Inhibitory neurons play a fundamental role in the normal operation of neuronal networks. Diverse types of inhibitory neurons serve vital functions in cortical networks, such as balancing excitation and taming excessive activity, organizing neuronal activity in spatial and temporal patterns, and shaping response selectivity. Serving these, and a multitude of other functions effectively requires fine-tuning of inhibition, mediated by synaptic plasticity. Plasticity of inhibitory systems can be mediated by changes at inhibitory synapses and/or by changes at excitatory synapses at inhibitory neurons. In this review, we consider that latter locus: plasticity at excitatory synapses to inhibitory neurons. Despite the fact that plasticity of excitatory synaptic transmission to interneurons has been studied in much less detail than in pyramids and other excitatory cells, an abundance of forms and mechanisms of plasticity have been observed in interneurons. Specific requirements and rules for induction, while exhibiting a broad diversity, could correlate with distinct sources of excitatory inputs and distinct types of inhibitory neurons. One common requirement for the induction of plasticity is the rise of intracellular calcium, which could be mediated by a variety of ligand-gated, voltage-dependent, and intrinsic mechanisms. The majority of the investigated forms of plasticity can be classified as Hebbian-type associative plasticity. Hebbian-type learning rules mediate adaptive changes of synaptic transmission. However, these rules also introduce intrinsic positive feedback on synaptic weight changes, making plastic synapses and learning networks prone to runaway dynamics. Because real inhibitory neurons do not express runaway dynamics, additional plasticity mechanisms that counteract imbalances introduced by Hebbian-type rules must exist. We argue that weight-dependent heterosynaptic plasticity has a number of characteristics that make it an ideal candidate mechanism to achieve homeostatic regulation of synaptic weight changes at excitatory synapses to inhibitory neurons. Inhibition in cortical networks serves a multitude of functions, including balancing and restricting the spread of excitation . A candidate mechanism that fulfills these requirements is calcium-dependent heterosynaptic plasticity. Therefore, we next consider calcium sources that can trigger plasticity in interneurons and evidence for heterosynaptic plasticity, including a novel form of weight-dependent heterosynaptic plasticity that we have recently described for major electrophysiological types of inhibitory neurons. Finally, we discuss how these diverse forms of plasticity might affect the overall excitatory drive of inhibitory neurons, and which of these forms of plasticity could contribute to homeostatic regulation of synaptic weights of excitatory inputs to inhibitory neurons.Research into plasticity of excitatory synaptic transmission to inhibitory neurons has revealed that mechanisms of plasticity can be connection-specific, i.e., determined by the identity of both the presynaptic and postsynaptic cells. Therefore, the description of plasticity studies below is organized both historically and by specific connections, defined by the location of interneurons and the source of axons forming the synapses. Throughout the description, we accentuate two further points that are important for the purposes of this review. First, that outcome of plasticity experiments is typically not uniform, implying that, in addition to the type of connection and detail of the plasticity induction protocol, further factors are involved in determining whether the result will be long-term potentiation (LTP), long-term depression (LTD), or no change. Second is the issue of input specificity of plastic changes. Because heterosynaptic plasticity might play a central role in balancing synaptic changes, we point to evidence for heterosynaptic changes even when considering results of studies aimed at investigation of homosynaptic plasticity . Co-occurring alongside homosynaptic plasticity is heterosynaptic plasticity, defined as changes at inputs that were not stimulated during the induction protocol .Two main protocols are most commonly used for the induction of long-term plasticity of synaptic transmission: afferent tetanization and pairing. Either protocol can induce only at activated synapses and not at any other of the hundreds or thousands of synapses on the postsynaptic neuron, only a few of which were contributing to the tested heterosynaptic response. Assessing changes at all unstimulated inputs is technically intractable. At the same time, all studies that specifically addressed changes at nearby synapses found that input-specificity breaks down at short distances  or selective mGluR1a antagonists  neurons from CA1 str. pyramidale required [Ca2+]i rises, thus restricting plasticity to the activated synapses, it was proposed that, in aspiny dendrites, input-specificity of plastic changes might be compromised. Indeed, direct tests revealed a lack of input specificity of synaptic changes in CA1 inhibitory neurons  different from those known for pyramidal cells, e.g., NMDA-independent , this form of plasticity was called “anti-Hebbian” , morphology , and pattern of expression of characteristic proteins  revealed further diversity of plasticity rules in interneurons , calcium-permeable AMPA-receptor channels (CP-AMPAR), and calcium-impermeable AMPA receptor channels (CI-AMPAR). The proportion of CP/CI AMPARs and of AMPARs/NMDARs varies across synapses . At spine synapses, the canonical source of calcium entry that can trigger synaptic plasticity is through NMDARs, and the spike neck helps to restrict the spread of intracellular calcium.Synaptic current and influx of calcium through the NMDARs and CP-AMPARs have distinct dependence on voltage (rightmost plot). Owing to a magnesium block at hyperpolarized potentials, opening of NMDAR channels requires both binding of glutamate to the receptor and depolarization to relieve the pore from magnesium block. This combination of requirements makes NMDAR a “coincidence detector” for coordinated presynaptic activity that supplies glutamate and postsynaptic activation that depolarizes the dendrite. CP-AMPARs are blocked at depolarized potentials by intracellular polyamines  subunit. AMPARs at synapses in excitatory neurons contain an edited GluRB subunit with positively charged arginine at a particular position of the pore-forming segment, which prevents calcium ions from passing through the pore. Inhibitory neurons, however, can express AMPARs that lack a GluRB subunit and are permeable for calcium. Because AMPARs are heteromers, the ratio of CP to CI AMPARs depends on the level of expression of the edited GluRB subunit  and also to differences in experimental conditions and plasticity induction protocols see  as well Box 3Representative stimulation protocols used to induce long-term plasticity in inhibitory neurons. Note that these protocols are same or similar to those used to induce plasticity in excitatory neurons , and high frequency stimulation (HFS) typically use strong stimuli that evoke spikes in the postsynaptic neuron.Theta-burst stimulation . A canonical form of HFS uses 100 stimuli at 100 Hz  consist of pairing subthreshold stimulation with postsynaptic spikes with specific, strictly defined relative timing to induce spike-timing dependent plasticity (STDP). Bursts of postsynaptic spikes, which are more effective at causing calcium influx into the cell, are typically used. In bursts of lower frequency, each presynaptic stimulus is paired with one postsynaptic spike  and calcium-impermeable (CI) AMPARs as well as NMDARs. The ratio of CP/CI-AMPAR expression covaried with the expression of NMDARs, forming a continuum from synapses with mostly CP-AMPARs and weaker and slower NMDAR-mediated components to synapses with mostly CI-AMPARs but a strong and fast NMDAR component . Blockade of additional calcium sources, such as mGluR1α receptors or calcium release from intracellular stores via IP3 receptor or ryanodine receptor-mediated cascades, resulted in induction of LTD instead of LTP. Expression of both LTP and LTD involved presynaptic mechanisms , the authors concluded that LTP in str. lacunosum/moleculare interneurons was input-specific  as well as plastic changes at synapses that were not active during the induction .2+]i rise and intracellular cascades leading to long-term plastic changes could be interneuron specific. For example, in dentate gyrus interneurons, LTP depends on CP-AMPARs , different plasticity rules were found at connections made by L2/3 pyramids onto either low-threshold spiking (LTS) or FS cells . Blockade of specific receptors to these neuromodulators could either prevent induction of plasticity altogether or mediate a switch between LTP and LTD.Plasticity in inhibitory neurons is regulated by major neuromodulators, including acetylcholine, noradrenaline, adenosine, and glutamate , but in only 6 out of 17 cells when [Ca2+]i rise was reduced by blockade of calcium-permeable ACh receptors  synaptic and other ligand-gated mechanisms; and (b) nonsynaptic, voltage-gated mechanisms, such as back-propagating action potentials and voltage-gated calcium channels, and then consider how the interaction of diverse mechanisms determines calcium dynamics in interneurons.2+]i in interneurons include influx through NMDARs, calcium-permeable AMPARs, and calcium-permeable AChR channels and mechanisms coupled to mGluRs.Ligand-gated mechanisms contributing to the rise of [Ca2+]i rise that can trigger long-term plasticity in excitatory neurons  contribute to [Ca2+]i in response to nicotine was mediated by both CP-AChRs and voltage-gated calcium channels ; however, these sets also can be systematically different at synapses made at the same neuron by axons originating from different sources (connection-specific). At individual synapses, the contribution of diverse mechanisms to the total [Ca2+]i rise vary markedly around the mean “connection-specific” values. Moreover, [Ca2+]i rise at synapses of the same interneuron may be mediated by different combinations of ligand-gated calcium sources  and calcium influx  that may lead to long-term plasticity will be triggered. Manipulations that change the dynamics of intracellular calcium or the availability of intracellular cascades triggered by calcium rises may change the outcome of plasticity induction, e.g., between LTP and LTD.To summarize, the requirement for [Ca2+]i rise to the thresholds necessary to induce long-term plasticity not only at activated synapses, but also at nonactivated synapses, leading to heterosynaptic plasticity. By definition, heterosynaptic plasticity refers to changes at synapses that were not presynaptically activated during the induction protocol  evoked by depolarizing pulses without presynaptic activity  as well as for the subpopulations of inputs to identified FS neurons and identified non-FS cells  of plasticity in interneurons that can be induced at synapses that were not active during the induction: heterosynaptic plasticity. Heterosynaptic plasticity can be induced by episodes of strong postsynaptic activity, evoked either purely postsynaptically by trains of depolarizing pulses  is to preserve an overall synaptic drive and avoid excessive input changes, which may lead to runaway activation or complete silencing of a neuron. In theoretical and model simulation studies, homeostasis of total synaptic drive is typically achieved by normalization: after each iteration of learning and changes of the weights at a subset of synapses, the weights of all synapses are adjusted so that their total sum (or squared sum) remains constant  is the time scale of the induction of synaptic changes. Hebbian-type plasticity is induced within seconds or minutes, and to effectively counteract the tendency for runaway dynamics imposed by these fast plastic changes, homeostatic mechanism(s) should operate on a compatibly fast time scale . To be successful, homeostatic mechanism(s) must be generic enough 2+]i. It has been argued, in the broad context of synaptic plasticity at excitatory synapses, that an emphasis on [Ca2+]i rise as the triggering mechanism of plasticity can offer improved explanatory value over a fixation on learning rules, such as STDP  as associative plasticity but at nonactive synapses. Because bursts of spikes induce [Ca2+]i rise in any type of interneuron tested so far  as well as the function of keeping weights of individual synapses in working range. Regardless, it is unlikely to be the only mechanism at work and additional mechanisms operating at the synaptic, cellular, and network levels might be involved in homeostatic regulation of activation of inhibitory neurons.Inhibitory interneurons exhibit unique morphology, electrophysiology, and patterns of protein expression, which clearly differentiate them from excitatory cells but, at the same time, are highly heterogeneous among themselves. This remarkable diversity of inhibitory neurons opens up an opportunity to address both cell-type and connection-specificity of plasticity rules as well as to distill basic rules common for all plastic synapses.Diversity of distinct roles played by specific types of inhibitory interneurons in neuronal networks allows us to ask whether there are specific rules and mechanisms of plasticity that help to refine that circuit function. At the level of microcircuits, this could be studied, e.g., by comparison of plasticity in feed-forward vs. feedback inhibitory systems, or plasticity in inhibitory neurons targeting the dendrites and, thus, shaping input integration in pyramidal neurons vs. interneurons targeting the axon and the soma of pyramidal neurons and, thus, controlling their output. At the level of larger-scale cortical networks, relevant comparison(s) could be between plasticity in groups of inhibitory neurons serving distinct functions, e.g., mediating feature selectivity, shaping temporal patterns of activity and rhythms, or controlling and restricting spatial spread of activity. Progress of research that defines specific subpopulations and types of inhibitory neurons serving these and other specific functions opens up opportunities to address these kinds of questions.2+]i rise and intracellular machinery, which can support multiple forms of plasticity. How do these diverse mechanisms and forms of plasticity interact at one synapse? Most of the research has been aimed at disentangling the effects of specific mechanisms while their interaction received little attention so far. A further step toward understanding synaptic plasticity in inhibitory neurons would require knowledge of forms and mechanisms of plasticity that can be induced by natural patterns of activity, typical for each specific type of inhibitory neurons. The ultimate answer to this question would require studies during natural activity in vivo and should include modulation of plasticity rules by natural brain states.Finally, achieving a better understanding of plasticity in inhibitory neurons has intrinsic value for the field of plasticity as a whole. One common motif of plasticity of excitatory inputs to inhibitory neurons discussed in this review is that individual synapses are typically equipped with mechanisms, such as distinct sources of [CaNB, MC and MV designed and wrote the manuscript.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.


Programmed cell death (PCD) depicts a genetically encoded and an orderly mode of cellular mortality. When triggered by internal or external stimuli, cells initiate PCDs through evolutionary conserved regulatory mechanisms. Actin, as a multifunctional cytoskeleton protein that forms microfilament, its integrity and dynamics are essential for a variety of cellular processes . Decades of work have broadened our knowledge about different types of PCDs and their distinguished signaling pathways. However, an ever-increasing pool of evidences indicate that the delicate relationship between PCDs and the actin cytoskeleton is beginning to be elucidated. The purpose of this article is to review the current understanding of the relationships between different PCDs and the actin machinery , in the hope that this attempt can shed light on ensuing studies and the development of new therapeutic strategies. Cell death, according to the recommendations of the Nomenclature Committee on Cell Death, can be classified into two big categories: accidental cell death (ACD) and programmed cell death (PCD)  or as part of linear double helical polymeric microfilaments called F-actin (filamentous)   receptor superfamily) and CD44 death receptors requires actin, which is instrumental for stimulating these death receptors to elicit the downstream apoptotic responses in Jurkat cells  and myosin V protein complex  enters and accumulates within the nucleus, thereby eliciting apoptosis. Interestingly, p53 nuclear translocation can be attenuated by the increase of actin polymerization in the cytosol, thereby mitigating p53-triggered apoptosis  with high affinity and inhibits its activity , a novel type II anti-CD20 monoclonal antibody, can induce lysosomal cell death in lymphoma cell lines  decorated with chromatin fibers, histones and anti-microbial proteins . CorticaThus, emerging evidence supports the idea that the actin cytoskeleton is crucial for NETosis. However, it is currently unknown whether other components in the actin machinery engage actively in NETosis regulation. Further studies should be conducted to decipher the deeper relationship between NETosis and actin.Aspergillus fumigatus, is based on F-actin-dependent exocytosis , a programmed cell cannibalism, dictates a cell engulfment process that a loser cell  invades and is generally killed by its neighboring cell (winner cell/host cell/engulfing cell) through a mechanism involving autophagy proteins and lysosomal enzymes, however, without caspase activation  Overhol. Matrix Recently, it has been recognized that three core compartmentalized ring-like structures are assembled and sandwiched between the winner and loser cells: the contractile actomyosin, the adherens junction and the mechanical ring (Wang et al., In general, these data underline the fundamental roles of the actin machinery in entosis.Parthanatos, which depends on PARP-1 activation, PAR signaling and mitochondrial AIF translocation, refers to a form of cell death pivotal in multiple neural diseases  Berger . Four crThus, there is limited knowledge about whether the actin machinery is directly involved in the regulation of parthanatos.− gene SLC7A11 (Kang et al., Ferroptosis is a form of programmed necrotic cell death with high lipid peroxidation as its leading feature . The deaNevertheless, it remains unknown whether the actin cytoskeleton and its regulatory proteins are highly involved in the ferroptosis process.+,K+-ATPase pump by chemical screening of autosis inhibitors (Liu et al., +,K+-ATPase by cardiac glycosides efficiently rescue autotic cell death. Intriguingly, it was recently found that the physical interaction between Na+,K+-ATPase and the autophagy protein Beclin 1 is essential for autosis (Fernandez et al., +,K+-ATPase pump (Cantiello, +,K+-ATPase alpha 1 subunit may interact with the F-actin severing protein Cofilin (Lee et al., +,K+-ATPase plasma membrane retention through a protein called α-Adducin, which affects endocytosis and actin polymerization (Torielli et al., +,K+-ATPase alpha 1 subunit (Dash et al., +,K+-ATPase presents both on the plasma membrane and on the inner nuclear membrane (Garner, Autosis is a specific form of autophagy-dependent cell death induced by starvation or an autophagy-inducing cell-permeable peptide, Tat-Beclin 1  Liu et . Autosis Garner, .In all, the participation of the actin machinery in autosis remains inconclusive, but it is worth more efforts to dig deeper into their relationship.Most recently, a promising PCD called “Alkaliptosis” was discovered, which is caused by intracellular alkalinisation (Song et al., in vivo ozone-exposure mice model, is considered an anti-inflammatory form of regulated cell death in response to toxic levels of ROS (2O2-induced oxeiptosis cells also showed membrane blebbing (Holze et al., Oxeiptosis, initially found from an s of ROS  (Holze es of ROS . During s of ROS . PGAM5 is of ROS . Moreoves of ROS . Additios of ROS . IntriguTogether, these limited studies indicate that oxeiptosis could be well-associated with the actin machinery. However, due to the short discovery time from 2018, the direct relationship between oxeiptosis and the actin cytoskeleton remains underexplored.Programmed cell death plays instrumental and indispensable roles in embryonic development and disease progression in living organisms. To date, more than eleven kinds of PCDs are identified. However, the detailed mechanisms of most PCDs remain largely unclear. Different forms of PCD possess distinct signaling pathways, but interestingly, some of them may converge at a few common regulators. The actin cytoskeleton, a highly conserved and dynamic core cellular machinery, plays pivotal roles in a plethora of cellular processes, including morphogenesis, differentiation, cell motility, cell division, cytokinesis, membrane trafficking, etc. In the present review, we focus on the links between PCDs and the actin machinery proteins . Clear aIt is noteworthy that actin and a number of proteins involved in the actin machinery exist both in the cytoplasm and the nucleoplasm. While the cytoplasmic actin machinery claims its emerging role in PCDs, it remains mostly unclear whether the nuclear actin machinery is involved. Therefore, research surrounding the connections between PCDs and the nuclear actin machinery should be a high priority for exploration in the future.Most of the current observations have so far employed techniques dissecting the actin machinery and PCDs in fixed cells. However, life is not static. Future research should utilize time-lapse imaging to unravel the dynamic spatial-temporal relationship between the actin machinery and different PCDs in live cells.Readers should also notice that the discoveries about PCDs and the actin machinery mentioned in this review may be specific in some cell types or under specific conditions. Even the same actin depolymerization agent treatment may result in contrasting cell fates in different types of cells (Paul et al., Taken together, based on the studies mentioned above and given the profound roles the actin machinery plays in different PCDs, we hope that this review will stimulate further studies, and that bold guesses and hypotheses can be inspired and more secrets about PCDs and the actin machinery will be explored.WR, WZ, LC, and JH: conceptualization and writing—original draft preparation. JH: funding acquisition. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Mitochondrial function in endothelial cells (EC) is interconnected by a mesh of signaling molecules that cross pathways often . One sucvia several intermediates into coproporphyrinogen-III (CPO) by coproporphyrinogen oxidase (CPOX); CPO is then transported back into the mitochondria for the last two steps of the pathway. In the final step, ferrochelatase (FECH) incorporates ferrous iron into protoporphyrin IX (PPIX), synthesizing protoheme. Heme is then available to enable cellular processes by combining with enzyme subunits as a prosthetic group. For example, heme-iron is part of the catalytically active form of endothelial nitric oxide synthase (eNOS)  . Similare (eNOS) . Of coure (eNOS)  and somee (eNOS) .Apart from being a prosthetic cofactor for enzymes, heme’s regulated production ensures that active iron is sequestered before it can promote formation of reactive oxygen species (ROS) . Hence, FECH, was the first heme pathway component to be identified as a druggable target in pathological angiogenesis. FECH blockade  reduced proliferation, migration and endothelial tube formation in microvascular ECs. This effect was specific to ECs; FECH inhibition had a negligible effect on non-endothelial ocular cell proliferation. This anti-angiogenic effect was also seen in vivo: mice with a partial loss-of-function Fechm1Pas point mutation formed reduced neovascular lesions in the eye in the laser-induced choroidal neovascularization (L-CNV) model with features of wet AMD, as did mice with ocular Fech knockdown or inhibition  is able to normalize some of the mitochondrial physiology, like eNOS levels, complex IV activity, and ETC function . Effect ild-type , suggest to mice , highligOral supplementation of heme, while still achieving therapeutic antiangiogenic effects of inhibitors, could be considered . In ordevia inhibition of synthesis through intermediary enzymes or blocking heme transport (through FLVCR) provides for a novel therapeutic strategy, one that is primed to be explored in detail in vascular biology. Key questions that need to be addressed are: Is the role of heme in angiogenesis limited to ETC and eNOS or do other heme-containing proteins aid in anti-angiogenic effects? Which enzymes in the heme synthesis pathway are the most effectively targetable for treating pathological angiogenesis? What are the key differences in microvascular and macrovascular heme synthesis, and can we manipulate these therapeutically? Proliferative ECs appear to be particularly sensitive to heme loss, but is this sensitivity only relevant in vascular tissues? Most importantly, we also need to elucidate the contribution of heme and heme pathway intermediates in maintaining normal endothelial cellular physiology, to devise better strategies for future therapeutic interventions.Targeting intracellular heme, either TS, TC: wrote the paper, edited the paper, and approved final version.Related work in the Corson laboratory is supported by NIH/NEI R01EY025641, NIH/NCATS UL1TR001108, the Retina Research Foundation, the International Retinal Research Foundation, the BrightFocus Foundation, the Carl Marshall and Mildred Almen Reeves Foundation, and the Ralph and Grace Showalter Research Trust.TC is a named inventor on patent applications related to this topic.The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Ischemic heart disease is a common cause of end-stage heart failure and has persisted as one of the main causes of end stage heart failure requiring transplantation. Maladaptive myocardial remodeling due to ischemic injury involves multiple cell types and physiologic mechanisms. Pathogenic post-infarct remodeling involves collagen deposition, chamber dilatation and ventricular dysfunction. There have been significant improvements in medication and revascularization strategies. However, despite medical optimization and opportunities to restore blood flow, physicians lack therapies that directly access and manipulate the heart to promote healthy post-infarct myocardial remodeling. Strategies are now arising that use bioactive materials to promote cardiac regeneration by promoting angiogenesis and inhibiting cardiac fibrosis; and many of these strategies leverage the unique advantage of cardiac surgery to directly visualize and manipulate the heart. Although cellular-based strategies are emerging, multiple barriers exist for clinical translation. Acellular materials have also demonstrated preclinical therapeutic potential to promote angiogenesis and attenuate fibrosis and may be able to surmount these translational barriers. Within this review we outline various acellular biomaterials and we define epicardial infarct repair and intramyocardial injection, which focus on administering bioactive materials to the cardiac epicardium and myocardium respectively to promote cardiac regeneration. In conjunction with optimized medical therapy and revascularization, these techniques show promise to upregulate pathways of cardiac regeneration to preserve heart function. Ischemic heart disease is a common cause of end-stage heart failure that accounted for 38% of cardiac transplantation in the International Society of Heart and Lung Transplantation Database from 2005 to 2008, and has persisted as one of the main causes of end stage heart failure requiring transplantation from 1982 to 2012 . Heart fIn understanding ischemic heart disease, a brief review of the injurious cascade is beneficial. Pathologic myocardial remodeling due to ischemic injury involves multiple cell types and physiologic mechanisms. One key cell type is the cardiac fibroblast, an important modulator in both the structure and function of the heart. Playing a crucial role in extracellular matrix (ECM) regulation, cardiac fibroblasts modulate the rate of turnover and collagen deposition, both of which contribute to matrix dysregulation when upregulated. In an activated state, cardiac fibroblasts dysregulate the ECM by increasing ECM turnover via matrix metalloproteinase 9 (MMP-9) production and collagen deposition . MMPs arThe Renin-Angiotensin-Aldosterone System (RAAS) has been highlighted as a key mechanism that is activated by chamber distension. Increased levels of Angiotensin II promote cardiac fibroblast activation. Ultimately, this sequence results in a profibrotic state linked to eccentric hypertrophy, chamber dilatation and congestive heart failure. Neurohormonal adrenergic pathways may serve as short term compensation, but chronically upregulate RAAS and therefore fibroblast activation. Inflammatory cytokines such as TNF-α are overexpressed during heart failure and have been linked with increased MMP levels, contributing to ECM dysregulation and heart failure .Along with providing an initial insult that initiates the aforementioned pathways, ischemic injury results in endothelial injury and cardiomyocyte death, which induces the release of a variety of inflammatory cytokines including TNF-α, IL-1a, IL-1b, IL-6, and IL-8 . At thisIn recent years, acellular biomaterials have demonstrated potential for cardiac regeneration by promoting proangiogenic and antifibrotic pathways. Broadly, acellular biomaterials used in cardiac therapies are either derived from tissue sources or synthesized artificially. Though cellular therapies are gaining popularity and demonstrate promise in preclinical studies, clinical translation is accompanied with difficulties involving clinical effectiveness and feasibility . Acellul®, polytetrafluoroethylene, polyester-urethane, and textile grafts, but they will not be discussed in this review because they are not prepared from extracellular matrix components nor are they loaded with growth factors during manufacturing.Several commercially available patch biomaterials are composed of decellularized extracellular matrix (ECM) from multiple tissue sources. Numerous decellularization techniques are outlined in the literature; but they can be categorized as chemical , biologic , physical  and combinations of the aforementioned . ExampleOther than patch-based materials, hydrogels also show promise for cardiac regeneration. Like patch-based materials, they can be derived from multiple sources including but not limited to the extracellular matrix, recombinant collagen, proteoglycans, alginates, and synthetic polymers . These mHerein, we define and review promising surgical strategies that use acellular biomaterials to augment myocardial remodeling by promoting a pro-angiogenic and antifibrotic environment for improved post-infarct cardiac remodeling. We will focus on Epicardial Infarct Repair (EIR) and Intramyocardial Injection (IMI) because they are both procedures that can be used in conjunction with coronary artery bypass surgery to further improve cardiac function after revascularization. Additionally, with new materials entering this growing space, we will review preclinical evaluation modalities used to assess promising biomaterials for EIR and IMI.Epicardial infarct repair is an emerging surgical technique that involves placing bioactive patch materials on the epicardium via suture to modulate pathways toward regeneration , 2017. TEpicardial derived progenitor cells (EPDCs) may be key players in EIR-mediated regeneration because they can undergo epithelial to mesenchymal transition (EMT) to differentiate into myocardial cell types including fibroblasts, vascular smooth muscle cells, and possibly cardiomyocytes and endothelial cells . Thus, mIn vitro, acellular porcine SIS-ECM has promoted a quiescent, pro-angiogenic and antifibrotic fibroblast phenotype. The main pathway is thought to be through FGF-2 release, which inhibits pro-fibrotic TGF-B pathways  has been the most common unfixed biomaterial used in cardiac surgery, and it is one of the most extensively examined for use in cardiac regeneration. pathways . Previoupathways , b. In rpathways . Porcinepathways . Additiopathways . Having Glutaraldehyde fixation is a common strategy to prepare biomaterials in cardiac surgery but has not demonstrated promise for EIR in preclinical evaluation. Crosslinking caused by glutaraldehyde increases biomaterial tensile strength, allowing it to be useful in cardiac reconstruction. Glutaraldehyde materials, typically based from xenogenic or autologous pericardium, are commonly used in reconstruction of multiple structures in the heart including septal defects/ruptures between atria and ventricles, along with reconstruction of areas of the heart obliterated by infective endocarditis . For decin vivo models, focusing mainly on vascular and cardiac reconstruction have demonstrated that photofixed bovine pericardium is less immunogenic and calcific when compared to materials made from glutaraldehyde fixation  involves injecting hydrogels into the superficial myocardium to promote neoangiogenesis and attenuate pathologic remodeling . Figure Hydrogels are polymer-based networks that attract, contain and become swollen with water . They diInjectable ECM-based hydrogels have gained attention for IMI. These hydrogels incorporate micronized versions of acellular unfixed ECM materials used in EIR, which allows injection into the myocardium of different ECM components including collagen, proteoglycans and residing growth factors. Preclinically, it has been demonstrated in a mouse model that comminuted porcine SIS-ECM can be injected into a myocardial infarction model and both improve ejection fraction on echocardiography; also it reduced infarct size and upregulate neovascularization as demonstrated on histology . This stN-ethyl-N-(3-dimethylaminopropyl) carbodiimide and N-hydroxysuccinimide have promoted neovascularization and attenuated fibrosis in the border zones of infarcted areas , 2-Hydroxylethyl methacrylate (HEMA) and dextran improved neovascularization, decreases collagen deposition and improved cardiac function  were seeded to patch biomaterials and their arrangements were measured using imaging software; and those seeded onto bioactive materials demonstrated increased arrangement parameters representative of angiogenesis (Though not as well established, different ogenesis . Angiogeogenesis .ex vivo assessments of cardiac biomaterials (in vitro tissue culture (in vivo efficacy than 2D cell cultures (With more sophisticated cell culture techniques continuing to develop, microdevices are providing new opportunities for aterials . In an a culture . Tissue- culture . Co-cultcultures . Microflcultures . These mcultures . Larger cultures .In vivo models have also been used to evaluate biomaterials in both EIR and IMI. Rat infarct models have been used to assess cardiac function after addition of biomaterials using echocardiography, which can measure ejection fraction along with left ventricular end diastolic diameter, end systolic diameter and estimate LV mass (in vivo models, including mouse, rat and pig models; and these models facilitated evaluation by echocardiography and pressure volume loops, with the porcine models being compatible with MRI ( LV mass . Porcine LV mass . Both mo LV mass , 2017. Swith MRI . MRI alswith MRI .Histology and immunohistochemistry for neovascularization, scar deposition and presence of cardiomyocytes can be performed post-mortem . Given tGiven the early stages of both of these procedures, ideal characteristics of materials for both EIR and IMI can only be hypothesized. For both procedures, it would inherently be preferred to use bioactive materials that are able to modulate cellular activity and exosomes on order to recruit cells to promote regeneration. Additionally, given that many patients with end-stage heart failure receive subsequent procedures including transplant and ventricular assist device implantation, non-immunogenic and non-calcific materials may be beneficial to mitigate formation of intrapericardial adhesions, which would make redo surgery technically challenging and higher risk. In EIR, it would be preferable that materials do not impede diastolic relaxation, thus a balance between tensile strength and elasticity may be key. In IMI, viscosity may be important characteristic to examine because ideal hydrogels would be able to permeate from the multiple microinjection sites to cover the infarct zone and border zone but still be able to take a semisolid form for structural support. As well, rate of degradation may require consideration as more ideal hydrogels will be retained in the myocardium over the course of post-infarct healing.Bioactive materials that promote post-infarct cardiac regeneration present a game-changing opportunity to the field of cardiac sciences. Along with revascularization and medical management, surgeons can further guide healing by leveraging the unique opportunity to directly manipulate the heart. Reproducible evaluation strategies such as those discussed above will be needed for comparison, new pathways will continue to need to be explored and augmentation strategies may further enhance regeneration.Though EIR and IMI have both been developed to promote cardiac regeneration, there are key differences between these approaches. As EIR places a patch on the epicardial surface while IMI directly introduces a hydrogel that redistributes in cardiac tissue, these techniques demonstrate different levels of incorporation of biomaterials . No direIn terms of safety, initial preclinical experience in these techniques suggests they are both safe when performed appropriately. Current pre-clinical studies do not report complications related to sewing bioactive patches to the epicardium and there is currently a paucity of long-term data regarding mortality and stroke , 2017. AMultiple future directions exist in this field. As the field advances, it may be beneficial to examine other pathways through which biomaterials promote regeneration. Given that the RAAS and adrenergic neurohormonal pathways are known key pathways involved in heart failure, identifying ways to further manipulate them using biomaterials may enhance EIR and IMI . AugmentFuture uses of biomaterials for cardiac regeneration may extend beyond ischemic heart disease. It may be possible to apply these materials to cardiomyopathy unrelated to ischemic injury, to mitigate fibrosis and promote neoangiogenesis into cardiomyopathic areas. Thus, EIR and IMI may be useful to complement ventricular assist device insertion. As VADs decompress the heart and revascularization strategies will restore blood flow, application of bioactive materials in EIR and IMI will improve neoangiogenesis and antagonize fibrosis in more optimized conditions. With the waitlist mortality for cardiac transplantation increasing, cardiac regeneration therapies may help improve ventricular assist devices as destination therapy or bridge-to-recovery in patients, rather than bridge-to-transplantation . With fuAll authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.PF is a consultant for CorMatrix Cardiovascular Inc. PN is a partner with MDP Solutions. 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.


Over the past decade DL has regained popularity and has been successfully applied to such diverse fields as image , alsocalled deep structured learning or hierarchical learning, is an important subset of machine learning (ML). The distinction between DL and conventional “shallow” ML is that DL algorithms allow computational models composed of multiple processing layers to be fed with raw data and automatically learn multiple levels of abstract representations of data for detection and classification , 2 in Frontiers in Plant Science , 1 in Frontiers in Physiology , and 1 in Frontiers in Bioengineering and Biotechnology (Matsuzaka and Uesawa). These papers are well-split between human  or plant  disease diagnosis and chemical toxicity  or drug efficacy  prediction. CNN architecture dominated these studies, except three where autoencoder  or XGBoost  was employed. The input data varied from images  or converted images (Matsuzaka and Uesawa) to gene mutations , chemical molecular descriptors , phenotypes , physical examination records , and mixtures of different data profiles such as multi-omics data , chemical structures, human phenotypes, pathways, protein targets, and protein–protein interactions .Despite great success, there remain many technical challenges, one of which is how to integrate or transform subject-specific knowledge in order to adapt to DL algorithms and improve outcomes. Technical hurdles exist in data preprocessing, model selection , parametric function approximation , and model regularization and optimization. This Research Topic addresses these challenges and hurdles with a specific focus on the application of DL algorithms to chemical toxicity prediction and disease diagnosis, which has not been adequately explored  or distinguish drug-like compounds from common compounds . Luo et al. demonstrated that a CNN-based deepDriver could learn information within somatic mutation data and similarity networks simultaneously to enhance the prediction of cancer driver genes. A CNN-based, pixel-level semantic segmentation model was built for quantitative assessment of the severity of powdery mildew in cucumber leaves, achieving an average pixel accuracy of 96% . Xie et al. applied both CNN- and autoencoder-based DL and transfer learning techniques to automatically extract high-level abstract features from breast cancer histopathological images, which led to a significant improvement in cancer diagnosis. Zhang X. et al. reported a novel GroupNet model for multi-label chronic disease classification that outperformed other DL  and conventional ML  models.Optimization of existing DL-based tools:Fuentes et al. presented a two-tiered diagnosis system to address high false positive rates caused by class unbalance and variation. The system consists of a primary diagnosis unit that detects a set of bounding boxes that likely contain a disease in the image, a secondary diagnosis unit that verifies bounding boxes detected from the primary diagnosis unit using independent CNN classifiers trained with respect to each class, and an integration unit that combines the results from the primary and secondary units to effectively recognize 10 different types of diseases and pests in tomato. This system showed an improved recognition rate of 96%, 13% higher than previous work  analysis previously developed by Uesawa : Despite revolutionary breakthroughs, DL does not always provide better performance or superior solutions to any specific problem than cML. Such cML as Logistic Regression (LR), Random Forest (RF), and Naive Bayes (NB) were employed along with Deep Neural Network (DNN) to train classifiers with excellent precision (≥98%) and recall (up to 95%) for rare disease diagnosis implemented in a Rare Disease Auxiliary Diagnosis system . Idakwo et al. presented a case study where DNN and RF were compared with and without parametric optimization in terms of QSAR-based chemical toxicity prediction. Ji et al. compared XGBoost, a cML algorithm, with DeepSynergy, a DL algorithm, and other cML algorithms , and concluded that XGBoost outperformed other classifiers in both stratified five-fold cross-validation and independent validation in identifying synergistic or antagonistic drug combinations. These studies suggest that in the absence of large amounts of training samples , cML may be an alternative superior to DL in performance, as cML is less likely to over-fit and often computationally less costly. Even with available big data, DL algorithms need to be optimized to achieve outstanding performance . Furthermore, transfer learning was used in conjunction with DL to train a neural network model on a problem similar to the one being solved .Data preprocessing: In order to take advantage of the power of CNN, Matsuzaka and Uesawa converted SMILES text files into SDF image files, whereas Zhang X. et al. transformed physical examination records into multi-label class data using binary relevance and label powerset methods. Data rebalance techniques  and focal loss  or stratification  strategies were often performed to overcome the influence of skewed class distribution. Data preprocessing played a critical role in improving performance of DL- or cML-based classification.This collection of contributions highlights not only the promising outlook of DL applications in disease diagnosis and toxicity prediction, but also the necessity of optimizing DL algorithms in order to achieve superior outcomes. Given the remarkable success of DL application in classification problems, the focus of future efforts may now shift to quantification problems.PG proposed and edited this Research Topic. CZ and MC co-edited this Research Topic. All authors made a substantial, direct and intellectual contribution to this Editorial, and approved it for publication.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.


Compromised lung function is a feature of both infection driven and non-infective pathologies. Viral infections—including the current pandemic strain SARS-CoV-2—that affect lung function can cause both acute and long-term chronic damage. SARS-CoV-2 infection suppresses innate immunity and promotes an inflammatory response. Targeting these aspects of SARS-CoV-2 is important as the pandemic affects greater proportions of the population. In clinical and animal studies, fucoidans have been shown to increase innate immunity and decrease inflammation. In addition, dietary fucoidan has been shown to attenuate pulmonary damage in a model of acute viral infection. Direct inhibition of SARS-CoV-2 in vitro has been described, but is not universal. This short review summarizes the current research on fucoidan with regard to viral lung infections and lung damage. Lung function is critical to life. Intake of air results in gas exchange at the delicate sacs in the lung called alveoli. The blood vessels that pass through the lungs carry deoxygenated blood. Oxygen is replenished and carbon dioxide is expelled. The lining of the lungs, lung epithelial cells, and the smooth muscle cells that help sacs expand and contract, are pivotal to these gas exchange functions . ChronicThe recent surge of interest in respiratory viral effects on lung function is a result of the pandemic coronavirus, SARS-CoV-2 as well as prior coronaviruses SARS-CoV and MERS-CoV . VentilaBotryocladia occidentalis, and a highly purified fucoidan fraction from Saccharina japonica [Fucus vesiculosus and Undaria pinnatifida were not active in vitro [Dietary fucoidan has been shown to increase innate immunity in various models . In a cljaponica ,16. Howein vitro . In addiin vitro  althoughResearch work on lung damage attenuation and antiviral activity is continuing. In this mini-review, we aim to provide a snapshot of current fucoidan research with respect to lung function.Undaria pinnatifida enhanced vaccine responses [Influenza and Corona virus strains can develop resistance to conventional drugs, meaning that there is need for broad spectrum strategies. Seaweed metabolites have recently been reviewed for potential in influenza infection . Perieraesponses .A key feature of SARS-CoV-2 is a low initial innate immune response, allowing the viral infection to progress until a cytokine response becomes prevalent . The higRespiratory viruses including influenza, coronaviruses and RSV enter the respiratory system via receptor mediated mechanisms. Whilst some viruses attach to receptors in the upper tract, others tend to attach lower in the bronchi and the lung, depending on the cell surface receptors expressed . InfluenRecent research shows that fucoidan can restore a previously depressed lysozyme function in the gut , suggestFucoidans and other marine algal derived polysaccharides have shown direct inhibition of influenza virus entry to cells. This activity has been shown for fucoidan from different sources as shown in The recent pandemic with the Corona virus variant SARS-CoV-2 has been assessed in vitro with a variety of fucan, fucoidan, and heparin compounds. A key feature of COVID 19 infection is micro clotting, and the anticoagulant effects of heparin have proved lifesaving . HeparinFucus vesiculosus and Undaria pinnatifida, no activity was noted in an in vitro infection model [By contrast, in recent screening of unfractionated fucoidan from on model . There aChronic obstructive pulmonary disease (COPD) is a collective name for irreversible lung damage caused by chronic diseases such as asthma and bronchitis, smoking, and air pollution. The fibrosis induced by COPD leaves scars in place of functional lung tissue.Fucoidan may ameliorate a proportion of damage, acting as both an anti-inflammatory and inhibitor of epithelial-mesenchymal transformation. Fucoidan has been shown to protect against tobacco smoke MUC5 activation in bronchial cells  and inhiRespiratory viral infections can cause acute and chronic damage to the lung. The current pandemic corona virus SARS-CoV-2 inhibits innate immune responses and promotes strong inflammatory expression. Fucoidan preparations have potential as supplementary agents to limit damage subsequent to respiratory viral infections by restoring innate immune function and inhibiting inflammation. Additional studies are needed to explore this hypothesis. Direct in vitro inhibition of infection by fucoidan fractions in vitro is not universal. It remains essential to comply with public health information to prevent the spread of SARS-CoV-2 and other pathogens.


Pancreatic cancer is one of the most common malignant tumors of the digestive tract, and it has a poor prognosis. Traditional methods are not effective to accurately assess the prognosis of patients with pancreatic cancer. Immunotherapy is a new promising approach for the treatment of pancreatic cancer; however, some patients do not respond well to immunotherapy, which may be related to tumor microenvironment regulation. In this study, we use gene expression database to mine important immune genes and establish a prognostic prediction model for pancreatic cancer patients. We hope to provide a feasible method to evaluate the prognosis of pancreatic cancer and provide valuable targets for pancreatic cancer immunotherapy.We used univariate COX proportional hazard regression analysis, the least absolute shrinkage and selection operator, and multivariate COX regression analysis to screen 8 genes related to prognosis from the 314 immune-related genes, and used them to construct a new clinical prediction model in the TCGA pancreatic cancer cohort. Subsequently, we evaluated the prognostic value of the model. The Kaplan–Meier cumulative curve showed that patients with low risk scores survived significantly longer than patients with high risk scores. The area under the ROC curve  of the risk score was 0.755. The univariate COX analysis showed that the risk score was significantly related to overall survival , and multivariate analysis showed that the risk score was an independent prognostic factor . Correlation analysis found that immune genes are closely related to tumor immune microenvironment.Based on the TCGA-PAAD cohort, we identified immune-related markers with independent prognostic significance, validated, and analyzed their biological functions, to provide a feasible method for the prognosis of pancreatic cancer and provide potentially valuable targets for pancreatic cancer immunotherapy. Pancreatic cancer is a common malignant tumor of the digestive tract, which has the characteristics of difficult early diagnosis, rapid metastasis, and poor therapeutic effect. It is one of the most invasive and fatal malignant tumors in the world, and the prognosis is very poor. The five-year survival rate is less than 8% . SurgeryWith the increased understanding on the key role of immune system in the development of pancreatic cancer, immunotherapy such as chimeric antigen receptor T cell therapy and immune checkpoint inhibitor (ICBs) is very promising for the treatment of pancreatic cancer patients. Exciting results have been achieved in preclinical and clinical trials of pancreatic cancer , 6. HoweIn recent years, gene expression database has been used to mine valuable therapeutic genes, identify promising prognostic factors, and analyze the molecular mechanisms of various cancers. We used univariate Cox proportional hazard regression analysis, the least absolute shrinkage and selection operator (LASSO), and multivariate COX regression analysis to screen 8 genes related to prognosis from the 314 immune-related genes in the TCGA pancreatic cancer cohort. These can be used as the potential prognostic indicators of pancreatic cancer. The genes were used to establish the optimal risk model; survival analysis, univariate Cox proportional hazard regression analysis, and multivariate Cox proportional hazard regression analysis were used to evaluate the prognostic value of risk score. ROC curve and principal component analysis (PCA) were used to evaluate the accuracy of the model. Patients were divided into high-risk and low-risk groups according to the median risk score. Gene ontology (GO), Kyoto gene and genome encyclopedia (KEGG), and gene set enrichment analysis (GSEA) were used to explore the differences of key signal pathways between high-risk and low-risk groups. Single sample gene set enrichment analysis (ssGSEA) method was used to quantify immune cell infiltration, and the relationship between immune risk genes and tumor immune microenvironment was analyzed. The objectives of this study are to provide a feasible method to evaluate the prognosis of pancreatic cancer, to provide a powerful means of tumor prevention and treatment for regulating the body’s immunity against tumor, and to add new content in the development of new adjuvant drugs targeted at tumor immunotherapy.https://portal.gdc.cancer.gov/).IMMUNE_RESPONSE and IMMUNE_SYSTEM_PROCESS2 immune gene sets were obtained from Molecular Signatures Database (MSigDB), and a total of 314 immune-related genes were obtained. mRNA expression data and clinical data of 183 pancreatic cancer samples were obtained from the Cancer Genome Atlas (TCGA) database of pancreatic cancer. Then LASSO regression analysis was performed on these immune genes. LASSO regression analysis reduced the dimensionality of high-dimensional data by the sum of the absolute values of the limiting coefficients less than the predetermined value, and the variables with relatively small contributions will be given zero coefficients. Only the genes with non-zero coefficient in LASSO regression analysis were selected for further multivariate Cox regression analysis, and the resulting genes were used to build a predictive model. The risk score of each patient was calculated according to the mRNA expression level and risk coefficient of each risk gene, which was calculated by the following equation:Taking the median risk score as the cut-off value, the patients were divided into high-risk and low-risk groups for follow-up analysis.http://geneontology.org/), and the biological functions of different genes, including biological processes, cellular components, and molecular functions, were analyzed. The Kyoto Encyclopedia of genes and Genomes  analyzes a variety of biological information, including metabolic pathways, predicts the function of genes, and analyzes the roles of proteins and other macromolecules. The metabolic pathways and signal transduction pathways of significant enrichment in pancreatic cancer were revealed by pathway enrichment analysis (FDR < 0.05). Then, we performed Gene Set Enrichment Analysis  to reveal the signal pathways and biological processes in which differentially expressed genes were enriched between high-risk and low-risk subpopulations. The "ClusterProfiler" R package was used for visualization [The R language “EdgeR” package calculation was used to analyze the difference of mRNA between low-risk and high-risk groups. mRNA with FDR value less than 0.05 was annotated by Gene Ontology  samples. According to the immune cell marker genes, provided by Bindea et al. , we usedhttps://www.r-project.org/). R language "Survival" package and "survminer" package were used to draw Kaplan–Meier curve. Univariate and multivariate Cox proportional hazard regression analyses were also used to evaluate the relationship between risk scores and OS. ROC analysis was used to examine the sensitivity and specificity of survival prediction using the gene signature risk score. An area under the ROC curve (AUC) served as an indicator of prognostic accuracy. A P-value of less than 0.05 was set as statistically significant for all the analyses.All statistical analyses were carried out by R programming language  through single factor COX regression, Lasso regression, and multifactor COX regression, which significantly affects the prognosis of patients with pancreatic cancer Fig. . Some ofPrevious literatures have also reported similar findings. For example, Wei-Dong Shi identified 12 human pancreatic cancer highly metastatic cell lines, SW19 × 90HM cells, including ITGA7 through microarray analysis . MedichePathway analysis found that high-risk groups were significantly positively associated with well-known cancer signaling pathways such as hypoxia, glycolysis, epithelial-mesenchymal transition, MTORC1 signaling pathway, P53 channel, apoptosis, E2F Targets, MYC Targets V1, and MYC Targets V2. Hypoxia is a common feature of malignant tumors, which is the result of increased oxygen demand due to cancer cell proliferation, tumor vascular dysfunction, and insufficient blood supply. Hypoxic tumor cells mainly rely on glycolysis to obtain energy and participate in the process of tumorigenesis, metastatic invasion, and treatment tolerance. This existing research confirms that hypoxia can regulate tumor immune microenvironment by regulating a variety of immune cells. Low oxygen levels significantly reduce the proliferation and activation of T lymphocytes, reduce the NKG2D receptors on NK cells and thereby inhibit the killing function of NK cells, increase tumor-associated macrophages to induce angiogenesis, and reduce inflammation to promote tumor progression –36. On tNew evidence confirms that disturbances in the immune response in the tumor microenvironment play a decisive role in tumor development .As a tumIn conclusion, based on the TCGA-PAAD cohort, we identified immune-related markers with independent prognostic significance, verified, and analyzed their biological functions, to provide a feasible method to evaluate the prognosis of pancreatic cancer and provide valuable targets for immunotherapy of pancreatic cancer.


Preterm birth accounts for over 15 million global births per year. Perinatal interventions introduced since the early 1980s, such as antenatal glucocorticoids, surfactant, and invasive ventilation strategies, have dramatically improved survival of even the smallest, most vulnerable neonates. As a result, a new generation of preterm-born individuals has now reached early adulthood, and they are at increased risk of cardiovascular diseases. To better understand the sequelae of preterm birth, cardiovascular follow-up studies in adolescents and young adults born preterm have focused on characterizing changes in cardiac, vascular, and pulmonary structure and function. Being born preterm associates with a reduced cardiac reserve and smaller left and right ventricular volumes, as well as decreased vascularity, increased vascular stiffness, and higher pressure of both the pulmonary and systemic vasculature. The purpose of this review is to present major epidemiological evidence linking preterm birth with cardiovascular disease; to discuss findings from clinical studies showing a long-term impact of preterm birth on cardiac remodeling, as well as the systemic and pulmonary vascular systems; to discuss differences across gestational ages; and to consider possible driving mechanisms and therapeutic approaches for reducing cardiovascular burden in individuals born preterm. In spite of improvements in medical care, preterm-born individuals are at greater risk of all-cause mortality in young adulthood,3 as well as cardiometabolic diseases, including type 1 and 2 diabetes mellitus,4 hypertension,5 pulmonary vascular disease,8 early heart failure,9 and ischemic heart disease.10Preterm birth (<37 weeks’ gestation) affects over 10% of live births, with rates ranging from 5% to 18% worldwide.Preterm birth occurs during a key period of cardiovascular development, leading to an early physiological shift to a relatively hyperoxic environment with increased systemic and decreased pulmonary vascular resistance. As a result, animal and clinical studies across developmental stages have focused on observational and mechanistic insights into cardiovascular changes related to prematurity that may contribute to short- and long-term risk of disease Figure . In this9 published a register-based cohort study of 2 665 542 individuals born in Sweden from 1987 to 2012 to determine the association between preterm birth and the risk of incident heart failure. Individuals were followed up from 1 year of age until December 31, 2013, with a total follow-up time of 34.8 million person-years and 501 cases of heart failure. After individuals born with potentially confounding malformations were excluded, there were 305 heart failure cases and a follow-up of 34.2 million person-years. Incidence rates of heart failure were inversely related to gestational age at birth, with a 17-fold increased risk in those born extremely preterm compared with those born at term even after adjustment for maternal characteristics, subject sex, birth period, and birth weight for gestational age. While the adjusted risk of incident heart failure was 3.6× higher in subjects born very preterm compared with term, there was no significant increase in the risk of heart failure for subjects born moderate-to-late preterm.In 2017, Carr et al10 published a similar register-based cohort study in 2019 to investigate the association between prematurity and increased risk of ischemic heart disease in adulthood. A total of 2 141 709 individuals born in Sweden as singleton live births between 1973 and 1994 were included, with follow-up until the end of 2015. The total follow-up time was 30.9 million person-years, with 1921 individuals receiving a diagnosis of ischemic heart disease. Gestational age was inversely associated with ischemic heart disease risk across ages 18 to 43 years, including a strong association among individuals born late preterm. The strength of this relationship was higher in those individuals currently 30 to 43 years of age; interestingly, both preterm birth and early-term birth (37–38 weeks’ gestation) were associated with increased relative risks of ischemic heart disease  compared with individuals born full term between 39 to 41 weeks’ gestation.Crump et al11 A recent meta-analysis investigating cardiac differences between preterm-born and term-born individuals demonstrated that individuals born preterm have morphological and cardiac functional impairments across all developmental stages including neonatal life, infancy, childhood, and into young adulthood.12 These underlying cardiac differences in structure and function that are apparent as early as neonatal life may make the preterm heart more susceptible to heart failure and ischemic heart disease.13The third trimester is a period of rapid cardiac growth, primarily driven by cardiomyocyte hyperplasia. Birth results in a switch in cardiomyocyte growth from a fetal hyperplastic to a neonatal hypertrophic response.14 Preterm-born individuals had smaller left ventricular (LV) end-diastolic volumes, smaller internal LV cavity dimensions and lengths, as well as greater LV wall thickness and mass. These cardiac changes were independent of differences in body size and blood pressure between groups. Through the use of a novel computational atlas created from CMR images, it was found that the primary morphological feature contributing to the lower LV end-diastolic volumes was the reduction in LV length. Though the preterm-born young adults had no differences in LV ejection fraction, LV longitudinal systolic strain and strain rate, as well as diastolic strain rate, were reduced. In the same cohort of participants, right ventricular (RV) end-diastolic volumes were also lower and RV mass higher in preterm-born compared with term-born young adults, which could not be accounted for by differences in body size.15 Unlike in the LV, RV ejection fraction was lower in the preterm group, with 6% of young adults having values below the clinical normal range (<45%). Preterm-born young adults also had lower RV systolic strain and strain rates, as well as diastolic strain rate.The first study to investigate the cardiac impact of being born preterm in young adulthood was done using cardiovascular magnetic resonance (CMR) in 234 individuals, of whom 102 were born preterm with an average gestational age of 30 weeks.16 Using echocardiography, the study showed that preterm-born young adults had smaller LV end-diastolic volumes and dimensions and increased LV mass indexed to body size, as well as impaired longitudinal systolic strain. In the same cohort, body size indexed RV end-diastolic areas and volumes for echocardiography and CMR were lower in preterm-born individuals,17 with RV CMR revealing higher RV mass, lower RV ejection fraction, and a unique 3-dimensional geometry by computational atlas formation in those born preterm. Measurements of RV function by echocardiography, including RV fractional area of change and tricuspid annular plane systolic excursion, were lower in preterm-born compared with term-born young adults, with RV changes remaining significant when adjusting for pulmonary function parameters by spirometry.Similar findings have been reported in an independent cohort of 101 normotensive young adults, of whom 47 were born preterm with an average gestational age of 33 weeks.20 differences in mass are less consistent. While some studies using both CMR17 and echocardiography18 have reported higher LV and RV mass in preterm-born young adults compared with term-born controls, others have reported lower mass in those born preterm.21 A recent study using CMR in a group of 40 normotensive adolescents, of which 20 were born preterm with an average gestational age of 28 weeks, and 70 normotensive young adults, of which 38 were born preterm with an average gestational age of 29 weeks, showed that both LV and RV end-diastolic and stroke volumes were lower in the preterm groups, as was LV mass when indexed to body size.20 Interestingly, LV longitudinal systolic strain was higher in the preterm-born young adults in this study, as were RV longitudinal systolic and diastolic strain parameters. Further work is needed to explore these differences, taking into account variability in perinatal characteristics and interventions, as well as lifestyle factors throughout development, such as exercise activity level, socioeconomic status, and diet. How the heart will remodel with the development of other risk factors associated with preterm birth, such as pulmonary and systemic hypertension and obesity,22 remains to be determined and may account for some of the variability in results. Part of this variability in hypertrophic response may also be due to changes in perinatal clinical management, which have rapidly evolved in the 1980s and 1990s. Moreover, the most premature individuals, such as those born at <28 weeks’ gestation, may have the lowest cardiac endowment and thus the fewest overall number of cardiomyocytes. As such, cardiac mass may remain lower even if the individual cardiomyocytes are hypertrophied. Individuals born less premature, such as those born around 32 weeks’ gestation, may have the same early hypertrophic stimuli to increase cardiomyocyte size but are also more likely to have a greater total number of cardiomyocytes due to longer in utero development, which may ultimately drive higher mass relative to term-born controls , Kowalski et al19 reported similar carotid-radial PWV and augmentation index compared with term-born controls, despite smaller aortic diameters, higher blood pressures, and no difference in body mass index between groups. However, in a recent study by Barnard et al,45 aortic PWV was increased in 10 very preterm-born young adults compared with 12 term-born blood pressure and body mass index–matched controls.Arterial stiffness has been investigated in preterm-born individuals using surrogate indices such as pulse wave velocity , augmentation index (the reflection pressure wave modulated by vessel stiffness and blood pressure), and other measures of vascular elasticity. Arterial distensibility and elasticity depend largely on the ratio of elastin and the more rigid collagen in arterial walls. In humans, elastin synthesis peaks toward the end of gestation and continues into early childhood, declining rapidly thereafter, with minimal synthesis by adulthood.46 the majority of studies performed in adolescents and young adults born very or extremely preterm have not shown any alteration in endothelial function associated with preterm birth evaluated using brachial artery flow–mediated dilation or reactive hyperemia index.36 Studies reporting carotid intima-media thickness—an early marker of atherosclerosis and nonatherosclerotic remodeling—in preterm-born adolescents and adults have consistently shown no differences compared with term-born controls.36 In line with this, Hovi et al36 found that carotid intima-media thickness did not differ between very preterm and term-born adults, but because lumen diameter was much smaller in the preterm group, carotid intima-media thickness was increased relative to lumen diameter.Although a single study suggests diminished endothelial function in 32 young adults born extremely preterm,47 reported that, independent of retinopathy of prematurity, retinal vascular caliber and density were decreased in children and young adults born very preterm on average at 30 weeks. Furthermore, skin microvascular perfusion and density have been shown to be reduced and to correlate with higher blood pressure and circulating antiangiogenic factors.48 Reduced systemic angiogenic capacity could underlie impaired vascular growth. Neonatal exposure to high oxygen, which mimics preterm birth–related physiological conditions, reduced in vitro angiogenic capacity and systemic microvascular density in adult rats.50 Supporting this possibility, endothelial colony–forming cells collected from venous blood had altered in vitro proliferation and angiogenic capacity in young adults born extremely preterm, which correlated with increased blood pressure.51 Further work is needed to clarify the role of defective vascular tree development or repair and related mechanisms, such as epigenetic changes and accelerated senescence of progenitor cells,52 contributing to the development of cardiovascular diseases in individuals born preterm.At the microvascular level, Kistner et al53 Studies have also shown higher hemoglobin,54 evidence of sympathetic nervous autonomic system activation,55 and hypothalamus-pituitary-adrenal dysregulation56 in preterm-born adults, which all potentially contribute to higher blood pressure. A recent study of 101 young adults born on average at 27 weeks’ gestation compared with 105 young adults born at term found no association between preterm birth and markers of inflammation and oxidative stress, as well as no association between high blood pressure and other cardiovascular risk factors , suggesting a unique mechanism to hypertension and disease development.57 Perinatal interventions and complications that are common in preterm infants, including perinatal infection, accelerated postnatal weight gain, parenteral nutrition, and antenatal and postnatal steroids, have been shown to relate to increased vascular stiffness and may contribute to long-term cardiovascular remodeling.58 Further work is needed to look at the long-term effects of these early life interventions. In addition, the hereditary component of hypertension among individuals born preterm has not yet been fully investigated. Indeed, women who had preeclamptic pregnancies (an antecedent to 20%–30% of preterm births) or who had spontaneous preterm deliveries were recently shown to be at increased risk of future cardiovascular diseases.59 Whether genetically inherited factors add to the risk of systemic hypertension related to altered organ and vascular development and function as a result of being born preterm is plausible but remains to be addressed.Beyond altered vascular structure and growth, other elements may contribute to the etiology of hypertension in the preterm-born population. Studies of children and adults born very or extremely preterm have shown that preterm birth is associated with altered nephrogenesis and smaller kidneys, with the reduction in kidney size correlating with higher blood pressure in adults.6 This relationship persisted after adjusting for known risk factors such as congenital heart disease and bronchopulmonary dysplasia. Further, the association was even stronger in children and adolescents , likely reflecting improved neonatal survival of the most at-risk individuals.8In addition to the direct cardiac and systemic vascular effects of premature birth, individuals born preterm are at increased risk for pulmonary vascular disease as evidenced by both epidemiological and clinical data. The initial epidemiological data supporting prematurity as a risk factor for adult pulmonary hypertension come from a case-control study of adults in the Swedish pulmonary arterial hypertension registry. When compared with controls from the birth register, matched by birth year and hospital, premature birth was associated with an odds ratio of 3.08 for adult pulmonary arterial hypertension.60 Additional echocardiogram-based studies in adolescents and adults born preterm have reported an elevated tricuspid regurgitation velocity and lower pulmonary artery acceleration times in those born preterm, indicating increased pulmonary vascular resistance relative to term-born age-matched controls.61 The only right heart catheterization study conducted to date enrolled 11 young adults born preterm with an average gestational age of 28 weeks, of whom 5 of 11 satisfied criteria for pulmonary hypertension as defined by a mean pulmonary artery pressure >20 mm Hg. Furthermore, pulmonary vascular resistance and arterial elastance were significantly elevated among preterm adults, suggesting a stiffer pulmonary vascular bed overall.25 Among these subjects, RV-pulmonary vascular coupling was impaired in preterm-born relative to term-born subjects.62 In contrast, an echocardiography-based study of ventriculo-vascular coupling in young adults born preterm with an average gestational age of 33 weeks demonstrated preserved RV coupling relative to term-born adults.16 The lower gestational age in the catheter-based study further suggests that early RV-pulmonary artery uncoupling may be gestational age dependent. Further, the degree of uncoupling was unexpected for the mild elevation in afterload and supports the concept of prematurity serving as a direct insult to the RV as well. In summary, changes in RV function and pulmonary vascular resistance are present across gestational ages, and it is possible that RV-pulmonary vascular uncoupling will occur sooner even in those born moderate-to-late preterm, warranting further follow-up into mid and late adulthood.Recent clinical studies demonstrate the presence of mild pulmonary hypertension in a significant percentage of adolescents and young adults born moderately to extremely premature. Among 193 adolescents with an average gestational age of 27 weeks, nearly half had a mean pulmonary artery pressure by echocardiogram >20 mm Hg.63 These findings, however, were not confirmed in the aforementioned right heart catheterization–based study, possibly due to smaller sample size.25 Among the studies that have assessed the response to hypoxia, the hypoxic vasoconstrictor response appears intact and similar between term- and preterm-born subjects.63 Some of these studies have identified bronchopulmonary dysplasia as one of the possible key drivers of overt late pulmonary vascular disease, though it is unlikely to be the sole contributor.60Several studies have assessed the pulmonary vascular response to exercise or hypoxia. In an echocardiography-based exercise study, adults born premature demonstrated an exaggerated increase in estimated pulmonary pressure.65 Therefore, the lifetime impact may be significant even in relatively healthy individuals with a history of preterm birth.Finally, although the overall severity of pulmonary vascular disease appears mild in childhood and adult studies, a subset of premature infants develop more severe pulmonary vascular disease. Additional studies are needed to understand the natural history of pulmonary vascular-RV development in these high-risk individuals. In the meantime, even small elevations in mean pulmonary artery pressure are associated with a significant increase in all-cause mortality in adults.Mechanistic studies of the cardiac and vascular sequelae of premature birth are somewhat constrained due to limitations of available animal models. Whereas both small and large animal models can be delivered prematurely, there is limited-to-no ability to support the degree of prematurity that is encountered and survivable in humans. However, both may be informative regarding specific aspects of cardiovascular development and will be discussed here.66 The application of oxygen exposure in this model aims to mimic the relative hyperoxic environment common to premature birth. Birth results in an immediate transition to normoxia, which is relatively hyperoxic compared with normal fetal life. Although hyperoxic animal models do not recapitulate prematurity per se, they do mimic the developmentally inappropriate relative hyperoxia that a preterm infant experiences and is highly relevant to the developing heart. Specifically, at birth, the rodent heart is predominantly mononucleated, with terminal cell cycle arrest and transition from hyperplasia to hypertrophy for cellular growth occurring during the first week postnatally.67 When hyperoxia is applied, cell cycle arrest is accelerated through activation of DNA damage responses.68Rodent models have been used for decades to study the sequelae of premature birth, specifically as related to the development of bronchopulmonary dysplasia. Although models differ in the duration and severity, most utilize postnatal hyperoxia exposure to recapitulate the alveolar and vascular oversimplification characteristic of bronchopulmonary dysplasia.69 There appears to be some degree of pulmonary revascularization, only to have accelerated vascular pruning with aging.70 Pulmonary vascular disease is associated with bimodal RV dysfunction, with early uncoupling and RV dysfunction due to the severity of the vascular disease. There is a period of cardiac recovery, as the pulmonary hypertension improves, followed by late RV failure related to emergence of mitochondrial dysfunction and accumulation of mitochondrial DNA damage.71 Mitochondrial oxidation also drives cardiomyocyte loss beginning in the neonatal time period and may be rescued with administration of antioxidants such as mitoTEMP.72 Therefore, a diminished cardiomyocyte endowment may further contribute to cardiac dysfunction. In the LV, postnatal hyperoxia results in remodeling and impaired systolic function even before systemic blood pressure elevation, including an increase in LV cardiomyocyte hypertrophy, fibrosis, and in markers of premature senescence.73 Moreover, these early cardiac alterations increased the susceptibility of rodents to develop heart failure following pressure overload induced by angiotensin II infusion. Development of cardiac alterations in adulthood, including fibrosis and hypertrophy, was linked to upregulation of angiotension II receptors type 1 and 2 in the LV, signifying increased renin-angiotensin system activation, which was prevented with early treatment with the AT1 (angiotensin II type 1) receptor antagonist losartan and with an antagonist of the Toll-like receptor-4 proinflammatory pathway.75 This indicates that a number of deleterious mechanisms for myocardial development are triggered by preterm birth–related conditions along with neonatal oxidative injury.Postnatal hyperoxia exposure in rodents has been utilized to recapitulate both the late RV-pulmonary vascular and LV-systemic vascular complications of premature birth. Animals develop moderate-to-severe pulmonary hypertension in the neonatal period, with some ability to recover in adolescence and adulthood.76 It is noteworthy that preterm-born sheep also had an ≈7-fold increase in interstitial collagen deposition, even without the normal inflammatory and stress-related conditions that are commonly associated with preterm birth in humans.77 Nucleation and ploidy of the cardiomyocytes were also shown to be altered, supporting the argument that there are irreversible myocardial stress–related changes in DNA in the preterm-born lambs. At 14.5 months postnatal age follow-up, preterm-born sheep had thinner RV walls, a higher reserve of immature undifferentiated cardiomyocytes, lower cardiomyocyte numbers, and smaller cardiomyocyte areas with reductions in RV functional and adaptive capacity.In an ovine model of preterm birth (14 days premature), LV and RV cardiomyocytes were hypertrophied in the preterm-born lambs compared with controls at 9 weeks postnatal age.78 There is evidence that neonatal risk factors do appear to be modifiable. For example, exclusive human milk feeding during infancy, as compared with formula, was associated with larger LV and RV end-diastolic and stroke volumes and smaller pulmonary artery to aortic diameter ratios in adulthood.79 Ultimately, further study is needed to understand the role of intervention strategies throughout the life span, including lifestyle modifications such as exercise and pharmacological interventions, on improving cardiac remodeling and decreasing long-term cardiovascular risk.Currently, there are limited data to suggest specific therapeutic strategies in adults born preterm to treat hypertension or modify heart failure risk. Elevated plasma levels of angiotensin I and the presence of autonomic dysfunction and impaired heart rate recovery may suggest a potential role for angiotensin or adrenergic blockade, but these have not been specifically evaluated in preterm subjects.It is now clear that preterm birth is associated with increased risk of cardiovascular diseases including ischemic heart disease and hypertension, as well as increased risk of heart failure. The mechanisms are not completely understood, and current evidence indicates that the disruption of heart, vessels, and overall organ development associated with preterm birth contributes to disease risk, most likely in addition to hereditary components. While much remains to be unraveled regarding mechanisms, attention should now also be directed on how to effectively prevent hypertension and disease occurrence, from the neonatal period through adult life. Subclinical diseases, including high blood pressure and mild cardiac dysfunction, are detectable in young adulthood and might not be accompanied by classically associated risk factors such as obesity. Thus, recognition of preterm birth as a significant risk factor for cardiovascular disease becomes imperative for clinicians, parents, and the preterm-born adults. Birth history should be included in best practice guidelines from childhood to adulthood to permit healthy lifestyle counseling and appropriate screening. Among those symptomatic or at the highest risk, clinicians should consider that symptoms may be multifactorial, including a compilation of cardiac, pulmonary, and vascular sequelae of prematurity, and may require more nuanced testing and clinical evaluation, such as early utilization of exercise testing Figure . ModifyiA.J. Lewandowski is funded by a British Heart Foundation Intermediate Basic Science Research Fellowship (BHF FS/18/3/33292). A.M. Nuyt is funded by the Canadian Institutes of Health Research (CIHR 399001 and 313082), the Heart and Stroke Foundation of Canada, the Canadian Foundation for Innovation, and the Cercle Sainte-Justine Developmental Origins of Health and Diseases Research Chair. K.N. Goss is funded by a Parker B. Francis Fellowship Award and American Heart Association Career Development Award .None.


Food allergy (FA) is a growing public health concern affecting nearly up to 6–8% in children and 3–5% in adults with life-threatening potential. The increase in prevalence of FA in recent years has implicated environmental influences related to a modern life style in disease pathogenesis. This Frontiers Research Topic was designed to provide a timely collection on animal and clinical studies on new research directions in the etiology, prevention, and treatment of FA. We received a series of 14 original and review articles on the topic that span a wide range of exciting, new areas that will inform the research community on FA.+ T cells that secrete pathogenic T helper (Th) 2 cytokines and by allergen-specific immunoglobulin (Ig) E antibodies that trigger the release of inflammatory mediators from mast cells (MCs) and circulating basophils. Normally, ingestion of foods results in oral tolerance, therefore FA is thought to be a result of a failure of oral tolerance. Alterations in regulatory T cell functions, Th2 responses, microbiota, and/or food sensitizations via alternative routes, such as the skin, likely contribute to the failure of oral tolerance and to the development of FA. However, the mechanisms responsible for breakdown in oral tolerance remain poorly understood.FA can be defined as clinical immune responses to normally harmless food allergens. The disease is typically associated with CD4Satitsuksanoa et al. reviewed the range of immune regulatory mechanisms of tolerance to FA. Ingested food proteins may cause allergic immune responses leading to FA but how these proteins become immunogenic and cause food allergies is not completely understood. Tolerance to food is mainly acquired by dendritic cells, epithelial cells in the gut, and the gut microbiome. These authors found that a subset of CD103+ DCs is capable of inducing T regulatory cells (Treg cells) that express anti-inflammatory cytokines. Anergic T cells also contribute to oral tolerance by reducing effector cells. Similar to Treg cells, regulatory B cells (Breg cells) suppress effector T cells and contribute to the immune tolerance to food allergens. Saunders et al. reviewed allergic IgE responses and found that IgE memory response has unique features that distinguish it from classical B cell memory. Burton et al. investigated tissue-specific expression of FcγRIIb, a low-affinity IgG receptor on MCs in allergy. The authors combined flow cytometry, quantitative PCR, and immunofluorescence staining of MCs derived from the tissues of humanized mice, human skin, or fixed paraffin-embedded sections of human tissues, and demonstrated that FcγRIIb is absent from dermal MCs but expressed by MCs throughout the gastrointestinal tract. IgE-induced systemic anaphylaxis in humanized mice is strongly inhibited by antigen specific IgG; thus, these authors concluded that IgG signaling via FcγRIIb plays a role in suppressing hypersensitivity reactions. Krajewski et al. found that epigenetic regulation of MC activation during immune responses may occur via altered histone acetylation, and that exposure to dietary substances may induce epigenetic modifications that regulate MC function.A series of articles were directed at the immune regulatory mechanisms in FA tolerance. Dioszeghy et al. demonstrates that EPIT induced tolerance in sensitized mice through the induction of Foxp3+ regulatory T cells (Tregs), especially CD62L+ Tregs. Although both Langerhans cells (LCs) and CD11b+ dermal classical dendritic cells could induce Tregs, the absence of LCs during EPIT impaired treatment efficacy, indicating that LCs play a crucial role in skin-induced tolerance.The skin is a major immunologic organ that may induce protection, sensitization, or tolerance. Epicutaneous immunotherapy (EPIT) has been proposed as an attractive strategy to actively treat FA in humans. Hoh and Boyd showed that the gastrointestinal mucosa is a critical environmental interface in which plasma cells and B cells are exposed to orally-ingested antigens such as food allergen proteins. It is unclear how the development of B cells and plasma cells in the gastrointestinal mucosa differs between healthy humans and those with FA, and how B cells contribute to, or are affected by, the breakdown of oral tolerance. Furthermore, the human microbiome is an essential mediator in the induction of oral tolerance or FA. In another study with germ-free mice, Schwarzer et al. showed that microbiota-induced maturation and gut-homing of MCs is a critical step for the development of symptoms of experimental FA. This new mechanistic insight into microbiota-MC-FA axis could be exploited in preventing and treating FA in humans. Hayen et al. found that intestinal epithelial exposure to short-chain galacto-oligosaccharides and long-chain fructo-oligosaccharides enhanced the CpG induced Th1 and regulatory IL-10 response in a peanut-specific co-culture model. This suggests that such oligosaccharides are candidate for dietary adjunct in allergen-specific immunotherapy.The regulation of gut antibody responses also plays a role in regulating food allergens. In a review, Wright et al. found pre-existing gastrointestinal eosinophilia is common in adults with IgE-mediated peanut allergy. Eosinophilic inflammation in these subjects may be accompanied by mild endoscopic and histologic findings. Further, Sallis et al. found that eosinophilic esophagitis (EoE) patients with food impaction were indistinguishable from other EoE patients based on their tissue eosinophil count, serum IgE levels, or the mRNA transcriptome-based a probability score for EoE [p(EoE)] but in an elegant analysis, they showed that a distinct esophageal mRNA pattern identified EoE patients with food impactions. The EoE-specific mRNA pattern indicates that impaired motility may be one underlying factor for the development of food impactions in pediatric patients.While oral immunotherapy (OIT) has shown promise in treating food allergies, gastrointestinal symptoms are experienced by patients and few develop eosinophilic gastrointestinal disease. Fujimura et al. reviewed the influences of maternal factors over offspring allergies. They reviewed how food allergens, allergen-specific immunoglobulins, cytokines, genetics, and environmental factors transferred during pregnancy or breastfeeding influence offspring allergies and how such effects may be applicable to FA. They also discussed the mechanisms by which maternal factors, including the impact of immune complexes, transforming growth factor-β, vitamin A, and regulatory T-cell responses, contribute to the induction of neonatal tolerance vs. development of allergic responses to maternally transferred allergens.Finally, There is currently no cure for FA other than strict avoidance of identified foods. Key problems in this field that remain to be resolved are our insufficient understanding of the mechanisms of the breakdown in oral tolerance in FA and our understanding of the reasons why such mechanisms have recently taken such a strong base in the human population. We are at an exciting point at which discoveries about the etiology, mechanisms, treatment, and prevention of FA are critical to guiding future areas of research and identifying therapeutic options for food allergic patients.Johnson-Weaver et al. reviewed adjuvants and formulations that have shown pre-clinical efficacy in treating peanut allergies. In an analysis of 428 participants with positive food challenges, Purington et al. found those with a history of asthma, high allergen-specific IgE to total IgE ratio, and/or high values of allergen-specific IgE were also found to be at higher risk for severe reactions during food challenges. Their findings will help optimize food challenge dosing schemes in multi-food allergic, atopic patients, specifically at lower doses where the majority of reactions occur. In an analysis of a large food challenge dataset, baseline population characteristics, biomarkers, and challenge outcomes were studied to develop diagnostic criteria predictive of positive oral food challenges (OFCs) across multiple allergens in our multi-allergic cohorts . They found a history of atopic dermatitis and multiple food allergies were significantly associated with a higher risk of positive OFCs. The majority of food-specific skin prick tests, allergen-specific IgE, and allergen-specific IgE/total IgE thresholds calculated from cumulative tolerated dose (CTD)-dependent receiver operator curves had high discrimination of OFC outcomes and participants with values above the thresholds were more likely to have positive challenges.Currently, two forms of peanut immunotherapy, OIT and EPIT, are in Phase III clinical trials and have shown promise to desensitize patients with FA. However, there are several limitations with OIT and EPIT, such as allergic side effects, daily dosing requirements, and the infrequent outcome of long-term tolerance. Next-generation therapies for peanut allergy may overcome these limitations, particularly with adjuvanted immunotherapy. Overall, we strove to provide an overview of recent progress in the field of food allergy. Our 14 research articles provided novel findings in the field of environmental and genetic risk factors for food allergy, the mechanisms of food allergy: effector immune cells involved in the initiation, development and manifestations of disease, regulatory immune mechanisms, and insights into the prevention and treatment of food allergy.RC and MO: wrote and contributed substantial intellectual contribution to this editorial.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.