated performance over time on a memory for faces task, which was worse yet when alcohol intake was more frequent, above and beyond effects of age, sex, race, socioeconomic status, and assessment site, and in a model that accounted for repeated testing. Results suggest that alcohol-related blackouts appear to predict lasting changes in visual learning and memory, particularly of a facial nature, suggesting that memory for faces is sensitive to heavy alcohol use and that the late-adolescent/emerging adult brain is vulnerable to alcohol-related blackouts.This Research Topic contains two clinical studies. The first, presented by Macht et al. covers fetal and adolescent brain development and the impact of alcohol, particularly increases in proinflammatory signaling that modulate cholinergic neurons and hippocampal neurogenesis contributing to lasting pathology in adulthood. Ethanol and stress exposure studies find neuroimmune signaling causes persistent changes that can be reversed. The study described by Gomez et al. use fcMRI to show that AIE disrupts adult synchrony between brain networks related to deficits in behavioral flexibility, extending studies indicating that AIE causes long-lasting changes in adult executive prefrontal cortical functions. Interestingly, studies find fcMRI reductions within a subnetwork of affected brain regions statistically mediated errors committed during reversal learning. These results provide a novel link between persistent reductions in fcMRI brain functional connectivity and adult deficits in behavioral flexibility resulting from AIE. Interestingly, these learning deficits are extended in the studies by Barnett et al. that find AIE accelerates age-related onset of Alzheimer’s disease pathology in a mouse model due to proinflammatory gene induction that can be prevented by blocking microglial activation with minocycline.This Research Topic also contains five manuscripts that discuss the lasting impact of adolescent intermittent ethanol (AIE) on adult brains by using an underage drinking model in rodents. The review article by Towner et al., investigated the effects of AIE on neuronal activation and social preference using cFos-LacZ transgenic rats and found that AIE produces sex-specific social impairments that are potentially driven by differential neuronal activation states in regions important for social behavior, including the medial prefrontal and orbitofrontal cortices, nucleus accumbens, lateral septum, and central amygdala. Another study published by Chandler et al. investigated the effects of AIE on conditioned fear learning and memory in adulthood in rats. They demonstrated sex-specific changes in conditioned fear behaviors that are reversible by pharmacological interventions  targeting mGlu5 receptor activation. In one manuscript included in this Research Topic, studies conducted by Barney et al. focus on the effects of acute ethanol exposure on the expression of growth factors and microRNA expression profiling in dorsal hippocampus of adolescent and adult rats. They concluded that acute ethanol rapidly induced neuroimmune gene expression that was associated with changes in growth factors, in addition to decreasing the expression of several miRNA species in the hippocampus.Together, these studies emphasized that adolescent alcohol exposure has several negative consequences ranging from molecular to neuronal to circuitry and later, behavioral responses in adulthood. These studies summarize emerging developments in the field’s effort to pinpoint alcohol’s role in adolescent brain producing rapid and long-lasting impacts on neurobiology in adulthood and increasing vulnerability to adult psychopathology including development of alcohol use disorder.


There is remarkable variation in the rate at which genetic incompatibilities in molecular interactions accumulate. In some cases, minor changes—even single-nucleotide substitutions—create major incompatibilities when hybridization forces new variants to function in a novel genetic background from an isolated population. In other cases, genes or even entire functional pathways can be horizontally transferred between anciently divergent evolutionary lineages that span the tree of life with little evidence of incompatibilities. In this review, we explore whether there are general principles that can explain why certain genes are prone to incompatibilities while others maintain interchangeability. We summarize evidence pointing to four genetic features that may contribute to greater resistance to functional replacement: (1) function in multisubunit enzyme complexes and protein–protein interactions, (2) sensitivity to changes in gene dosage, (3) rapid rate of sequence evolution, and (4) overall importance to cell viability, which creates sensitivity to small perturbations in molecular function. We discuss the relative levels of support for these different hypotheses and lay out future directions that may help explain the striking contrasts in patterns of incompatibility and interchangeability throughout the history of molecular evolution. As gene sequences diverge, molecular interactions between proteins can be disrupted, resulting in harmful functional consequences. For some genes, these incompatibilities arise rapidly, contributing to the early stages of speciation. In other cases, they are slow to emerge, and interchangeability can be maintained for billions of years, as evidenced by examples of horizontal gene transfer and functional replacement events between highly divergent evolutionary lineages. This review explores explanations for why different types of molecular interactions follow these contrasting evolutionary paths that range from incompatibility to interchangeability.Drosophila simulans has been shown to produce major incompatibilities when paired with a single amino-acid substitution in an interacting aminoacyl-tRNA synthetase (aaRS) enzyme from Drosophila melanogaster (Xiphophorus) appear to be responsible for a lethal incompatibility  system as a nonhomologous alternative to produce iron-sulfur clusters  Class I and Class II families, and these two alternative forms have undergone numerous functional replacement via HGT . The enzDrosophila, telomeres are extended via a transposon-mediated system  enzyme consists of multiple subunits and catalyzes the conversion of acetyl-CoA to malonyl-CoA, a key early step in fatty acid biosynthesis . Experims at all . Thus, tc maturation. Many eukaryotes retain the ancestral bacterial-like enzyme, which consists of subunits encoded by six or more genes; however, this heteromeric complex has been lost and replaced by a single-gene system (the holocytochrome c synthase or HCCS) many times throughout eukaryotic evolution  tRNAs from the cytosol . In suchThe idea that aaRSs could readily evolve to charge a novel tRNA substrate (see above) or undergo HGT across divergent lineages that span the tree of life  may seemThe hypothesis that functional replacement is more likely to occur for proteins with limited molecular interactions is also supported by examples such as the extensive HGT in the peptidoglycan biosynthesis pathway for endosymbiotic bacteria/organelles . The enzGenes that are sensitive to changes in dosage  are often toxic when experimentally introduced into a host . As suchOne prediction arising from this dosage hypothesis is that genes that exhibit frequent functional replacement events can also readily be found in transitional states in which both copies are functional, implying that dosage effects of expressing two copies are not prohibitively costly. For example, as described above, the plastid heteromeric ACCase has been replaced in some taxa by importing the homomeric cytosolic ACCase, and species with both versions functioning in the plastid simultaneously have also been identified . SimilarSalinispora bacteria is harmful, explaining why the two pathways are never found in the same strain  in e strain . It is uOverall, these lines of evidence indicate that dosage sensitivity is a significant contributor to incompatibilities. As such, it is not just the nature of physical interactions that limits interchangeability but also the balance associated with levels of gene expression. However, the body of evidence in support of dosage sensitivity as a determinant of incompatibility versus interchangeability is arguably less extensive than for the other principles addressed in this review. Therefore, performing more systematic tests of this hypothesis will be important for further assessing its generality.β ring, which also exhibit faster rates of amino-acid sequence evolution than α subunits. Therefore, the combination of rapid evolution and protein–protein interactions may have an especially large effect.Genes can evolve at remarkably different rates due to variation in the strength and efficacy of selection, the balance between positive and purifying selection, and differences in the underlying mutation rate . Becausec oxidase complex, showing that substitutions in mitochondrial-encoded subunits tended to precede substitutions at nearby sites in nuclear-encoded subunits. This apparent selection for compensatory or coevolutionary changes is one explanation for the observation that proteins targeted to the mitochondria often evolve faster than other nuclear-encoded proteins  genome and the nucleus . For exaproteins ; howeverproteins . Taxa inproteins .Silene), this experiment controlled for divergence time, isolating effects of evolutionary rate variation.Although accelerated rates and coevolutionary signatures from comparative-genomic studies are often assumed to be associated with a faster buildup of incompatibilities between divergent taxa, direct functional tests of this assumption have been rare. Nonetheless, some more targeted functional studies have engineered chimeric enzyme complexes or interaction networks by substituting in genes from donor species with varying levels of sequence divergence . For exaPRDM9 gene is the best characterized example of a locus contributing to reproductive incompatibilities in mammals, and it undergoes unusually fast rates of sequence evolution  have the potential to be involved in more genetic incompatibilities. However, this potential for incompatibilities may be mitigated by slower rates of evolution, as it has long been suspected that pleiotropy could act as a constraint on evolution . There iMany of the genetic features we have discussed are not independent of each other, resulting in confounding effects that are difficult to disentangle. For example, as noted above, the functional importance of genes is associated with their degree of integration into protein–protein interaction networks . In otheless HGT (It is possible that adequately accounting for the effects of some features may also reveal additional principles that determine the balance between incompatibility and interchangeability. For example, we hypothesize that genes that are widespread across the tree of life would have a higher chance of functional replacement given the ample supply of potential donors. However, at face value, the available data do not support this hypothesis, as the most anciently conserved and widely distributed genes exhibit less HGT . NeverthE. coli as a model system for high-throughput transgenic analyses to systematically screen the effects of gene transfer and functional replacement (E. coli.Functional wet-lab analyses have provided a key complement to comparative-genomic and phylogenetic approaches in understanding the mechanisms of molecular incompatibility and interchangeability. Most of these groundbreaking studies have relied on the power of lacement . Howeverlacement , there aA rapidly growing approach in the field of molecular evolution involves the use of phylogenetics to infer the sequence of ancestral protein-coding genes, which can then be synthesized and expressed . Such reAn exciting recent development is the increasing use of experimentally evolved bacterial populations and whole-genome sequencing to track the effects of HGT across generations in the laboratory . These sevac184_Supplementary_DataClick here for additional data file.


Oligodendrocytes are derived from a subtype of glia called oligodendrocyte precursor cells (OPCs). The potential functions of OPCs beyond oligodendrogenesis however, have remained elusive. In their latest study, Auguste et al. demonstrate that OPCs could play a regulatory role in synaptic connectivity in the developing and adult mouse visual cortex - a function that is independent of oligodendrogenesis. They use confocal microscopy and fluorescence in situ hybridization to elegantly visualise OPCs in the developing and adult mouse visual cortex. By doing so, they show that OPCs are likely to play a key role in regulating experience-dependent synaptic refinement. Specifically, they reveal that OPCs are capable of engulfing presynaptic thalamocortical inputs to the primary visual cortex during critical developmental windows in which refinement is heightened. Through a series of imaging studies, they present evidence that the engulfed synapses are likely to be degraded within phagosomal compartments. Auguste et al. then go on to show that not only does this engulfment appear to be heightened by sensory experience , but is also affected by the depletion of microglia, which are already known to play a crucial role in synaptic phagocytosis. This strongly suggests the existence of microglial-OPC communication in the context of synaptic refinement.Oligodendrocyte precursor cells (OPCs) are a subtype of glial cell that differentiate into oligodendrocytes. Other than being precursors for oligodendrocytes however, the question of whether OPCs possess additional, independent functions has so far remained largely unanswered. A recent study from Auguste et al.Overall, this study makes an intriguing contribution to our understanding of how OPCs respond to sensory experiences. Whilst future studies will need to address remaining unknowns such as whether sensory experience changes the rate at which OPC engulf synapses, the finding that OPCs can influence synapse number provides valuable insights into developmental and disease mechanisms in the brain.


This thesis analysed the implementation of the German medical specialists’ contract in cardiology, a managed care programme within the state of Baden-Wuerttemberg. Research focused on exploring differences between participating and non-participating physicians, their motivation to participate, actual implementation of the programme and its perceived effects. Mixed methods consisting of questionnaires and qualitative telephone interviews with cardiologists and general practitioners showed that participants were older than non-participants, participation was mainly financially driven and implementation was successful regarding medical aspects, but less so regarding patient services and communication between providers. The majority of physicians in the study perceived little to no impact of the programme on quality and efficiency of cardiology care. Still, they saw their expectations fulfilled. In 2009, two German health insurers introduced the medical specialists’ contract in cardiology (cardiology programme) within the state of Baden-Wuerttemberg (approximately 11 million inhabitants). This managed care programme is the first selective contract in Germany targeted at medical specialists in ambulatory health care. As a medical specialists’ counterpart to general practitioner(GP)-centred care, it aims for efficient, high quality cardiovascular care, coordinated between medical specialists and GPs in the ambulatory sector. Key features of the programme include quality-related requirements for medical specialists, strict adherence to clinical guidelines and standardized means and regulations for communication between GPs and medical specialists. Participating physicians receive a higher reimbursement than in usual care. Patients, in turn, are promised the overall benefit of improved cardiology care as well as mainly access-related services, such as faster appointments compared to usual care [The cardiology programme is the first one of its kind in Germany and subsequent selective contracts for other medical fields were designed in a similar fashion. Still, no evaluation of the cardiology programme had taken place yet. This thesis aimed to understand implementation of this selective contract and to ultimately allow for an assessment of whether and how managed care programmes can be successfully implemented in Germany and how they are implemented de-facto. The thesis examined four specific research questions: 1) Are there systematic differences between physicians who participate in the programme and those who do not? 2) What motivates physicians to participate in the cardiology programme and what are barriers? How are the initial motives and expectations of participating physicians related to the programme’s aims in this regard? 3) How are the contents of the programme actually implemented by participating medical specialists and cooperating GPs? What is the role of context factors for the implementation? 4) To what degree do participating physicians perceive effects of the programme on patient care?The study was performed using a mixed-methods approach. The qualitative phase included telephone interviews with practice-based medical specialists active in cardiology care inside and outside the programme as well as GPs inside and outside GP-centred care. The quantitative phase included written questionnaires for practice-based medical specialists active in cardiology care inside and outside the programme as well as GPs in GP-centred care.Telephone interviews were conducted with 23 medical specialists inside and 11 medical specialists outside the cardiology programme. Furthermore, 18 GPs inside and 8 GPs outside GP-centred care were interviewed. The written questionnaire was completed by 75 medical specialists inside and 21 medical specialists outside the cardiology programme as well as 73 GPs participating in GP-centred care.Medical specialists participating in the cardiology programme were significantly older than non-participants  = 3.44; p = 0.002), and +3.9 years in the quantitative study  = 2.27; p = 0.025). Additionally, they cooperated with significantly more GPs  = –2.35, p = 0.021)). Participation in the cardiology programme was largely financially driven . Care-related aspects, such as a desire to improve certain elements of patient care  or to improve cooperation with GPs , were considered important by fewer respondents. Non-participants mainly perceived barriers to participation originating from concerns about additional administrative (66.7%) and financial burden (28.6%) in the programme [Implementation of the cardiology programme was heterogeneous: Purely care-related elements of the programme, such as adherence to clinical guidelines and preferred prescription of generic medication were comprehensively implemented by participating physicians, but also by usual care providers outside of the programme. Regarding access to care for participating patients, waiting times for appointments exceeded the programme’s limits in 63.0% of the practices. Physicians identified the high numbers of participating patients as a barrier to timely access. Discrepancies were also found for cooperation- and communication-related requirements when it comes to working with GPs: Implementation on both sides varied with respect to contents and quality: Reports were transmitted significantly faster than in usual care  – meanwhile, the pre-structured report forms provided for GPs were used regularly by only about 23% of physicians. Relevant context factors that affected implementation were regional aspects and especially the structure and staffing of the individual practices [Regarding effects of the cardiology programme on health care, physicians by the majority perceived vague effects or none at all. Still, 70.27% of participating physicians stated that their own expectations regarding the programme were met. For physicians who named financial aspects as a motive to participate there was a positive association between the motive and the degree to which their expectations were met . The same goes for those who participated because they expected additional, diagnostic possibilities .The thesis showed that managed care per se can be feasible in the German context. However, the results suggested that certain obstacles need to be recognized beforehand: Physicians might be motivated to participate in a managed care programme for financial reasons rather than medical reasons. This demands caution, since in a worst-case scenario, such motives can result in a focus on financial aspects at the expense of patient care 5. On the679For actual implementation of managed care, the results showed that time-sensitive services beyond usual care require careful planning of capacities, so their availability is ensured even when there are high numbers of participating patients. Inconsistent implementation of cooperation-related aspects then suggested a low practicability of the cooperation requirements with a resulting de-facto redesign by the physicians 121314. M1213Finally, the participating physicians perceived little effect of the programme on health care. Later, this has partly been backed up by research on the outcomes of the cardiology programme: There were fewer hospitalisations and a positive effect of participation on mortality for some patients. However, the results were not clearly linked to the cardiology programme itself, since the researchers could not rule out a selection bias introduced by the physicians regarding which patients were made aware of the programme 1617. The16These ambiguous outcomes and little differences to usual care suggest that the quality of usual cardiology care might already be high and that the cardiology programme simply does not tackle actual gaps in ambulatory cardiology care in Germany. Managed care that aims at bridging gaps in a certain field within the ambulatory sector can only reach this aim when these deficits and gaps are identified beforehand. In this regard, future programmes might want to involve patients and the public in the design phase to ensure a broader perspective on possible gaps in ambulatory care and to ensure that patients’ needs are understood and covered. In Germany, future research and similar programmes also should consider focusing on integration of care in larger regions with explicit differences in quality and availability of care that go beyond a single state, such as they still can be found between East and West Germany.


Psychometric network models revealed that difficulties in emotional awareness, emotional clarity, and access to emotion regulation strategies were differentially related to behavioral and emotional engagement, establishing an indirect link with teacher and/or peer relations. Nonacceptance of emotional responses, emotional awareness, and impulse control difficulties were uniquely related to teacher and/or peer relations, establishing an indirect link with student engagement. Causal discovery analysis suggested that student emotional engagement is an empirically-plausible direct cause of increased access to emotion regulation strategies. These findings uncover potential pathways through which emotion regulation hampers or facilitates learning at school, providing information useful for the design of school curricula and teacher training programs.Emotion regulation is theorized to shape students’ engagement in learning activities, but the specific pathways via which this occurs remain unclear. This study examined how emotion regulation mechanisms are related to behavioral and emotional engagement as well as relations with peers and teachers. The sample included 136 secondary school students (59,7% girls; M Adolescence is a critical period for learning effective emotion regulation. The significant emotional, social, and cognitive challenges  related to lower levels of behavioral and emotional aspects of student engagement as well as weaker supportive relations with teachers and connections with peers in the classroom. Because student engagement and peer/teacher relations are not independent classroom processes . Applying the Degree of Urbanization method  included 59.7% female and 38.1% male respondents. A small number (2.2%) of the participants preferred not to mention or did not report their gender. The participants answered all items of the measures below .Teachers from the participating schools recruited students from grades 9 and 10. The students and their parents received an information letter and consent form. 136 of 153 parents (88.9%) and all 136 students provided consent to participate. The sample  when face-to-face education was allowed. During this period, the Belgian government issued various regulations within the school context to stop the spread of the coronavirus. Social distancing and quarantine measures interfered with daily school activities, such that many adolescents were not able to attend school or followed classes online. This context increases the importance of this study on emotion regulation within the classroom because quarantine and online learning may impose challenges to emotional and social functioning  of the individual nodes in the estimated network were not significantly correlated in the present study . This suggests that differential variances of emotion regulation facets, teacher and peer relations, or aspects of student engagement did not affect their centrality in the estimated network.The relative importance of the nodes within the network  was examined using the (one-step) expected influence metric  in observational datasets to identify empirically plausible causal relations between their constituent variables see Fig.  2. TheseThis study used the Greedy Fast Causal Inference (GFCI) algorithm to infer empirically plausible causal relations between markers of emotion regulation, behavioral/emotional engagement, as well as peer and teacher relations. The GFCI algorithm searches the space of penalized likelihood scores of all possible acyclic causal relations among the measured variables to produce a preliminary assessment of likely causal pathways. This preliminary result is then iteratively refined by ruling out causal models that imply patterns of conditional independence inconsistent with the data. The output of this procedure is a partial ancestral graph (PAG), with the edge type Table  2 varyinTo better ensure graph stability, the GFCI algorithm was repeated on 10,000 jackknifed re-samples of the study data. These re-samples were created by randomly deleting 10% of cases from the study dataset. The original dataset was included as an additional re-sample. Results were aggregated into a single, consensus PAG by depicting the edge type (including: “no edge”) and orientation most commonly present in the PAGs created from the jackknifed re-samples. The full FCI rule set was employed. Default values for remaining parameters were used. For example, the penalty discount (c) used for generating the initial likelihood scores (BIC) was set to 1, the alpha value used in conjunction with Fisher’s z tests to determine conditional independence and refine the preliminary results was set to 0.010, and one-edge faithfulness was not assumed. Because causal discovery algorithms recover causal pathways more effectively when they are provided with prior knowledge  related to only one emotion regulation facet, namely emotional awareness. Neither emotional nor behavioral engagement was directly related to non-acceptance of emotional responses or impulse control difficulties.Regarding the indirect paths in the network, the network plot in Fig. With respect to the relation between student engagement and peer/teacher relationships, the network plot shows that teacher support is positively related to both emotional and behavioral components of student engagement. Peer relations were only linked with emotional engagement.Expected influence values were computed for all nodes in the network to examine their centrality or relative importance within the network. Fig. The PAG generated by GFCI included several potential causal relations between markers of emotion regulation, behavioral/emotional engagement, and peer and teacher relations. The final graph, which is depicted in Fig. Emotion regulation is theorized to shape students’ engagement in learning activities, but the specific pathways via which this occurs remain unclear. This study examined how emotion regulation mechanisms are related to behavioral and emotional engagement as well as relations with peers and teachers during the global COVID-19 pandemic. When direct relations between emotion regulation difficulties and student engagement were inspected, this study observed that emotion regulation difficulties were differentially linked to components of student engagement. Higher levels of emotional engagement were uniquely related to greater recognition of and attention to one’s own emotions  as well as a better ability to understand one’s own emotions . Emotional engagement was also related to less endorsement of the belief that one can do little to regulate emotional distress (limited access to emotion regulation strategies). This suggests that those students who display negative emotions about participating during learning activities in the classroom may experience difficulties with emotional awareness, emotional clarity, and access to strategies to regulate emotions. With respect to behavioral engagement, only emotional awareness explained a significant portion of the variance. More active student participation in learning activities was related to higher levels of students’ recognition and attention to their own emotions. This indicates that adolescent students who are more aware of their emotional experiences try harder and are more persistent during learning activities. Of note, other aspects of emotion regulation difficulties, such as non-acceptance of emotional responses and impulse control difficulties, were not related to components of student engagement.consequences, rather than causes, of emotion acceptance and access to strategies that are perceived as effective is remarkable. Awareness and clarity of emotions are often considered key steps preceding the implementation of effective emotion regulation strategies , teachers could develop behaviors that support effective emotion regulation. To target impulse control difficulties, teachers could learn how to help students to control their behavior when they are upset. To facilitate students’ emotional awareness and acceptance of emotions, teachers could engage in conversation and discussion with students about diversity in emotional responses to classroom and life events, provide affirmation of the emotions students may experience and support them to express their thoughts and feelings . To improve social integration within the classroom, teachers may need to counter the negative relation between nonacceptance of emotional responses and peer relationships. This could be achieved by monitoring students to better ensure that they do not judge emotions peers express and by teaching students to treat each other with respect. This requires teachers have a proper understanding of social-relational processes within the classroom. Again, such social and emotional skills could be trained as part of preservice and inservice programs.Several limitations of this study point to future directions. First, the cross-sectional nature of this study weakens claims about causality. It is thus unclear whether emotion regulation difficulties have a negative impact on teacher/peer relationships and student engagement, or vice versa. Future longitudinal research with multiple waves of data collection is required to gain insight into the direction of relationships between emotion regulation difficulties, student engagement, and teacher/peer relationships. This seems particularly interesting now that students are returning to in-person schooling after the acute phase of the SARS-CoV-2 pandemic but are now experiencing higher levels of mental health issues (Holmes et al., At present, little is known about the specific pathways via which emotion regulation shape students’ engagement in learning activities as well as relations with peers and teachers. This study used advanced statistical modeling of data from secondary school students to map the complex interplay between emotion regulation difficulties, student engagement, and relations with peers and teachers. This study uncovered direct and indirect pathways through which specific emotion regulation may hamper vs. facilitate student learning by impairing student engagement and social relations at school. These findings enable a better understanding of specific mechanisms underlying emotional, social, and cognitive challenges faced by adolescents within school contexts. This may inform the design and focus of interventions targeting adolescents’ mental health and school performance in future work.Supplementary Information


This symposium traces the nearly 30 years of development projects, trials, and transformations that continue to occur in efforts to make an evidence-based psychoeducation program (Savvy Caregiver) available to family members and friends who provide care to community-dwelling persons living with dementia illnesses. Savvy seeks to enhance caregivers’ knowledge and skills for providing care and to enhance their competence and confidence (sense of mastery) in being able to guide their persons through days that are as safe, calm, and pleasant as possible. Over this period of time, Savvy has clarified its target participant group (focusing on primary caregivers rather than larger family groups), moved from having concurrent sessions for caregivers and persons living with dementia, continued to develop strategies that enable broad implementation while maintaining program fidelity, demonstrated the effectiveness of a synchronous/asynchronous online version that extends program reach (Tele-Savvy), and is currently exploring in an ongoing pilot how best to deliver a fully asynchronous version of the program that employs continuing education principles (Tele-Savvy@Home). The individual presentations will describe the main developmental milestones  and the structural adaptations that enabled them. Particular emphasis will be placed on design decisions linked to maintaining a psychoeducational orientation and to program emphasis on developing or strengthening caregivers’ self-efficacy for providing effective day-to-day care. Savvy’s experience may help investigators in designing new interventions, particularly online interventions or in considering augmentation or delivery platform change of established interventions.


Abstract Asthma with irreversible or fixed airflow obstruction (FAO) is a severe clinical phenotype that is difficult to treat and is associated with an accelerated decline in lung function and excess morbidity. There are no current treatments to reverse or prevent this excessive decline in lung function in these patients, due to a lack of understanding of the underlying pathophysiology. The current paradigm is that FAO in asthma is due to airway remodeling driven by chronic inflammation. However, emerging evidence indicates significant and critical structural and functional changes to the lung parenchyma and its lung elastic properties in asthma with FAO, suggesting that FAO is a ‘whole lung’ problem and not just of the airways. In this Perspective we draw upon what is known thus far on the pathophysiological mechanisms contributing to FAO in asthma, and focus on recent advances and future directions. We propose the view that structural and functional changes in parenchymal tissue, are just as (if not more) important than airway remodeling in causing persistent lung function decline in asthma. We believe this paradigm of FAO should be considered when developing novel treatments. Asthma with irreversible or fixed airflow obstruction (FAO) is a clinical phenotype that is underappreciated and, subsequently, undertreated because our understanding of this phenotype is limited. Asthma with FAO is often (mis)labelled as chronic obstructive pulmonary disease (COPD) yet may develop despite nil-to-negligible smoking history or exposure to noxious agents. The prevalence of FAO is higher in those patients with severe asthma, being most frequent in older patients with long standing history of the condition . There iThere is no standard definition of fixed or persistent airflow obstruction, despite irreversibility in asthma being recognised for decades . This laUse of a fixed cut off of 0.7 lends itself to overestimation of disease in older people and underestimation in younger people . PreservAirway remodeling is currently thought to be the main mechanism by which FAO develops. Remodeling involves a wide array of pathophysiologic structural changes, including thickening of the reticular lamina, mucus gland hyperplasia, increased vascularity, and increased airway smooth muscle layer due to hyperplasia, hypertrophy and/or increased volume fraction of extracellular matrix . These cStructural parenchymal abnormalities in asthma were first demonstrated in post-mortem lungs of patients with severe asthma . AbnormaParenchymal tissue is the major determinant of elastic recoil in the lung, which helps to maintain the alveolar driving pressure and subsequently airway calibre during exhalation. The structural damage evident in the lung parenchyma in FAO may well lead to a loss of lung elastic recoil and, in turn, a reduction in the driving pressure during maximal expiratory flow and, therefore, reduced expiratory airflow. Moreover, with loss of alveolar attachments  and fracIn a classical paper, Pride et al. posited a ‘waterfall’ model to describe the determinants of maximal expiratory flow . We suggPeople with asthma are thought to have ‘stiffer’ airways as demonstrated by reduced airway distensibility . ReducedASM mechanics may also contribute to FAO, although this is only speculative based on mostly models from C. Seow et al. and J. Freberg et al. ASM is a dynamic organ that can adapt mechanically to its mechanical environment to optimise force generation and stiffness. The fluid or plastic nature of ASM, as it has been referred to, might facilitate ASM becoming stiffer when either the airway wall matrix becomes stiffer or the lung tissue becomes more compliant or its attachments to the outer wall of the airway become damaged. Any of these changes might then reduce the regular and rhythmic stretches from normal breathing, and intermittent larger stretches from regular sighs, which have proposed as being critical to maintaining compliance in ASM .Airway stiffness and progressive airway narrowing due to airway and/or parenchymal lung remodelling likely contribute to the decline in lung function in asthma , which dWhile we have presented the functional significance of parenchymal changes in patients with asthma and FAO, the pathophysiologic mechanisms responsible for parenchymal remodeling and loss of lung elastic recoil in these patients are poorly understood. However, several factors and mechanisms may be involved in the pathogenesis of FAO in asthma .Activation of proteolytic cascades which affect parenchymal tissue have been proposed as an underlying mechanism for FAO  and seemex-vivo conventional CT, whole lung micro-CT and micro-CT of extracted cores are an important structural component of age-related decline in lung function of healthy, non-smoking individuals   . TherefoSeveral other factors including genetics, steroid use, air pollution, smoking exposure, frequent exacerbations, viral infections etc. that have been associated with loss of lung function  or FAO dWhile current main asthma treatments of inhaled corticosteroids and bronchodilators may have some benefit in asthma patients with FAO and allergic airway inflammation, they are not effective in preventing or reversing FAO. This is probably party due to a late diagnosis of FAO after irreversible damage/changes to the lungs and airways have already occurred, and partly because currently treatments are targeting the inflammatory process only. Newer biological treatments targeting allergic and eosinophilic inflammation also have limited effects; while omalizumab, an anti-IgE monoclonal antibody, reduced exacerbation rate it does not improve lung function in patients with FAO irrespective of bronchodilator (BD) reversibility . MonocloAltogether, the current data demonstrates that FAO is a ‘whole lung’ problem with strong evidence for structural and function changes to not only the airways but also the lung parenchyma causing FAO. This idea challenges the current concept of intrinsic airway narrowing resulting from airway remodeling as the sole cause of FAO in asthma. Current asthma treatments of inhaled corticosteroids and bronchodilators are not effective in preventing or reversing these lung abnormalities. Therefore, novel treatments are to be developed that need to consider this model of FAO. However, the underlying mechanisms for parenchymal remodeling in asthma remain poorly understood, as is the extent of its contribution to FAO relative to airway remodeling. As such, further asthma studies that focus on structure-function relationships, and the underlying cellular and molecular mechanisms that cause airway and parenchymal remodeling are needed to develop novel treatment strategies.


Why is animal behavior variable? The main goal of this Research Topic is to showcase the latest research and perspectives that address this fundamental yet often overlooked question in behavioral neuroscience. Five original research articles and seven reviews by leading neuroscientists provide diverse insights on this question through various behavioral models.Ethologists have long noted that animals and humans often respond differently to the same sensory stimuli. Although variability is common in nature, its study as an essential biological feature has faced friction in lingering ideas, such as small organisms being simple stimulus-response automata. Connectomes, complete maps of neural connectivity, are miraculous accomplishments, but their singular, structural nature can reinforce the feeling that nervous systems are non-varying. On the other hand, these data also revealed many previously unknown synaptic connections, suggesting more alternative routes between neurons and brain regions than necessary for simple stimulus-response routines. Indeed, numerous studies have demonstrated that even a well-defined neural circuit can produce a variety of behavioral outputs. Traditionally, different origins of behavioral variability have been studied in discrete frameworks . These distinctions do not necessarily reflect the differences in underlying mechanisms, which likely act in superposition in real organisms. To visualize the richness of mechanisms discussed in this Research Topic, we placed the areas covered by each article on a 2-dimensional map. One axis represents the timescale of behavioral variability, and the other axis represents its mechanistic levels .Mueller et al. While it is clear that inter-specific variability is caused by heritable genetic differences between species , within-species variabilities might also arise from non-heritable causes such as noise in gene expression due to environmental factors. Both heritable and non-heritable variations affect behavior through multiple cellular and physiological mechanisms, including varying circuit connectivity. Using olfactory-guided behavior of the common fruit fly Drosophila melanogaster, Tao and Bhandawat discuss potential genetic contributions for behavioral variability, while Rihani and Sachse illustrate variabilities in neuroanatomy and physiological properties of neural circuits that can be the source of individual behavioral differences. In parallel, Tamvacakis et al. discuss the impact of variability in circuit wiring and gene expression patterns in key neurons driving flexibility in mollusk swimming behavior.The term “variability” often refers to a within-group difference in observable behavioral outputs that cannot be explained by the factor of interest, e.g., a stimulus or genetic variations within the group. For instance, Darwin was unaware that finches in the Galapagos Islands consisted of multiple species until his colleague ornithologist John Gould pointed that out. In this case, what was initially perceived as anatomical variability within a group turned out to be species-specific characteristics. Knowledge on taxonomy coupled with rigorous quantification of behavior helps distinguish intra- and inter-specific variabilities, as shown by Lee and Duvall consider egg diapause, an alternative state of arrested development under harsh environmental conditions, in the mosquito Aedes albopictus. This is an intriguing example of how external factors drive alternative reproductive strategies within a genetically homogeneous population. Similarly, Hageter et al. demonstrate that temperature fluctuations during Zebrafish development affect specific aspects of turning behavior. Another example is the effect of social experiences, which can profoundly impact animal behavior. Faure et al. discuss how complex social interactions in rodents can reinforce individual differences with significant fitness consequences. As discussed in the above three papers, specific genes likely play an essential role in converting experience during different development timescales into behavioral adaptations. Recent advances in sequencing technology can illuminate key genetic networks that are important for generating behavioral variability in response to changes in environmental conditions.Besides wiring variation, an alternative source of variability is multiple, discrete developmental programs within a species. Weiss and Donlea discuss how sleep (or the lack of it) can impact the neural functions of developing and mature brains, along with the behavioral consequences of sleep disruption. Arousal levels can be controlled in a behavior-specific manner as well. Palavicino-Maggio and Sengupta describe neurogenetic factors—namely neuromodulators—affecting aggression in Drosophila melanogaster. Across animal species, neuromodulation is a key to generating behavioral variability within and among individuals. Underscoring its importance, many articles in this Research Topic touch upon neuromodulation: Faure et al., Tamvacakis et al., Tao and Bhandawat, de Bivort et al., and Rihani and Sachse all discuss the significance of neuromodulation in the context of their behavioral paradigms. A review by Maloney argues that neuromodulation can drive behavioral variability by diversifying the dynamics of a circuit that controls a given behavior. Since many neuromodulators have similar behavioral effects across species, the cellular mechanisms of neuromodulation are critical to understanding how the nervous systems with (largely) identical connectivity can generate variable behavioral outcomes within and across individuals.Genetic, environmental, and stochastic factors underlie stable behavioral idiosyncrasies, but that is not the only source of variability. The same animal often behaves differently when tested at different times, suggesting that parallel factors cause intra-individual fluctuations in behavior. The so-called “internal state” is often used without a clear scientific definition, but several types of “internal states” have been well-studied across species; among them is the general arousal state. Tamvacakis et al.). “Big data” of behavior have become amenable for analysis relatively recently thanks to newly developed computational and experimental toolkits. de Bivort et al., Mueller et al., and Hageter et al. showcase the power of behavioral data collected from a large number of animals when isolating biases characteristic of each animal—or individuality. In all three articles, it is noteworthy that individual behavioral biases are represented as probabilities of exhibiting particular choices rather than the simple presence or absence of a given behavior. Thus, individuality may be expressed as differences in the sequencing or abundance of behaviors rather than their kinematics. Through the meta-analysis of published data, Tao and Bhandawat found that stochastic choice likely generates larger inter-individual variability in olfactory-guided behavior than genetic or neuromodulatory differences. How stochasticity arises in the nervous system remains an important question in neuroscience. Nande et al. demonstrated through modeling that behavior-specific modular organization of the nervous system makes the behavioral output more robust against perturbation while imparting long-term internal-state-like dynamics. In other words, the difference between what is regarded as a “stereotypical behavior” and a “variable behavior” may reflect differences in the way the neural circuits that control the given behaviors are structured.While distinguishing inter- and intra-individual variability seems straightforward in concept, a large amount of data and repeated measures from the same individual are often necessary to distinguish these two variabilities (see also The diverse aspects of behavioral variability covered in this Research Topic compel us to ask whether these phenomena can be explained under a single framework. Even a “simple” nervous system turns out to be complex enough to generate behavioral variability. Despite large-scale neural recordings and flourishing “omics” data from molecules to behavior, the level of our current understanding of gene expression regulation, synaptic plasticity, neuromodulation, and circuit development and reorganization still seems insufficient to create cell and circuit models that provide quantitative hypotheses to account for behavioral variability. Rigorous behavioral analysis will also be critical but almost certainly insufficient. Scientists and editors alike love “clean” behavioral data with small error bars that fit together into tidy neurobiological narratives. But the exclusive pursuit of such results limits progress in identifying the origins of behavioral variability, which is so salient to every scientist who performs a behavioral experiment. We hope this Research Topic advances variability discourse in the behavioral neuroscience community and brings us a few steps closer to a mechanistic understanding of the neural functions that generate behavioral variability.KA wrote the initial draft, which was substantially edited by all four co-authors. All the co-authors approved the final manuscript for publication. All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.KA would like to acknowledge support from NIH NIGMS R35GM119844.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. 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Individuals who face the greatest health burdens often have the fewest communication resources to draw from to help them cope. Communication infrastructure theory provides a framework for understanding how communication resources and context constrain and enable connections to health enhancing information. Data collected from 1,609 older adults through in-depth interviews and a random sample survey in one midwestern county in Michigan as part of a multi-year, multi-level community engaged study and a statewide random digit dial telephone survey showed that age influenced integration in a communicative structure. Findings suggest that the dynamics of living into late old age result in communication disparities through diminishing interpersonal resources, activity, and opportunities to congregate. Actionable knowledge and strategies provided to community leaders on how to connect with the hardly reached, individuals age of 75 and older, are presented.