Disturbed eating behaviours have been widely reported in psychotic disorders since the early 19th century. There is also evidence that antipsychotic (AP) treatment may induce binge eating or other related compulsive eating behaviours. It is therefore possible that abnormal eating patterns may contribute to the significant weight gain and other metabolic disturbances observed in patients with psychosis. In this scoping review, we aimed to explore the underlying psychopathological and neurobiological mechanisms of disrupted eating behaviours in psychosis spectrum disorders and the role of APs in this relationship. A systematic search identified 35 studies that met our eligibility criteria and were included in our qualitative synthesis. Synthesizing evidence from self-report questionnaires and food surveys, we found that patients with psychosis exhibit increased appetite and craving for fatty food, as well as increased caloric intake and snacking, which may be associated with increased disinhibition. Limited evidence from neuroimaging studies suggested that AP-naïve first episode patients exhibit similar neural processing of food to healthy controls, while chronic AP exposure may lead to decreased activity in satiety areas and increased activity in areas associated with reward anticipation. Overall, this review supports the notion that AP use can lead to disturbed eating patterns in patients, which may contribute to AP-induced weight gain. However, intrinsic illness-related effects on eating behaviors remain less well elucidated, and many confounding factors as well as variability in study designs limits interpretation of existing literature in this field and precludes firm conclusions from being made. Psychosis is the hallmark feature of various psychiatric illnesses, including schizophrenia (SCZ), schizoaffective disorder, schizophreniform disorder and bipolar disorder . It is aAntipsychotic (AP) medications are currently the cornerstone treatment for psychotic disorders . UnfortuWeight gain, a common consequence of AP treatment, occurs when there is a positive energy balance, meaning that energy intake exceeds energy expenditure . Beyond Looking beyond social, environmental and behavioural factors, energy homeostasis is controlled by intricate physiological pathways. Patients with SCZ may have subclinical metabolic dysregulations including dyslipidemia , hyperglWhile the physiological homeostatic mechanisms underlying altered eating patterns in this population have been the subject of recent meta-analyses and reviews ,20, lessGiven the high metabolic comorbidity observed in psychosis spectrum disorders, elucidating the psychopathological and neurobiological mechanisms underlying disrupted eating behaviours is crucial in helping to improve both the physical and psychological well-being of patients. In this scoping review, we aim to provide a comprehensive overview of disordered eating behaviours observed in psychosis spectrum disorders. We synthesize evidence from clinical studies employing self-report questionnaires and surveys to measure changes in food intake, craving and appetite, as well as behavioural neuroimaging studies to further explore the neurobiological mechanisms underlying these disturbances in eating patterns. In an attempt to distinguish illness intrinsic effects from those caused by treatment with APs, we present separately, when possible, results from studies examining AP-naïve patients , and healthy controls (HCs) or AP-naïve patients beginning APs.Our protocol was developed using the scoping review methodological framework proposed by the Joanna Briggs Institute . The objAn a priori search strategy was developed and tested in consultation with the Education and Liaison Librarian for the Institute of Medical Science at the University of Toronto. Databases searched included Ovid MEDLINE, Ovid EMBASE, Ovid PsychINFO, EBSCO’s CINAHL, CENTRAL on Wiley and Scopus. A grey literature search was also performed by mining references from relevant articles and review papers identified in the search, as well as searching SCOPUS for conference proceedings. Vocabulary and syntax were adjusted across databases. There were no language, date or methodology restrictions, with the exception of case studies and opinion pieces, which were excluded from the results. The specific search string for each database can be found in Article screening, including automatic duplicate removal, was completed using Covidence . Two autA data extraction template was created and piloted among study authors  and was refined and finalized based on data extracted from a sample of studies. The information displayed in Studies were summarized and presented according to their relevant category: (1) Studies describing eating patterns, food preferences and diet composition using dietary recall, food diaries and food frequency questionnaires; (2) studies measuring self-reported appetite, hunger and/or satiety using a mix of validated questionnaires and semi-structured interviews (see Table 3); and (3) studies using neuroimaging methodologies to assess neurobiological changes in relation to aspects of eating or food intake. A narrative summary of each study is reported in its respective subsection, with overlap in other subsections if applicable. Where appropriate, tables were created to concisely summarize characteristics of included studies and relevant findings (see Tables 4–6).Our initial search revealed 3545 results, which was reduced to 2654 after removal of duplicates. Following title and abstract screening, 94 studies were assessed for full-text eligibility. A total of 35 studies that considered dietary composition, food preference and cravings and/or eating patterns in patients with SCZ or HCs exposed to APs were deemed eligible and included in our qualitative synthesis , the Dutch Eating Behavior Questionnaire (DEBQ), visual analog scales (VAS), the Food Craving Inventory (FCI), the Food Craving Questionnaire (FCQ) and the Food Frequency Questionnaire (FFQ). The TFEQ addresses three aspects of eating behaviour including restriction of food intake, loss of control of food intake and responsivity to internal hunger cues. Previous studies in the general population indicate that increased body weight is positively associated with TFEQ scores ,32,33, pOur search yielded 9 studies that described dietary composition  . Only twSeven of the included dietary composition studies compared patients with healthy controls ,59,60,61Three cross-sectional studies ,58,59 reThe three remaining case-control studies also noted differences in nutritional patterns between patients and HCs, including increased fat consumption and more frequent snacking in patients ,62. InteThe final study included in this section explored eating behaviour differences between HCs and patients with SCZ on OLA treatment. This study revealed that that 70% of the OLA-treated patients reported ingesting a significantly greater amount of food than usual, with no compensatory increase in physical activity levels .Only one dietary composition study explored the effects of APs on food intake and energy expenditure in patients . The stuConsistent with the patient-only studies discussed above, an HC study conducted by Fountaine et al. revealed that volunteers randomized to receive olanzapine gained more weight and consumed significantly more calories than those randomized to placebo . InteresIn total, there were 19 studies ,77,78,79Seven studies ,66,67,68onset of episodes of binge eating during the current medication regime [Consistent with the dietary composition studies discussed above, all five patient studies ,65,66,67n regime , found tn regime  and adven regime  revealedSimilar to the findings mentioned above, two case-control studies conducted by Khazaal et al. found evidence of a link between psychosis and disordered eating. In their first study , the autOur search identified 12 studies ,74,76,77Conclusions from longitudinal studies regarding the effects of AP medications (particularly SGAs) on appetite were mixed. For example, two studies, one in which patients were randomized to receive olanzapine or risperidone , and anoIn the only cross-sectional study identified, Sentissi et al. compared eating behaviour between AP-naïve or AP-free, FGA-treated and SGA-treated patients with SCZ . They foAll five studies comparing patients and controls were cross-sectional studies. Generally, there were mixed results regarding group differences in appetite/satiety, which highlights a need for longitudinal studies in this area.In one study, although patients experienced increased hunger (VAS) and decreased satiation compared to HCs following a standardized meal , the groIn contrast to the studies discussed above, Schanze et al. (2008) found no group differences between patients with SCZ, patients with major depressive disorder, and HCs in any of the TFEQ domains . FurtherOur search retrieved two randomized, double-blind, placebo-controlled studies in HCs examining subjective appetite/hunger following short-term SGA exposure. In the first study, Roerig et al. (2005) found that two weeks of either olanzapine or risperidone exposure led to weight gain compared to placebo, although only olanzapine reached statistical significance . The autn = 22) patients [n = 9) or had been medication free for at least six weeks (n = 20) [Our search yielded seven studies that used neuroimaging methodologies to study food preference and eating behavior in patients with SCZ. The characteristics of these studies and a summary of their main findings can be found in patients , and one(n = 20)  (SectionA study by Stip (2015) and colleagues compared brain activity (fMRI) in response to videos of food in patients with SCZ before and after initiating or switching to olanzapine therapy . The autIn an earlier publication  as the two aforementioned studies by Stip and colleagues ,85, simiIn a similar but independent fMRI study, Grimm et al. (2012) asked chronic patients with SCZ and HCs to rate their appetite levels on a VAS following presentation of neutral or appetitive stimuli . Even afIn a structural MRI study, Emsley and colleagues  investigIn a recent fMRI study, Borgan et al. (2019) investigated neural responsiveness to appetitive stimuli in untreated FEP patients and HCs . CompariWe retrieved one neuroimaging study in HCs, which examined the effects of seven days of olanzapine administration on fMRI responses to visual stimuli  as well as to receipt of an actual food reward . OlanzapWe performed a scoping review, which aimed to explore associations between psychosis spectrum disorders, food consumption, and disruptions in appetite and eating behaviors. Our search retrieved 35 studies, which we subsequently organized into three sections based on main theme or methodology: (1) Food composition and dietary preference, (2) patterns of eating behaviour and subjective appetite and (3) neural correlates of appetite and eating behavior. These sections are discussed individually, followed by a discussion of postulated mechanisms, and a more general discussion of limitations and future directions of this field.The studies identified in our search provide evidence that overconsumption, in the form of both increased frequency and quantity of food consumption, differs between patients and HCs ,58,59,60Disentangling the extent to which observed differences in caloric intake and dietary composition relate to biological factors intrinsic to the illness and/or AP treatment is challenging. While work in AP-naïve FEP populations can be helpful in delineating intrinsic illness related factors, only two of the dietary composition studies we retrieved included AP-naïve individuals ,57. HoweIt is also important to consider socioeconomic, environmental, and lifestyle factors that may precipitate a snowball effect on unhealthy dietary patterns among patients. Patients with psychosis spectrum disorders tend to belong to lower socioeconomic status (SES) groups ,90. ThisSynthesis of the studies identified in our search revealed a positive association between BMI/weight and altered appetite, hunger and/or food cravings in patients with psychosis spectrum disorders ,65,69,72In addition, APs may increase appetite and response to both internal and external hunger cues (as assessed by the TFEQ), putting patients at higher risk of overeating and subsequent weight gain ,74,83,89Longitudinal HC studies also provide mixed evidence regarding the effects of APs on appetite and eating behaviors. Some studies indicate increased appetite, body weight and food intake following olanzapine treatment, indicative of a potential causal link ,87, whilA variety of neuroimaging strategies have been employed to examine neurobiological mechanisms implicated in food intake patterns in patients, with a majority of the work (six out of seven retrieved studies) focusing on functional changes captured by fMRI in response to appetitive cues. Unfortunately, though, the different behavioural paradigms and brain regions of interest of each study made it difficult to draw any broad conclusions or generalizations. Two studies suggest that APs may contribute to disrupted appetite regulation and eating behaviour by increasing activation in areas involved in action planning and homeostatic signals , and regIn determining the relative effects of illness vs. AP treatment, one AP-naïve study did not report any neural differences between patients or controls, indicating that food-related neural processing is not intrinsically dysregulated in SCZ . In contWhile the contributing effects of intrinsic illness related factors vs. those of AP medications remain difficult to separate, existing theoretical frameworks may provide a neurobiological rationale for the differences in eating behaviours and appetite between patients with pychosis spectrum disorders and HCs. The postulated disruptions in hedonic/motivational and homeostatic mechanisms in patients with pyschosis spectrum disorders are summarized in The mesolimbic dopamine reward system is instantiated by a network of brain structures innervated by dopaminergic projections from the ventral tegmental area (VTA), including the nucleus accumbens (NAc), hypothalamus, amygdala, and PFC regions ,97 see . MesolimIn turn, increased dopaminergic transmission in the striatum is a core neurobiological feature of SCZ that responds to first line AP treatment ,101. TheMoreover, reward hypoactivity, which is related to negative symptoms of SCZ ,105, mayAdditionally, disrupted function in the DLPFC, ACC and mediodorsal nucleus of the thalamus has been associated with impaired executive function in SCZ . AnalogoThe limited body of literature reporting on AP-naïve FEP patients precludes direct attribution of any dysregulations to inherent illness factors. However, APs share the uniting property of dopamine 2 (D2) receptor antagonism, which may mimic decreased D2 receptor availability, and thus contribute to the reward deficiency/overcompensation phenotype. Indeed, a relationship between reduced D2 receptor function and reward dysfunction has already been observed in obesity . Beyond Homeostatic mechanisms of food regulation are thought to be primarily regulated by the hypothalamus, a region anatomically situated to confer accessibility to hormones  and nutrients  in the blood and cerebral spinal fluid (CSF) to relay information about the body’s energy stores to the brain  see Fig. The topA key strength of this scoping review is that the search was broad, allowing for a comprehensive overview of the current state of the literature pertaining to eating behaviours and food consumption in psychosis spectrum disorders. Moreover, to the best of our knowledge, this is the first review to summarize the findings of neuroimaging studies that sought to elucidate the neurobiological mechanisms underlying eating behaviours among psychosis spectrum patients.Nevertheless, there are some limitations which must be addressed. First, our search revealed high heterogeneity in both study design and questionnaires employed, which made comparing studies difficult and precluded conclusions from being made. Second, the majority of studies used subjective self-report measures of appetite/craving, results of which may be influenced by factors outside of hunger . AdditioImportantly, very few of the studies identified in our search considered AP-naïve FEP patients, with the vast majority involving patients who had previously been exposed to AP therapy. This makes it difficult to determine whether any abnormal eating patterns observed in patients are intrinsic to the illness or secondary to the effects of APs. Additionally, while HC studies are a good way to remove the confounding effect of illness, they preclude identification of any interaction between intrinsic dysfunction in eating and AP effects. Prospective studies in which AP-naïve patients are exposed to APs would be particularly useful in exploring this illness-treatment interaction. Moreover, it should also be considered that studies in chronic patients with SCZ are confounded by cumulative illness associated lifestyle factors and treatments, which may affect both eating patterns and weight gain ,117. FurFinally, many of the studies comparing patients with HCs did not match groups on key sociodemographic and physiological  factors see , constitWhile disruptions in hormones involved in homeostatic mechanisms of appetite control in patients with pychosis spectrum disorders have been the subject of several reviews and meta-analyses, our scoping review highlights the behavioral and neurobiological underpinnings of altered eating behaviour in this population. Our synthesis of evidence from food surveys and self-report questionnaires generally supports the notion that patients with pychosis spectrum disorders exhibit increased appetite and craving for fatty food, increased caloric intake and increased frequency of (over) consumption, which may be associated with increased disinhibition. Early evidence also suggests that disturbed eating behaviours in this population could be mediated by abnormal processing of food-related stimuli within neural systems related to the mesolimbic reward circuit. In addition, it is possible that impaired cognitive restraint and executive functioning intrinsic to psychosis may make patients more susceptible to developing disordered eating patterns in response to weight gain and/or increased appetite and cravings. Future prospective studies with larger samples and AP-naïve populations are needed to improve the evidence base in this field and help dissect the intrinsic and extrinsic illness factors involved in disturbed appetite regulation. This will have important implications for development of pharmacological and behavioral interventions which, by targeting cardiometabolic comorbidities, may have the potential to increase patient life span and improve overall quality of life.


Muscle plasticity is defined as the ability of the muscle to respond to changes in environmental conditions. Muscle plasticity is exceptionally dynamic in fish; this is attributed in part to their ectothermic (cold-blooded) nature and ability of indeterminate or continual growth, throughout their lifespans. The molecular mechanisms regulating muscle growth in fish are not completely characterized; however, recent advancements have established that microRNAs and DNA methylation are important mechanisms regulating muscle plasticity. This review examines these mechanisms and describes how they are regulated by genetic and environmental  factors and they in turn affect muscle growth and plasticity in fish.Growth rates in fish are largely dependent on genetic and environmental factors, of which the latter can be highly variable throughout development. For this reason, muscle growth in fish is particularly dynamic as muscle structure and function can be altered by environmental conditions, a concept referred to as muscle plasticity. Myogenic regulatory factors (MRFs) like Myogenin, MyoD, and Pax7 control the myogenic mechanisms regulating quiescent muscle cell maintenance, proliferation, and differentiation, critical processes central for muscle plasticity. This review focuses on recent advancements in molecular mechanisms involving microRNAs (miRNAs) and DNA methylation that regulate the expression and activity of MRFs in fish. Findings provide overwhelming support that these mechanisms are significant regulators of muscle plasticity, particularly in response to environmental factors like temperature and nutritional challenges. Genetic variation in DNA methylation and miRNA expression also correlate with variation in body weight and growth, suggesting that genetic markers related to these mechanisms may be useful for genomic selection strategies. Collectively, this knowledge improves the understanding of mechanisms regulating muscle plasticity and can contribute to the development of husbandry and breeding strategies that improve growth performance and the ability of the fish to respond to environmental challenges. Fish species that exhibit indeterminate growth display an exceptional ability for continual muscle growth throughout their life by an increase in muscle fiber number (hyperplasty) and in muscle fiber size (hypertrophy) ,4,5,6,7.Myogenic regulatory factors are basic helix-loop-helix transcription factors that drive the process of myogenesis, including MPC proliferation and differentiation . PrefereSignaling molecules play a significant role in regulating the expression of these MRFs, thus determining the fate of myogenesis. TGF-β family members are responsible for satellite cell maintenance while hedgehog signaling is responsible for transition from proliferative to quantile mitosis. Satellite cell markers Pax7 and Pax3 are downregulated and differentiation factor MyoD is upregulated by hedgehog in teleosts, thus determining myogenic commitment. Additionally, insulin-like growth factor-I (IGF-I) and insulin regulate myogenesis by binding to receptor tyrosine kinase and initiating signaling cascades. Growth factor signaling enhances myogenic proliferation and differentiation via mitogen-activated protein kinase (MAPK), Ras/Raf, and PI3K pathways thus controlling muscle regeneration, MPCs proliferation, and differentiation, respectively . The sigTubercle bacillus and later in calf thymus DNA [mC. Until recently it was believed that methylation of cytosine is restricted to CpG dinucleotide. Advanced sequencing techniques as well as the ability to map sequences at base pair resolution disclosed non-CpG methylations. Non-CpG methylations are less frequent than CpG methylations and are seen in mammalian oocytes [Chemical modification of DNA bases was first reported in ymus DNA ,37. Furtymus DNA ,39. Sincymus DNA ,41,42. Dymus DNA . The majymus DNA ,45. A me oocytes , adult b oocytes , and emb oocytes . In gene oocytes . Introdu oocytes ,51,52 by oocytes .Studies in mammals confirmed the regulatory role of DNA methylation during myogenesis, including activation of MPC, proliferation, and differentiation. Comparative studies to understand the methylation landscape among myogenic differentiating cells and mature skeletal muscle suggested loss of methylation in mature fibers. In mice differentiating muscle cells exhibit approximately 90% higher methylation rates when compared to mature myofibers . DiffereMost advances in the knowledge of epigenetic regulation of muscle plasticity in fish have occurred only within the last five years; findings have provided support for DNA methylation as a mechanism affecting muscle growth . CompariSeveral studies have characterized the role of DNA methylation in response to temperature variation during early rearing stages. In Atlantic salmon, higher embryonic incubation temperature (4 °C vs. 8 °C) increases post-embryonic growth rates; in first-feeding larvae this response was associated with both reduced DNA methylation of the Myogenin promoter and higher Myogenin expression . EffectsAlthough most studies have focused on changes in muscle Dnmt expression as an indicator of regulation of DNA methylation capacity, fewer have investigated changes in methylation of MRFs that affect myogenesis and muscle plasticity. As previously mentioned, in two studies improved growth rates induced by higher embryonic incubation temperatures corresponded to hypomethylation of the Myogenin promotor and increased expression in muscle ,67. In rSmall RNAs, particularly microRNAs (miRNAs), are extensively studied as post-transcriptional microregulators of gene expression governing either mRNA stability, rates of translation, or both . StudiesMyogenesis involves orchestrated interaction of various mechanisms involving signaling pathways and coordinated gene expression of various myogenic regulatory factors (MRFs). The role of miRNA in myogenesis was first established in Dicer mutant mice exhibiting reduced muscle miRNA, perinatal death, and decreased skeletal muscle with abnormal myofiber morphology and apoptosis of myoblasts . This stLarimichthys crocea) [In several fish species, including rainbow trout ,90, zebr crocea) .Schizothorax prenanti [Piaractus mesopotamicus) [Unique miRNA expression profiles are reported in muscle during different developmental stages in common carp , the rayprenanti , and pactamicus) , supporttamicus) , tilapiatamicus) , Chinesetamicus) , and blutamicus) . Notabletamicus) . Expresstamicus) . Howevertamicus) . VariatiMicroRNAs can determine muscle cell fate very early during somatogenesis. Fish exhibit two distinct muscle types, slow and fast muscles, and the role of miRNAs in muscle cell type determination was reported by studies using fish as model species. Ubiquitously expressing miR-214 synchronizes Hedgehog signaling in zebrafish by translational repression of its negative regulator Su(Fu), thus coordinating a balance among slow and fast muscle cell types. Knockdown of miR-214 in zebrafish embryos led to the development of fewer to a complete absence of slow muscle cells , and henUnderstanding the role of miRNAs as a mechanism regulating muscle function during physiological perturbation has been the focus of numerous studies in fish. Perhaps one of the most significant environmental factors affecting muscle growth in fish is the availability of nutrients; several studies support that both nutrient intake and diet composition affect miRNA expression in muscle. Experimental designs that involve feed deprivation and refeeding have been valuable for identifying miRNA biomarkers for anabolic and catabolic responses. When Chinese perch  and grasTemperature is an additional factor that affects miRNA expression. In zebrafish, changes in muscle growth trajectories (hyperplasia vs. hypertrophy) induced by manipulation of embryonic incubation temperature were associated with differential expression of miRNAs, with increased Myogenin expression in the higher temperatures that improved growth performance . SimilarIn addition to biological factors of exogenous origin, endogenous factors such as hormones are established as regulators of muscle physiology through mechanisms involving miRNAs. Physiological changes in salmonid skeletal muscle during sexual maturation are characterized by protein degradation and lipid loss ,127. By Within the last decade significant advancements in the knowledge of molecular regulation of gene expression have established that miRNAs and DNA methylation are significant mechanisms affecting expression of myogenic regulatory factors and muscle plasticity in fish. Genetic, environmental, and physiological factors cause differential expression of miRNAs and DNA/gene methylation in muscle that are directly linked or correlated with growth responses. These findings are reported in model species like the zebrafish and stickleback as well as fish species significant for aquaculture such as rainbow trout, Atlantic salmon, Chinese perch, and tilapia. Continued advancements in our understanding of the molecular mechanisms regulating muscle plasticity is central for the development of novel genetic markers to aid in selective breeding for enhanced growth. It is also valuable for the development of husbandry strategies that improve the capacity for muscle growth through, for example, diet, photoperiod, or temperature manipulation that enhance aquaculture production efficiency and advance global food security.


Aphids are a major issue for commercial crops. These pests drain phloem nutrients and transmit ~50% of the known insect-borne viral diseases. During aphid feeding, trophic structures called stylets advance toward the phloem intercellularly, disrupting cell wall polymers. It is thought that cell wall-modifying enzymes (CWMEs) present in aphid saliva facilitate stylet penetration through this intercellular polymer network. Additionally, different studies have demonstrated that host settling preference, feeding behavior, and colony performance of aphids are influenced by modulating the CWME expression levels in host plants. CWMEs have been described as critical defensive elements for plants, but also as a key virulence factor for plant pathogens. However, whether CWMEs are elements of the plant defense mechanisms or the aphid infestation process remains unclear. Therefore, in order to better consider the function of CWMEs and cell wall-derived damage-associated molecular patterns (DAMPs) during plant–aphid interactions, the present review integrates different hypotheses, perspectives, and experimental evidence in the field of plant–aphid interactions and discusses similarities to other well-characterized models such as the fungi–plant pathosystems from the host and the attacker perspectives. This review highlights the different hypotheses, perspectives, and evidence that point to cell wall polymers and modifying enzymes as relevant plant traits for aphid resistance/susceptibility. At present, the consensus model of plant cell wall architecture consists of cellulose microfibrils anchored to the cell membrane, cross-linked by hemicelluloses, and embedded in a matrix of pectic polymers  which allow them to break down these carbon-rich polysaccharide networks, gain access to the cytosolic content, and hence colonize the host. However, as a reciprocal evolutionary process, plants have developed mechanisms to monitor and adjust the composition, abundance, and distribution of the interacting polymers and its modifying enzymes to protect cell wall integrity under biotic stress circumstances. Since the feeding strategy of aphids is based on a trophic structure (stylet) that penetrates the cell wall and injects CWMEs in salivary secretions, several questions have arisen in the field of understanding the feeding behavior of aphids. These include: what is the significance of these enzymes and of the target polymers during the plant–aphid interaction and could CWMEs in aphid saliva facilitate the penetration of stylets through the extracellular matrix or can penetration be explained simply by mechanical motion? Therefore, by integrating different hypotheses, points of views, and experimental evidence in the field of plant–aphid interactions, and by comparison with other well-studied models (e.g. fungi–plant interaction), here we review and discuss the influence of cell wall polymers and CWMEs during plant–aphid interactions .Aphids are a global threat due to the nutrient losses caused by phloem drainage, which significantly decreases crop yields -linked galacturonic acid  units as part of their scaffold  and pectate lyase enzymes , causing cell wall loosening, or ionic cross-linking with other de-methylesterified HG chains through calcium bridges which generally leads to cell wall stiffening . TherefoBotrytis cinerea  showed increased resistance to Pseudomonas syringae pv. tomato (Fragaria × ananassa PME (FaPE1) in F. vesca enhanced fruit resistance to B. cinerea (Nicotiana attenuata (NaPME1) leads to an increased performance  of Manduca sexta larvae compared with wild-type plants . By exploiting this valuable information, pmei13 mutants as host compared with wild-type genotypes. Moreover, pmei13 mutants showed an increased susceptibility in terms of phloem accessibility and nutrient drainage, since aphids reached the phloem significantly faster on mutant plants concomitant with longer phloem sap ingestions compared with the wild-type genotypes, revealing that PMEI13 is a critical factor involved in plant resistance against aphids. Moreover, the study also showed that M. persicae infestation induced a significant increase in total PME and PL enzymatic activities along with an increase in the abundance of de-methylesterified HGs and methanol emissions. These results are particularly interesting considering that an increase in total PME and PL activities could lead to the production of OGs; therefore, the modification of HGs observed in early aphid infestations could correspond to a plant defense mechanism against aphids. Indeed, this hypothesis was previously proposed by The role of the salivary CWMEs for the aphid pathogens is thus still unclear. Nevertheless, and in order to obtain a clearer and more holistic perspective, it is necessary to study and understand the protective function of plant CWMEs during aphid infestation. M. persicae, since the population of aphids that fed for 6 d on transgenic lines was reduced by up to 99%.On the other hand, in a dual free choice assay, M. persicae compared with control plants. Therefore, both studies point to methanol as a critical element influencing the host preference and colonization performance of aphids, and it is logical to postulate that the timing and concentration of the methanol emission could lead to different responses (positive or negative) on aphid behavior and plant responses in a species-specific manner.In addition to the production of OGs during pectin degradation, the de-methylesterification of HGs caused by the action of PME also leads to the production of methanol -linked backbones of glucose, mannose, or xylose in an equatorial configuration at the C1 and C4 residues. Hemicellulose structure, synthesis, and biological functions have been reviewed in detail elsewhere , the transcript abundance of ENDOTRANSGLUCOSYLASE/HYDROLASE 1 (AgXTH1) rises significantly in systemic phloem tissue. Then, in a subsequent study, the influence of Arabidopsis XTH33 (homologous to AgXTH1) on aphid infestation behavior was evaluated, revealing that aphids significantly preferred to settle on xth33 mutants compared with the wild-type genotype  glucan chains synthesized by CELLULOSE SYNTHASE A (CESA) protein complexes at the plasma membrane. As soon as the chains are synthesized, they gather together via intermolecular hydrogen bonding, leading to the formation of cellulose microfibrils (Cellulose is built up of β-ofibrils .d-(1→4) glucan polymer, cellulose participates in the basal responses during infection by forming papillae structures along with callose to limit the penetration and spread of the pathogen . Additionally, like the pectic oligomers (OGs), cellulose dimers (cellobiose) act as DAMP signals with defense-eliciting activity through the activation of MAPK signaling cascades, leading to an up-regulation of salicylate-, jasmonate-, and ethylene-related genes in Arabidopsis  glucan linear homopolymer of glucose residues with less frequent β-d-(1→6) glucan branches  in Arabidopsis increases callose deposition at the early stage of infection (6 h) compared with wild-type plants, leading to a phenotype described as complete resistance to penetration, upon infections with two powdery mildew fungi, virulent Golovinomyces cichoracearum and non-virulent Blumeria graminis. This study revealed that callose–cellulose papillae could abolish the infection process, regardless of the compatibility of the pathosystem. Moreover, in a later study, by using localization microscopy, In the context of biotic stress, it has been described that during fungal infections, callose along with cellulose forms amorphous clogging deposits (papillae) at the sites where pathogen CWMEs have degraded plant cell walls, and hence limits the penetration and spread of the attacker  members, similar to WAKs.Colonization behavior and performance of aphids are influenced by alterations in the methanol emissions of host plants. However, a deeper understanding of the influence of this product of PME reactions is needed, since the timing and concentration of the emissions seem to produce different effects on plant–aphid interactions.Considering the impact of cell wall polymer status and CWMEs on pathogen infections and aphid behavior, cell wall-related elements could represent an input to develop new crop traits pointing to insect/pathogen resistance.Whether stylet penetration is only performed by mechanical forces or corresponds to a CWME-assisted process is an ongoing question that has not yet been clearly answered due to the complexity of separately analyzing both components. Nevertheless, the current availability of whole-genome sequences of different aphid species plus the accessibility to gene editing/silencing techniques represent the opportunity to elucidate the intriguing feeding strategy of aphids.


Recent studies have demonstrated substantial phenotypic overlap, notably social impairment, between autism spectrum disorder (ASD) and schizophrenia. However, the neural mechanisms underlying the pathogenesis of social impairments across these distinct neuropsychiatric disorders has not yet been fully examined. Most neuroimaging studies to date have focused on adults with these disorders, with little known about the neural underpinnings of social impairments in younger populations. Here, we present a narrative review of the literature available through April 2020 on imaging studies of adolescents with either ASD or early-onset psychosis (EOP), to better understand the shared and unique neural mechanisms of social difficulties across diagnosis from a developmental framework. We specifically focus on functional connectivity studies of the default mode network (DMN), as the most extensively studied brain network relevant to social cognition across both groups. Our review included 29 studies of DMN connectivity in adolescents with ASD (Mean age range = 11.2–21.6 years), and 14 studies in adolescents with EOP (Mean age range = 14.2–24.3 years). Of these, 15 of 29 studies in ASD adolescents found predominant underconnectivity when examining DMN connectivity. In contrast, findings were mixed in adolescents with EOP, with five of 14 studies reporting DMN underconnectivity, and an additional six of 14 studies reporting both under- and over-connectivity of the DMN. Specifically, intra-DMN networks were more frequently underconnected in ASD, but overconnected in EOP. On the other hand, inter-DMN connectivity patterns were mixed (both under- and over-connected) for each group, especially DMN connectivity with frontal, sensorimotor, and temporoparietal regions in ASD, and with frontal, temporal, subcortical, and cerebellar regions in EOP. Finally, disrupted DMN connectivity appeared to be associated with social impairments in both groups, less so with other features distinct to each condition, such as repetitive behaviors/restricted interests in ASD and hallucinations/delusions in EOP. Further studies on demographically well-matched groups of adolescents with each of these conditions are needed to systematically explore additional contributing factors in DMN connectivity patterns such as clinical heterogeneity, pubertal development, and medication effects that would better inform treatment targets and facilitate prediction of outcomes in the context of these developmental neuropsychiatric conditions. Autism spectrum disorder (ASD) and schizophrenia are heterogeneous conditions that share several phenotypic and genomic features –4. For iAdolescence or youth ages 10–24; ; 24. As In addition to contextual changes in the social environment, adolescence is also a period marked by significant neural changes, particularly in the prefrontal cortex, a major hub in several brain networks associated with social functioning , 36–41. Although the social brain is not a specifically defined network, there is general consensus in the literature that the medial prefrontal regions, the temporoparietal junction, anterior and lateral temporal regions, anterior insula, and the posterior cingulate cortex/precuneus subserve several crucial social functions , 40, 47.Disrupted DMN functional connectivity has been implicated in several psychiatric conditions with associated social difficulties , 59–61, Hence, the current article aims to further explore cross-sectional studies on DMN connectivity in ASD and early-onset psychosis (EOP) during the adolescent years. For this purpose, we reviewed the literature available through April 2020 in PubMed, Google Scholar, and PsycINFO on DMN connectivity in adolescents with ASD and/or EOP, using search terms including “default mode network, functional connectivity,” combined with “adolescence, autism, ASD, Asperger’s” or “psychosis, adolescent-onset psychosis, adolescent-onset schizophrenia, first-episode psychosis, early-onset psychosis, early-onset schizophrenia”. The initial literature search revealed 160 relevant studies in ASD and 46 in EOP. Studies were subsequently included in the review based on age-range spanning adolescence and patient groups meeting diagnostic criteria for either ASD or EOP. All included studies were also required to have a control group of typically developing adolescents. Additionally, we focused only on empirical studies that included either: 1) static resting-state analysis or dynamic functional connectivity (DFC) analysis that examines temporal variations in connectivity patterns across the duration of the scan –68, and Traditional seed-based analysis (SBA), wherein the time-series from a seed-region are correlated with all other voxels in the entire brain or a mask of the DMN , 70.SBA that quantify the amplitude of low-frequency fluctuations (ALFF), i.e., the magnitude of signal intensity of spontaneous fluctuations for a given brain region. In ALFF analyses, the time-series from a given seed-region are transformed into a frequency domain from which the power spectrum are obtained , 71.Independent component analyses (ICA), a data-driven method wherein whole-brain signal are decomposed to identify spatially and temporally independent components. Software templates of the DMN are then used to identify components that correspond to this network .Support vector machines (SVM) are data-driven supervised machine-learning methods using pattern recognition algorithms to automatically classify neuroimaging data into typical or atypical categories .Self-organizing map (SOM) algorithm, a clustering analysis technique wherein voxels are organized on a two-dimensional matrix with each node representing clusters of voxels that are highly correlated and nodes that are closer together on matrix representing neural networks , 73.Regional Homogeneity (ReHo), a voxel-based approach to measuring brain connectivity wherein the similarity between the time-series of a given voxel and its nearest neighbors within a network is evaluated .Granger Causality Analysis (GCA), a statistical method that allows for prediction of causality between functional connectivity of two seed-regions/nodes from time-series data .Network Homogeneity (NH), a voxel-wise measurement of homogeneity and cohesiveness of each voxel within a functional network that provides an index of network integrity .Our final review included 29 studies of DMN connectivity in adolescents with ASD ; hence, functional connectivity of a network can vary in terms of connectivity strength and directionality during different temporal “windows” or timepoints of a scan , 119, Adnegative functional connectivity between the DMN and the task-positive central executive network, not observed in adolescents with ASD. These findings support the theory of a crucial maturational shift in DMN connectivity patterns during adolescence which is likely significantly impacted in individuals with ASD such that the typically expected strengthening and honing of DMN connectivity is disrupted in this population during this age period. However, the mechanism underlying the shift in DMN connectivity patterns after the onset of puberty is not fully understood in ASD yet, and requires further exploration to elucidate differential trajectories and their impact on symptomatology.A few studies have also explored the maturational trajectory of DMN connectivity in individuals with ASD , 84, 100So far, only one study has systematically examined sex differences in DMN connectivity in ASD . This stIntellectual functioning is another variable of interest relevant to DMN connectivity in adolescents with ASD, given the wide range of cognitive abilities in this population . Most ofLastly, several of the studies (12 out of 29) included in our review have examined the relationship between aberrant DMN connectivity in adolescents with ASD and behavioral measures of symptom severity such as the Autism Diagnostic Observation Schedule ADOS; , 123, thPrior research on adults with schizophrenia spectrum disorders suggests that disrupted DMN connectivity may play an important role in the pathophysiology of schizophrenia . SpecifiMore recent studies of DMN connectivity in adolescents with EOP offer some insight into neural anomalies in the earlier stages of this disorder Table 2.One study comparing adolescents at clinical high risk for psychosis (CHR) to drug-naïve adolescents with a diagnosed psychotic disorder suggested that while both groups showed increased connectivity between DMN and cerebellum compared to TD control groups, the connectivity strength was attenuated in those with overt illness . On the Studies of youth with EOP receiving anti-psychotic medication mostly showed overconnectivity relative to healthy controls within the DMN , 109, asCurrent symptom severity may also impact DMN connectivity patterns in adolescents with EOP. Ten out of 14 studies reviewed here examined the relationship between DMN connectivity and symptom severity on the Positive and Negative Syndrome Scale (PANSS), a widely used measure in schizophrenia . Out of between DMN and salience network was more characteristic of EOP, whereas in ASD the atypical connections were primarily found within the salience network. Studies examining the maturational trajectory of resting state networks in ASD suggest that DMN connectivity appears to decrease from childhood to adolescence  rather than measures of social functioning or social cognition per se. One reason for the absence of specific social cognition measures across studies might be the use of shared datasets which provides researchers with large sample sizes, but a limited amount of common behavioral data collected across all contributing sites. Another reason could be the absence of  studies , 88 and  studies  used theIn this review, we have summarized resting state functional MRI studies of DMN connectivity from empirical studies in two different clinical populations involving marked social impairment, autism spectrum disorder and early onset psychosis, during the crucial developmental window of adolescence. While the literature thus far has helped shed some light on both the common and unique patterns of DMN connectivity across these two groups, several gaps remain in our understanding of how DMN connectivity might contribute to the unique pathophysiology of both neuropsychiatric conditions. First, there have been far fewer studies on DMN connectivity in EOP than ASD adolescents. This may be due in part to difficulties in ascertaining adolescents with EOP compared to adults with psychotic disorder, given its relatively lower prevalence , 134. AnAN and CB took the lead role in reviewing papers and drafting the manuscript. MJ and SL assisted in reviewing papers and preparing tables. All authors read and approved the final manuscript. All authors contributed to the article and approved the submitted version.This work was supported by the National Institute of Mental Health K99MH113820 (author AN).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.


Acute myeloid leukemia (AML) cells modulate their metabolic state continuously as a result of bone marrow (BM) microenvironment stimuli and/or nutrient availability. Adipocytes are prevalent in the BM stroma and increase in number with age. AML in elderly patients induces remodeling and lipolysis of BM adipocytes, which may promote AML cell survival through metabolic activation of fatty acid oxidation (FAO). FAO reactions generate acetyl-CoA from fatty acids under aerobic conditions and, under certain conditions, it can cause uncoupling of mitochondrial oxidative phosphorylation. Recent experimental evidence indicates that FAO is associated with quiescence and drug-resistance in leukemia stem cells. In this review, we highlight recent progress in our understanding of fatty acid metabolism in AML cells in the adipocyte-rich BM microenvironment, and discuss the therapeutic potential of combinatorial regimens with various FAO inhibitors, which target metabolic vulnerabilities of BM-resident, chemoresistant leukemia cells. In the bone marrow (BM) microenvironment, AML cells modulate their metabolic state to respond to extracellular stimuli, like hypoxia and nutrient availability, and can therefore undergo cell kinetic quiescence, proliferation, or differentiation . GlucoseAcute myeloid leukemia (AML) is primarily a disease of the elderly, with 75% of AML patients greater being over 60 years old at diagnosis . In adulA recent study demonstrated that BM-resident adipocytes markedly impaired the antileukemia efficacy of various chemotherapeutic agents, and that the rate of relapse after chemotherapy was higher in obese mice compared to their normal-weight counterparts , 9, 10. Although reports are increasing regarding the roles of altered energy metabolism during tumor progression, including AML tumorigenesis, studies focusing on fatty acid metabolism in this process remain relatively rare, and the molecular mechanisms associated with fatty acid metabolism and the tumorigenic properties of AML progenitors or LSCs are poorly characterized .Interestingly, while it triggers various adaptive mechanisms that contribute to survival of AML cells, inhibition of FAO disrupts metabolic homeostasis, increases reactive oxygen species (ROS) production, and causes apoptosis in AML cells . Therefo2 that are oxidized in the electron transport chain to produce ATP  followed by ligation of PPARγ. Activated PPARγ then induces downstream target genes, including tic BCL2 . In facttic BCL2 , 26.In mitochondria, fatty acids that are consumed in FAO are imported in to the matrix by uncoupling protein 2 (UCP2), which can cause mitochondrial inner membrane uncoupling with the proton motive force dissipated as heat . Mitocho2+ influx via AdipoR1is necessary for the activation of AMPK  , which i of AMPK . BM adip of AMPK . HSPs th of AMPK , supportLSCs are a subpopulation of AML cells in the BM microenvironment that become resistant to drugs by entering a quiescent state, which is induced by growth factor signaling, epigenetic regulation, and altered metabolism , 39. FAOBM-resident LSCs exposed to adipocytes also exhibit a pro-inflammatory phenotype inducing lipolysis in vicinal adipocytes that further fuels FAO in the leukemic cells .Adipocytes support survival and growth of various types of tumor cells including prostate and breast cancers by stimulating mitochondrial metabolism in tumor cells due to high energy lipid transfer , 45. Niede novo from AML patients were dependent on amino acid metabolism for oxidative phosphorylation , a key therapeutic target, hydrolyzed plasma asparagine and glutamine to disrupt metabolic homeostasis. ASNase also induces a compensatory increase of FAO and cellular respiration to overcome metabolic stress, and the inhibition of FAO by etomoxir markedly increased the sensitivity of acute lymphocytic leukemia (ALL) cells to ASNase .in vitro and in vivo  cells. The fatty-acid derivative and FAO inhibitor AIC-47 reversed the TKI-induced upregulation of FAO and exhibited synergic cytotoxicity with imatinib , 64. In  in vivo . These fHere we have described recent evidence for the role of fatty acid metabolism and FAO in AML survival in the adipocyte-rich BM microenvironment. Metabolic alterations in leukemia cells have drawn increasing attention as an important therapeutic objective, and encouraging results with reagents that targeting fatty acid metabolism have been achieved in preclinical leukemia models. Leukemic cells may be critically dependent on certain metabolic pathways as their molecular heterogeneity suggest. Hence, the metabolism changes in leukemia cells vs. their normal hematopoietic counterparts can be used to generate a therapeutic window of selective sensitivity for the tumor cells. Nevertheless, tumor cells can adapt quickly to nutrient deprivation via activation of multiple metabolic bypass processes with support by their microenvironment. In this manner, FAO inhibition triggers various adaptive mechanisms that enhance AML survival in the BM, suggesting the inadequate usefulness of FAO inhibitors when used as alone . AlternaIn conclusion, recent studies have highlighted the importance of understanding AML cell metabolism in the BM microenvironment, and emphasize the potential of drug combinatorial strategies aiming at metabolic vulnerabilities of resistant AML cells and LSCs. The metabolic adaptation of AML cells and the variation of fatty acid metabolism signify an attractive therapeutic target for use against hematological malignancies. Emphasis should be placed on ROS as the executioners of cytotoxicity by metabolism-targeting therapeutics, and predictive biomarkers of response to these drugs should be explored, since both are critical to improving clinical outcomes. More comprehensive mechanistic findings from future studies may reveal that therapeutic targeting of fatty acid metabolism and FAO, especially in elderly patients with increased adiposity in the BM microenvironment, will hopefully increase the efficacy of related chemotherapeutic agents as well as reduce their toxicity.All authors have contributed to the preparation of the manuscript and reviewed/approved it in its final form.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.


New corona virus disease COVID-19 is a pandemic outbreak viral infection that is highly contagious. The disease can affect any age groups. Majority of patients show mild or no symptoms. Immunocompromised patients and patients with co-morbidities are more vulnerable to have more aggressive affection with higher rate of complications. Thus, cancer patients carry a higher risk of infection. Diseased patient can transmit infection throughout the disease course starting from the incubation period to clinical recovery. All healthcare workers contacting COVID-19-positive patients are at great risk of infection, especially the anesthesiologists who can be exposed to high viral load during airway manipulation. In the National Cancer Institute of Egypt, we apply a protocol to prioritize cases where elective cancer surgeries that would not affect patient prognosis and outcome are postponed during the early phase and peak of the pandemic till reaching a plateau. However, emergency and urgent surgeries that can compromise cancer patient’s life and prognosis take place after the proper assessment of the patient’s condition.This review aims to spot the management of cancer patients undergoing surgery during the COVID-19 pandemic in the National Cancer Institute, Egypt. All age groups are susceptible to infection by COVID-19, but a high rate of complications usually occurs with immunocompromised patients and older patients with co-morbidities  is considered a community crisis that threatens the world nowadays Singhal . The Wor Singhal , 2020b. The disease may present by variable clinical manifestations like fever, cough, shortness of breath, sore throat, rhinorrhea, headache, chest pain, diarrhea, nausea, and vomiting  was first discovered in Wuhan city, China  .Clinical presentations range from asymptomatic or mild symptoms to severe disease-causing death  reverse transcription-polymerase chain reaction (RT-PCR) on respiratory tract specimens  is usually the first responding antibody eliminating pathogens before sufficient immunoglobulin G (IgG) is produced, while IgG serves as the most robust antibody-based immunity   pandemic, it was reported that they present with similar features to the general population, except for anemia and hypoproteinemia, which are more frequently found in this cohort. Both could be considered a major consequence of nutritional deterioration in cancer patients, which may adversely affect immunocompetence and increase the susceptibility to respiratory pathogens  examination especially with an initial false-negative reverse transcription-polymerase chain reaction (RT-PCR) results Xie , 2020b. Chest radiographs are of little diagnostic value in early stages, as it has a high specificity of up to 90% but a low sensitivity of about 25% for detection of COVID-19-related lung opacities, whereas CT findings may be present even before symptom onset  (88%), bilateral involvement (88%), posterior distribution (80%), multi-lobar involvement (79%), and peripheral distribution (76%); however, consolidative opacities (32%) mainly present in the elderly population Xie . Other CElective cancer surgeries not affecting patient survival or disease prognosis are postponed during the peak and allowed during the plateau for proven COVID-19-free patients. Surgical treatment of cancer patients should be time sensitive with prioritization of emergency cases during the pandemic peak when all the health care workers and resources are consumed in the management of COVID-19-positive patients , and surgery is their primary mode of treatment and postponing their surgeries would likely affect their survival or results in the advancement of their cancer stage or significantly affect their outcome.Breast cancer: Surgery is considered urgent for cases of malignant phyllodes, patients with progressive disease on chemotherapy, and angiosarcoma  should undergo urgent surgery if the patient is symptomatic or has bleeding. Very early stages of gastric cancer that can undergo endoscopic resection are better to be managed by endoscopy if available. Early gastric cancers should be managed by surgery , Fig. The patient is considered highly suspected COVID-19 if there is a history of traveling from high-risk areas, contact with cases of proved COVID-19 or contact with patients who have fever or respiratory symptoms within 14 days, and clustered cases onset, in addition to at least two clinical presentations of fever and/or respiratory symptoms, radiological features of pneumonia, a normal or decreased (white blood cell) WBC count, normal or decreased lymphocyte count in the early stage of onset  will assess the patient as follows: assessment and evaluation of respiratory status through checking arterial blood gasses, X-ray, and/or CT chest radiography; full assessment of airway; and assessment for signs of shock or organ failure. Patients can present at the time of assessment with fever, chest crepitations, wheezing, and desaturation. Complete blood count, CT chest, liver function, and renal function tests should be requested.General or regional anesthesia can be performed according to the site of surgery and patient’s condition, provided normal coagulation profile, platelet count, and function.Performing regional anesthesia is better adopted whenever possible, thus avoiding airway manipulation and consequently reducing exposure to aerosols during coughing  emerged as a crisis that was stated to be a pandemic by WHO. Cancer patients are more vulnerable to get infected with more morbidity and mortality. Judgmental evaluation and management of each cancer patient should be considered during the pandemic especially during the peak of the disease. Elective cancer surgeries that can be delayed without threatening the patient’s life or prognosis should be postponed till the plateau is reached; however, emergency and urgent surgeries that can affect the patient’s life or prognosis should take place. All healthcare workers especially the anesthetists are at great risk for infection. Full precautions and strict adhesion to infection control measures must be adopted.


Epilepsy affects about 1% of the world’s population, and up to 30% of all patients will ultimately not achieve freedom from seizures with anticonvulsive medication alone. While surgical resection of a magnetic resonance imaging (MRI) -identifiable lesion remains the first-line treatment option for drug-refractory epilepsy, surgery cannot be offered to all. Neuromodulatory therapy targeting “seizures” instead of “epilepsy” has emerged as a valuable treatment option for these patients, including invasive procedures such as deep brain stimulation (DBS), responsive neurostimulation (RNS) and peripheral approaches such as vagus nerve stimulation (VNS). The purpose of this review is to provide in-depth information on current concepts and evidence on network-level aspects of drug-refractory epilepsy. We reviewed the current evidence gained from studies utilizing advanced imaging methodology, with a specific focus on their contributions to neuromodulatory therapy. Epilepsy affects about up to 1% of the world’s population . The twoDespite its efficacy, resective surgery cannot be offered to all patients with refractory seizures. Specifically, bilateral or multifocal seizures, proximity to or overlap of the ictal zone with eloquent cortical areas, and lack of distinctive imaging abnormalities represent potential surgical contraindications . MoreoveNeuromodulation refers to the process of electrically or chemically altering signal transmission of the central nervous system through implantable devices to excite, inhibit or modify neuronal activity, to elicit therapeutic effects . It is aFrom a basic perspective, a network is formed by a given number of items that exhibit pairwise associations . The braFunctional connectivity is usually estimated from statistical relationships of neurophysiological signals between brain regions , with tinodes (brain regions) connected by edges , demonstrating dense internal connectivity, but relative segregation from the rest of the network. By analyzing metrics of centrality, nodes with high degrees of connectivity and prominent roles can be identified, which are thus referred to as hubs. Measures of local efficiency, such as clustering coefficient, reflect connectional density within the local environment, whereas path length describes the average number of connections between nodal pairs assessing efficiency of information flow at a global scale [small world characteristics of brain networks in healthy individuals exhibiting short paths and high clustering [Graph theory offers a powerful framework for the mathematical representation and analysis of complex systems and allows for the quantification of organizational patterns of brain networks . In grapal scale . These mustering , a confiAnother relevant parameter, particularly in epilepsy, stems from the relative importance of a node within a specific network, i.e., centrality . MeasureControllability may be another metric of interest in epilepsy, as it measures the ability to exert control, i.e., induce transition from an initial state to a desired final state. Sparse inhomogeneous networks, which are often found in real-world complex systems, have proven to be most difficult to control, whereas dense and homogeneous networks can be controlled using a few driver nodes .Finally, it should be noted that, irrespective of the investigated modality, a functional core of any human brain network is likely formed by associations between high-centrality nodes of an underlying structural network, thus displaying high overlap between these conceptually separate domains .Clinical manifestations of seizures likely involve similar large-scale brain networks active during the inter-ictal state . A netwoTemporal lobe epilepsy (TLE) is the most commonly studied syndrome from a network-level perspective. Recent studies have revealed widespread structural  and funcWhile a structural brain lesion is considered the core of the epileptogenic focus , extra-lPatients who require neuromodulatory treatment for unfavorable seizure control likely exhibit a distributed seizure network with rapid propagation; seizures may be bilateral or even multifocal . Longer The therapeutic principle of DBS is the direct modulation of pathological activity within certain brain networks , thus maVarious structures have been targeted by DBS for the treatment of refractory epilepsy in the recent past; however, robust evidence from randomized controlled trials currently only exists for two targets, i.e., the anterior nucleus of the thalamus (ANT)  and hippEvidence from the landmark Stimulation of the Anterior Nucleus of the Thalamus in Epilepsy (SANTE) trial  revealedSelection of stimulation parameters form a critical part of any successful DBS application. Besides the SANTE trial, only small cohort studies have reported data on stimulation settings. Usually, starting frequencies were set between 90 and 185 Hz, with a pulse width between 60 and 150 μs and amplitudes between 1 and 10 V; most studies utilized alternate cycling. Importantly, most studies described adjustments made at the “physicians discretion” . ClearlyAs in other applications of DBS, both target selection and precision of electrode placement are crucial steps for treatment success. Ongoing development and refining of MRI acquisition protocols now allow for an accurate ANT visualization , which wYu and co-workers recently demonstrated desynchronization of large-scale epileptic networks following high-frequency ANT stimulation. Importantly, stimulation was found to suppress pathological HC seizure activity and disrupted connectivity across various cortical areas, leading to an overall reduction in seizure frequency . PreviouHigh-quality connectome datasets have already been harnessed to identify connectivity patterns associated with favorable treatment response in movement disorders . More reElucidation of specific hub-to-hub and network interactions harbors potential to significantly improve therapeutic response . InteresFinally, it should be noted that, despite its success and growing clinical use, DBS may not be universally offered to all patients with refractory seizures who are ineligible for resective surgery. Although evidence on ideal candidate selection is still very limited, contraindications to ANT-DBS therapy in epilepsy generally include progressive disease etiologies, coexisting psychiatric disorders, frequent psychogenic seizures, MRI and surgical contraindications as well as poor patient compliance. It is thus critical to conduct interdisciplinary case discussions to weigh the expected benefits against potential risks of ANT-DBS treatment in order to define realistic therapy goals .Responsive neurostimulation (RNS) constitutes another form of implantable electrical current delivery. Contrasting the open-loop concept of DBS, RNS  is event-triggered and delivers stimulation after detection of predefined seizure biomarkers based on electrocorticography (closed-loop) . The devDespite its success, several challenges remain for routine RNS utilization, which need to be addressed in future studies. Adequate target localization and definition of the stimulation zone is crucial for successful RNS therapy. Many centers use bilateral depth electrodes for these purpose, an invasive and risky procedure which offers limited sampling . MoreoveVagus nerve stimulation (VNS) differs in many ways to the two highly invasive methods outlined above. First and foremost, VNS is targeted towards the peripheral part of a cranial nerve, thus carrying fewer risks than any other treatment involving a craniotomy. With >100.000 implanted devices, VNS has emerged as an effective, safe and well-tolerated intervention for certain patients with intractable seizures, particularly children with partial or generalized epilepsy . HoweverSignificant progress has been made in recent years in the understanding of the neurobiology underlying VNS response. While initial attempts mostly relied on protein detection and enzyme tracing methods, multimodal neuroimaging now allows for an increasingly detailed characterization of the “vagus afferent network” (VAN), leading to the identification of critical brainstem nuclei and circuitry . Given iBy combining connectomic profiling with machine learning, Mithani and co-workers were able to establish predictive factors for VNS treatment response. The authors harnessed both functional and structural connectivity data in combination with support-vector-based machine to accurately predict treatment response . EfficacEnhanced connectivity between the thalamus, anterior cingulate and insular cortices has been associated with better response to VNS . FurtherNeurostimulation has emerged as an efficacious, safe and well-tolerated treatment modality, thus greatly enhancing the neurosurgeon’s armamentarium, especially for patients where curative surgery is not possible or might have failed. While significant advances have been made in neurostimulation, no single modality has yet reached the effectiveness of resective surgery. Notwithstanding its proven clinical effectiveness, neurostimulation still faces significant challenges. Most importantly, candidate selection for ANT-DBS and RNS has not been standardized as of yet and largely depends on institutional procedures; indeed, robust guidelines currently only exist for VNS. Future research should therefore be directed at advancing our understanding of epileptogenic networks, facilitating development of robust biomarkers to allow for defined selection criteria and formulation of guidelines. Network-informed neurostimulation and individualized connectomics nevertheless harbor the potential to greatly improve the seizure outcome in difficult-to-treat epilepsies.


After vigorous growth through the last decades, aquaculture industry reached a key milestone in 2014 when the aquaculture contribution to the supply of fish for human consumption overtook that of wild-caught fish for the first time. Fast developing aquaculture has achieved potential to feed 9.7 billion people by 2050 in a context of climate change, economic and financial uncertainty, and growing competition for natural resources FAO, . HoweverImportant progress has been made with genetic markers to support breeding schemes in the past decades, but now the flourishing applications of the next generation of genome sequencing technologies enables a further and bigger leap ahead. The genomes of more and more aquaculture species have been sequenced or are being sequenced, which facilitate the fast development of genome-scale technologies and tools. Genomic tools and resources combined with new more sophisticated bioinformatic tools are now available for many major aquaculture species, including reference genome sequences and their annotations, genome-wide polymorphic markers and genotyping platforms, high-density and high-resolution linkage maps, transcriptomic resources, and more recently, breakthrough techniques for understanding regulatory mechanisms underlying gene expression. Genomic scale fine mapping and genetic regulation of important performance traits, such as disease resistance, growth rate, sexual determination, and tolerance to various environmental stressors, have been studied for better understanding the regulatory mechanisms. Genome information supporting selective breeding programs have been initiated and are prepared to apply in many key aquaculture species.It is our great pleasure that this Research Topic is presented to its readers. The present Research Topic focusing on genetic dissection of important traits in aquaculture collects 36 articles including two review articles and 34 original research articles from a total of 305 authors. The contributions cover diverse aquaculture species of finfish, shellfish, shrimps, crabs, and algae, representing the latest progress on genetic dissection of economically important traits with genome-scale tools and technologies. Herein we classified these articles into different topics to be highlighted.Lateolabrax maculatus)  and three draft genomes of Sterlet sturgeon (Acipenser ruthenus) , Kanglang white minnow (Anabarilius grahami) , and a brown algae (Saccharina japonica) . Linkage maps have been considered as the traditional genetic tool for trait dissection and construction of highly-dense chromosome-scale maps is addressed in several contributions. Three high-density linkage maps, for mud crab (Scylla paramamosain) , black tiger shrimp (Penaeus monodon) , and channel catfish   respectively, were constructed based on Restriction Site associated DNA sequencing (RAD-seq or derivative methodologies). Sex- and growth-related traits are mapped in these three new linkage maps accordingly. The increasing genome resources and tools will facilitate genetic studies on important traits to tackle genomic selection in those aquaculture species.Developing genome resources and genome-scale genetic tools constitute a fundamental step for genome-wide genetic analysis. In the past decade, reference genomes of aquaculture species have been quickly assembled linked to the advances in genome sequencing technologies and assembly algorithms as well as computation power enhancement. Four new reference genomes are reported in this issue, including a chromosome-level reference genome of Chinese Seabass (Carassius carassius), X-Ray tetra (Pristella maxillaris), tongue sole (Cynoglossus semilaevis), sea urchin (Strongylocentrotus intermedius), and Pacific oyster (Crassostrea gigas) treated at differential temperature and salinity or presenting significant differences in growth performance or ploidy are reported in this issue . Additionally, comparative genomics and phylogenetic analysis of immune-related genes aid at understanding of the structure and function of the immune system of Senegalese sole  . Non-coding RNAs play important roles in transcriptome and translation regulation. Investigation on sncRNA, circRNA and miRNA was conducted in European sea bass (Dicentrarchus labrax)  and turbot  , providing insights into the regulation mechanisms in these two species. DNA methylation, the most widely studied and most well-understood epigenetic modification, has been reported to play crucial roles in gene regulation processes, such as those related to sexual development. Piferrer et al. discuss the model of Conserved Epigenetic Regulation of Sex (CERS) and the use of CERS to make testable predictions on how sex is epigenetically controlled and to better understand sexual development primarily in fish. DNA methylation profiles in disease-resistant and disease-susceptible Chinese tongue sole against Vibrio harveyi infection are also compared and the results highlight that artificial selection for disease resistance may change methylation levels in important immune-related genes .Comparative transcriptomics is an effective approach to compare gene expression profiles between different samples that are challenged with different conditions or exhibit distinct phenotypes, which provides insights into molecular functions and biological processes underlying target traits. Comparative transcriptomics in tilapia, Chinese seabass, crucian carp  and black tiger shrimp  via QTL mapping with high-density genetic linkage maps. Disease resistance is critical for aquaculture species, and resistance traits against sea lice, myxozoan parasite Enteromyxum scophthalmi and acute hepatopancreatic necrosis disease (AHPND) in Atlantic salmon  , turbot , and Pacific white shrimp (Litopenaeus vannamei)  are respectively reported. GWAS on very diverse traits including growth, body shape, feed conversion ratio (FCR), filet quality, polyunsaturated fatty acids (PUFAs) content and glycogen content are also reported, indicating that this is a key and active research field in aquaculture .Many economically important traits in aquaculture are quantitative traits. Quantitative trait loci (QTL) mapping and genome-wide association studies (GWAS) are primary approaches to dissect the architecture of such traits, and to identify genomic regions, the underlying genes and eventually causative mutations that contribute to trait variation. Recent advances in high-throughput genotyping technologies facilitate more accurate trait dissection in many aquaculture species using GWAS and QTL mapping. Here we collect a number of articles under this topic, representing over one third of all contributions. Sex determination loci and candidate genes are identified in channel catfish  populations in Latin America using a 50K SNP panel, and population genetic analysis revealed short-range LD decay for three populations.Research communities in some aquaculture species have developed high density SNP genotyping arrays, which expedite population genomic studies and germplasm evaluation of those species. Palaiokostas et al. on KHV resistance breeding in common carp. Flourish applications of genome selection are expected on more and more farmed species in aquaculture industries in the foreseeable future. In addition to genome selection, Wang, Yang et al. highlight their findings on generating goldfish-like fish via interspecific hybridization of female koi carp × male blunt snout bream and indicate the potential to form new species.Abundant genome resources, well-established genotyping technologies and well-characterized germplasms have boosted genome selection applications on the aquaculture species, as it is demonstrated in this issue by Overall, advances of genomic technologies and their quick applications are accelerating genetic dissection of important traits in many aquaculture species. The better understanding of the genetic basis and gene regulations of economically important traits will further expedite genetic improvement using diverse approaches, and ultimately ensure the fast and sustainable growth of aquaculture industries globally.We hope the aquaculture community will find this Research Topic to be an informative and useful collection of articles. As editors of this topic, we would like to thank the authors for their contribution to novel knowledge of this topic. We are grateful to all referees for their careful evaluation of the papers sent to them. Appreciation is also expressed to the numerous colleagues who responded to the call for papers, but whose interests could not be accommodated within the confines of this Research Topic. Finally, we glad to acknowledge Frontiers in Genetics for supporting this Research Topic.PX prepared the draft editorial. LD, PM, and GY revised the manuscript. All authors contributed to the article and approved the submitted version.PX was employed by the company Ningde Fufa Fisheries Company Limited. The remaining 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.