Placental abruption is the separation of the placenta from the lining of the uterus before childbirth. It is an infrequent perinatal complication with serious after-effects and a marked risk of maternal and fetal mortality. Despite the fact that numerous placental abruption risk factors are known, the pathophysiology of this issue is multifactorial and not entirely clear. The aim of this review was to examine the current state of knowledge concerning the molecular changes on the maternal–fetal interface occurring in placental abruption. Only original research articles describing studies published in English until the 15 March 2021 were considered eligible. Reviews, book chapters, case studies, conference papers and opinions were excluded. The systematic literature search of PubMed/MEDLINE and Scopus databases identified 708 articles, 22 of which were analyzed. The available evidence indicates that the disruption of the immunological processes on the maternal–fetal interface plays a crucial role in the pathophysiology of placental abruption. The features of chronic non-infectious inflammation and augmented immunological cytotoxic response were found to be present in placental abruption samples in the reviewed studies. Various molecules participate in this process, with only a few being examined. More advanced research is needed to fully explain this complicated process. Placental abruption is defined as the early complete or partial separation of the placenta from the lining of the uterus with the development of a retroplacental hematoma before delivery . PlacentPlacental abruption may be associated with a variety of complications, even in the case of an instant availability of highly qualified medical personnel and efficiency in saving the mother and the child. The complications are related to iatrogenic prematurity, poor condition of the newborn at birth necessitating hospitalization in the neonatal intensive care unit, prolonged hospital stay and an intervention in the mother. The examples of more common complications of placental abruption include severe hemorrhage, fetal demise, maternal death, premature labor, low birth weight, repetitive transfusions, coagulopathy, or invasive procedures including hysterectomy . AccordiThe exact cause of placental abruption is not entirely clear, and several risk factors are known. Overall, the risk factors of developing placental abruption include advanced maternal age, a history of placental abruption, the use of stimulants, increased arterial pressure , or fetal growth restriction (FGR)), infectious agents, polyhydramnios, preterm or prolonged rupture of membranes, a history of cesarean section, multiple pregnancies or thrombophilia ,10. As rRORA gene was associated with a 21% reduction in the odds of placental abruption. Most of the data in this area have been summarized recently. According to a well performed genome-wide association study and a meta-analysis of genome-wide association studies by Workalemahu et al. from 2018, the genetic loci suggestively associated with placental abruption included rs4148646 and rs2074311 in ABCC8, rs7249210, rs7250184, rs7249100 and rs10401828 in ZNF28, rs11133659 in CTNND2, and rs2074314 and rs35271178 near KCNJ11, rs76258369 near IRX1, and rs7094759 and rs12264492 in ADAM12. Additional analyses performed by the authors revealed that the majority those genes are connected to trophoblast-like cell interaction, or in the endocrine or cardiovascular systems or cellular function pathways. However, their role still needs further research [For example, Qiu et al. found that rs2899663 single nucleotide polymorphism of the The etiopathogenesis of placental abruption is multifactorial. According to the current concept of ischemic placental disease, placental abruption is one of the manifestations of impaired placental function comprising PE and FGR. According to the available literature, the pathophysiological mechanisms leading to the occurrence of such complications include uteroplacental ischemia (the placenta becoming underperfused) and placental insufficiency beginning during placental implantation ,15. It iIn the majority of cases, placental diseases are related to the abnormalities of the vascular and immune system. The disruptions lead to necrosis, inflammation, vascular problems and, ultimately, to placental abruption ,17. PhysImmune tolerance is necessary at the interface between the mother and fetus . The matThe immunological alterations occurring in placental abruption remain mostly unknown, yet some of them have already been established. The disruption of the NKs and T cell balance may result in preterm placental abruption ,17. AccoRecent studies also suggested an important role of the cytosolic multiprotein oligomers responsible for the activation of inflammatory responses. Therefore, they were called inflammasomes in the pathophysiology of placental abruption. Many different factors are connected with the fine-tuned regulation of inflammasome assembly and the final effect  in this It is worth mentioning the abnormal separation of the placental tissue, which may partially be included in placenta accreta spectrum, i.e., a range of the pathologic adherence of the placenta, including placenta increta, placenta percreta, and placenta accreta ,35. The A successful pregnancy involves various interactions between trophoblasts and maternal immune cells. These interactions allow the development of a new life in the uterus while the mother’s immune system remains intact . The plaThe methods of the analysis and inclusion criteria were specified in advance. The inclusion and exclusion criteria are summarized in The above criteria were strictly balanced in order to minimize the overall bias of this review. Animal studies were excluded to ensure the examined processes indeed occurred in humans. Studies concerning in vitro fertilization were excluded to minimize the influence of iatrogenic interventions on the maternal-fetal unit. To establish the data concerning the molecular changes on the maternal–fetal interface, studies examining only blood serum, genetic mutations or histopathological examination only were excluded.Two electronic databases were used in this systematic search: MEDLINE (through PubMed) and Scopus. The search strategy for each database is presented in A systematic literature search retrieved 708 citations. The Scopus search was indexed to exclude the MEDLINE articles. The remaining duplicates were removed using the automatic EndNote X9  duplicate finder, followed by a manual search. An eligibility assessment was performed independently in an unblinded standardized manner by two reviewers. Details regarding the selection process are summarized in a custom-built PRISMA flow chart in https://ntp.niehs.nih.gov/ntp/ohat/pubs/riskofbiastool_508.pdf, accessed on the 11 April 2021). The OHAT Tool was developed to enable risk of bias assessment in all kind of studies. Six types of bias  are rated based on the four-point scale: “definitely low risk of bias”, “probably low risk of bias”, “probably high risk of bias” and “definitely high risk of bias”. Other possible sources of bias, not included in the scale, have been discussed in a separate paragraph.The risk of bias for the interpretation of the data was analyzed with the use of the modified Office of Health Assessment and Translation (OHAT) Risk of Bias Rating Tool for Human and Animal Studies  was 34, and the average was 38. The main inclusion criteria entailed studies describing immunological changes occurring in the maternal–fetal interface in placental abruption, although we excluded studies in which only blood serum tests were conducted (studies where blood sample tests were a part of the research were not excluded). Summarized outcomes of all the included studies are available in The first studies concerning the problem were conducted over 30 years ago by Altshuler et al. (1983)  concerniBleeding is clinically inseparably associated with placental abruption. Apparently, it may be regarded both as the cause and as the result of placental abruption. Even first trimester bleeding, according to different studies, may increase the risk of placental abruption itself ,57,58, aDuring placental abruption, the decidua is exposed to bleeding-derived clotting factors, thrombin  being one of the most abundant ,54,55 anThe dysregulation and increase of THR activity has the potential to cause PTB . It alsoIt is known from the clinical practice that bleeding—manifested or latent—causes uterine contractions. It may be understood as a mechanism protecting the mother and expelling the fetus in case of the danger of a pathological intrauterine bleeding. Nishimura et al. (2020)  focused THR induces fetal membrane (FM) weakening in several different ways. Following Kumar et al. (2011) , THR is A link between inflammation and bleeding was reported by many researchers ,47,48,53An inflammation or infection was clinically confirmed to be associated with an increased risk of placental abruption . In factThe existence of tissue-specific angiogenic factors has been postulated for many years ,7,8,9. HIn the last decade, the endocrine-gland-derived vascular endothelial growth factor (EG-VEGF), also called prokineticin 1 (PROK1), emerged as a specific placental angiogenic factor that controls numerous aspects of normal and pathological placental angiogenesis, such as recurrent pregnancy loss (RPL), gestational trophoblastic diseases (GTD), FGR and PE.EG-VEGF factor and its receptors PROKR1 and PROKR2 are among recently investigated angiogenic factors that are specific to the placenta. Authors should refer to the literature concerning EG-VEGF in the placenta and in relation to pregnancy pathologies that lead to FGR and preeclampsia, two key pathologies that are associated with placental abruption. Compared to VEGF, EG-VEGF and its receptors are less ubiquitous, which may open huge perspectives in their consideration in the etiology of placental abruption .During early pregnancy, EG-VEGF/PROKR1 peaks at 8–11 weeks of gestation and then gradually decreases by the end of the first trimester, whereas PROKR2 expression is maintained over the first trimester. EG-VEGF promotes the proliferation of anchoring trophoblasts and inhibits early EVT migration and invasion. In the first trimester human placenta, anchoring trophoblastic plugs obstruct the spiral arteries and prevent maternal oxygenated blood from entering into the intervillous space ,86.PK1 may have a novel role as a mediator of the inflammatory response in the placenta. PK1 was found to induce a time-dependent increase in the expression of IL-8  and COX-The role of cyclooxygenases (COXs) at the time of implantation and during pregnancy is well known, with successful implantation being associated with the prostaglandin (PGs) induction by COX1 and COX2 ,89. A prMoreover, nitric oxide, peroxynitrite and the enhanced expression of NO synthase (NOS), which are footprints of an inflammation and are found in the placenta of patients with CA, also seem to be present in samples collected from placental abruption patients. Probably the cascade of placental injury is similar in cases of CA and placental abruption. According to Nakatsuka et al. (1999), nitric oxide and its metabolites may play an important role in this cascade . ActivatAs presented in Decidua plays a crucial role in the process of human reproduction. The proper placentation process depends on the adequate invasion of the extravillous trophoblast into the decidualized endometrium and the modification of spiral arteries. The disruptions of this process may lead to all of the main causes of perinatal or maternal morbidity and mortality including FGR, PE, PTB and placental abruption. Decidualization causes the change in human endometrial stromal cell expression of tissue factor (TF), type-1 plasminogen activator inhibitor (PAI-1), matrix metalloproteinases (MMPs) and others , which iReceptor-binding cancer antigen expressed on SiSo cells  is a type II membrane protein described in the context of placental abruption ,29. It iMetallothionein (MT) is a low molecular weight protein with a high cysteine content and a marked affinity for divalent metals ,106,107.A strong clinical association was observed between placental abruption and subsequent PPROM . It was A few links may connect placental abruption with PPROM. An inflammation at the maternal–fetal interface is a likely common pathway leading to preterm birth in both placental abruption and PPROM cases ,122,123.Tissue factor is a transmembrane glycoprotein  and a prAccording to Kuczynski et al. (2002) , the higWhen the myometrium and placenta are destroyed during the placental abruption, the substances from the damaged tissues, TF and tissue factor pathway inhibitors, among others, are believed to be able to be reinfused to the circulation and affect the whole system ,132,133.In human pregnancy, the placenta-derived high progesterone concentrations at the maternal–fetal interface are stable until the delivery of the fetal–placental unit . ProgestWe summarize the most important molecular aspects in the maternal–fetal interface in placental abruption in https://ntp.niehs.nih.gov/ntp/ohat/pubs/riskofbiastool_508.pdf, accessed on 11 April 2021). The evaluation results are summarized in Due to the variety of the included study types, the risk of bias in the individual studies was assessed using the above-described OHAT Tool adapted by the authors for the needs of this review (The present review combined data across studies in order to estimate the relevant effects and molecular changes occurring in placental abruption. The main limitation of this review, as with any overview, is that in the methods, examined tissues or cell cultures, the equipment used is different across studies and the measured outcomes are sometimes contradictory. Therefore, the collective analysis of studies based on different methodologies poses a major challenge in terms of interpretation. Another significant limitation is the low number of patients from whom the samples were obtained. This does not allow the exclusion of the influence of individual predispositions. Moreover, the quality of the studies varied, so the publication bias might account for some of the effect we observed. The small quantities of the examined samples was a considerable problem in the majority of studies. Smaller trials are, in general, of less value for the formation of generalized conclusions and may have led to an overestimation of observed effects. Another limitation is the relative weakness of human studies compared to animal models, where timing in pregnancy and sampling after the stimulus to parturition can be tightly defined. Conversely, there were some cell culture studies included in the review in which the timing and exposure were easier to control. However, we have to remember that in vitro study results are not always parallel to clinical results.The disruption of the immunological processes in the maternal–fetal interface plays a crucial role in the pathophysiology of placental abruption. The features of chronic or augmented non-infectious inflammation and increased decidual cytotoxic activity were found to be present in placental abruption samples in the reviewed studies. Such processes result in the improper timing and order of the reproductive tract changes and the preterm separation of the placenta. Tissue factor, thrombin and cytokines seem the most crucial mediators of those processes. However, still more data are necessary to extract details concerning their influence.Co-signaling and immunomodulatory molecules constitute a very interesting and uncharted direction. They are mainly investigated in the context of carcinogenesis, but they may also influence the process of the maternal tolerance to fetal antigens. The discovery of clinically useful biomarkers determining whether processes leading to inflammatory and coagulation network disruption has already started would be crucial for defining high risk patients. The establishment of the mechanisms responsible for immune tolerance changes may help find anchor points for the immunotherapy of various high-risk pregnancies. It might lead to the concept of individualized medicine, as it seems impossible to find one therapy for the whole complex condition. The first steps have already been taken, but a great part of the necessary research still lies ahead.


In solid tumours, cancer cells that undergo epithelial mesenchymal transition (EMT) express characteristic gene expression signatures that promote invasive migration as well as the development of stemness, immunosuppression and drug/radiotherapy resistance, contributing to the formation of currently untreatable metastatic tumours. The cancer traits associated with EMT can be controlled by the signalling nodes at characteristic adhesion sites  where the regulation of cell migration, cell cycle progression and pro-survival signalling converge. In haematological tumours, ample evidence accumulated during the last decade indicates that the development of an EMT-like phenotype is indicative of poor disease prognosis. However, this EMT phenotype has not been directly linked to the assembly of specific forms of adhesions. In the current review we discuss the role of EMT in haematological malignancies and examine its possible link with the progression towards more invasive and aggressive forms of these tumours. We also review the known types of adhesions formed by haematological malignancies and speculate on their possible connection with the EMT phenotype. We postulate that understanding the architecture and regulation of EMT-related adhesions will lead to the discovery of new therapeutic interventions to overcome disease progression and resistance to therapies. Epithelium integrity is maintained by the apical-basal polarity of epithelial cells generated by adhesions at cell-cell junctions and with the basal lamina. However, under specific physiological conditions, epithelial cells lose the contacts with neighbouring cells and the subjacent matrix, adopting a highly motile mesenchymal phenotype. This cell behaviour is called epithelial-mesenchymal transition (EMT) and it is critical for tissue morphogenesis during embryonic development and in adulthood for wound healing ,2. At thEMT is also thought to play a central role in cancer progression by facilitating the invasive behaviour of tumour cells, enabling tissue infiltration and the formation of metastatic foci ,8. ConseThe induction and maintenance of EMT is highly regulated by extracellular signals during embryonic development, tissue repair and tumour progression. These include chemical cues such as cytokines, chemokines, the presence of reactive oxygen species (ROS)  and hypoEMT can be reversed by a process known as mesenchymal-epithelial transition (MET). The coordination of EMT and MET is critical in both physiological and pathological conditions . During In cancer cells, gene mutations and/or the influence of the tumour stroma may induce patterns of expression of epithelial and mesenchymal markers resulting in particular EMT phenotypes ,10,35. TA substantial body of evidence supports the central role of EMT in the invasive behaviour and the metastatic disease of carcinomas such as lung, prostate, colon, liver, pancreatic and breast cancers . HoweverThis review will emphasize the development of EMT-phenotypes during tumour progression of haematological malignancies. We will discuss the current understanding of the specific molecular EMT features described in haematological cancers and propose possible associated adhesomes formed by haematological tumour cells that may facilitate this invasive and aggressive phenotype.Haematopoietic cells derive from the mesoderm and, therefore, have a mesenchymal developmental origin, however, the expression of EMT-like signatures with upregulation of canonical mesenchymal markers has been described in all types of haematological malignancies  . The curIn particular, the actual correlation between the higher levels of EMT markers with a more motile phenotype, which is a key EMT feature, has not yet been studied in great depth in haematological malignancies in comparison to solid tumours. The majority of the studies have concentrated on various other tumour traits that may explain the correlation between expression of EMT signatures and the poor prognosis of patients. For example, the expression of EMT TFs has been associated with the repression of differentiation markers, correlating with more aggressive forms of haematological malignancies. Increased expression of ZEB1 promotes the methylation and downregulation of B-Cell Lymphoma protein 6 (BCL6), a key transcription factor that promotes differentiation of B cells and whose expression is associated with a benign profile . A correOnly a few of these studies have addressed the connection between the expression of EMT markers and increased cell migration. In paediatric anaplastic large cell lymphoma cells, expression of the oncogenic protein anaplastic lymphoma kinase (ALK) correlated with expression of higher levels of TWIST1. Downregulation of TWIST1 in these cells inhibited invasive migration and reinstated the efficacy of therapeutic drugs . In MLL-Multiple myeloma is the haematological tumour where the EMT phenotype has been studied in more depth, and there is substantial evidence of the acquisition of a migratory phenotype orchestrated by the EMT program ,43,51,54Taken together, the studies in haematological malignancies indicate a compelling connection between expression of EMT markers and poor prognosis . In addiCell adhesion molecules and associated proteins, in addition to anchoring cells to the surrounding microenvironment and facilitating migration, are known to regulate gene expression and cell cycle progression ,57,58,59We propose that to identify effective therapeutic targets for aggressive tumours, it is imperative to investigate the signalosomes at cell adhesions formed in cancer cells that have developed an invasive EMT phenotype. It is then essential to understand the architecture and regulation of EMT-related adhesions. The onset of the EMT process requires the reorganisation of filamentous actin (F-actin) microfilaments and microtubules in coordination with the reticular assembly of intermediate filaments of upregulated vimentin, while cells acquire migration polarity. Polarised cells display a distinctive protrusive leading edge and a contractile rear end that facilitates motility. Polymerisation of F-actin is the driving force that pushes the cell membrane at the leading edge, forming finger like protrusions containing parallel bundles of linear actin filaments called filopodia, or sheet like extensions shaped by the formation of a branched network of F-actin, called lamellipodia. Filopodia are generally thought to detect and integrate chemotactic signals that will determine the directionality of the cell movement  and theyNascent actin filaments polymerising at the cell membrane are shaped by various families of actin binding proteins. Formins are responsible for the linear polymerisation of F-actin in filopodia while fascin cross-links the formed filaments in parallel bundles ,69. FormEqually relevant for the development of an effective EMT phenotype in cancer cells is the formation of lamellipodia. F-actin assembly at lamellipodia is controlled by the Arp 2/3 complex, a multimeric protein that promotes lateral branching of polymerising actin filaments. Activation of the actin nucleation-promoting factors N-WASP/WASP and Scar/WAVE, downstream of the Rho-GTPases Cdc42 and Rac, respectively ,80, reguBoth filopodia and lamellipodia need to be stabilised by clusters of cell adhesion molecules called focal contacts that dynamically tether the membrane on the surface of neighbouring cells or on the surrounding extracellular matrix. In cells undergoing EMT, the cell adhesion molecules identified at focal contacts include proteoglycans  and integrins . These iFocal contacts that sustain filopodia and lamellipodia during EMT also show the capacity for local degradation of the extracellular matrix. CD44 clustered at focal contacts can form a complex with the metalloprotease (MMP) MT1-MMP at lamellipodia  suggestiInvasive focal contacts are also critical for the development of other cancer traits such as drug resistance. Targeting the cholesterol-rich domains  that contribute to integrin clustering inhibits the signalling at adhesion sites, blocking migration while re-sensitizing drug-resistant cancer cells to therapeutic drugs . These dInvadopodia are F-actin dependent adhesions that protrude at the ventral surface of a cell, belonging to a larger family of adhesions called invadosomes, which also include podosomes ,90,91. WThere is recent evidence indicating that the formation of invadopodia is coupled to cell cycle progression and EMT. Expression of invadopodia constituents is increased in G1, correlating with the enhanced capacity for degradation of the extracellular matrix of cancer cells . AdditioCancer cells form microtubule-based cell long tubular membrane protrusions used for cell migration that receive myriad names within the established literature ,109. As Assembly of McTNs and invadopodia are interchangeable in breast cancer cells. The activation of Src kinase promotes the diversion towards the formation of invadopodia, whereas the repression of Src activity leads to the assembly of McTNs . This inIn contrast to solid tumours, in haematological malignancies there is a paucity of published studies that clearly connect the development of the EMT phenotype with the formation of specific types of adhesions. However, there is strong evidence that haematological tumours can form adhesions that are structurally and/or functionally related to those formed in solid tumours undergoing EMT. The following adhesions below have been observed in haematological tumour cells and display close similarities to the EMT-related adhesions formed in solid tumours. We propose that these adhesions should be investigated in the future in the context of EMT-like processes in haematological malignancies.In general, haematological cancer cells in in vitro culture do not readily attach to plastic, and only a small proportion of cells form small and labile focal contacts on extracellular matrix proteins such as fibronectin by clustering integrins and associated proteins. These adhesions contain many components present in focal contacts assembled by cancer cells undergoing EMT in solid tumours including Src kinases, FAK, p130Cas, Cbl, Abi1 and CrkL ,120,121,Similarly to invadopodia, podosomes are sites of attachment and localised secretion of metalloproteinases that under normal physiological conditions mediate the migration of normal myeloid cells across tissue boundaries. In osteoclasts, podosomes facilitate migration on the bone surface and they can mature into an actin structure called the sealing zone that creates a confined area for secretion of acidic enzymes and proteases to dissolve the bone matrix. In vitro, TPA/PMA activated myeloid leukaemia cells can also form podosomes , which sThe modulation of the signalosome in podosomes may not only affect the migratory capacity of haematological tumour cells but also the expression of genes involved in cell survival, proliferation and secretion of cytokines, critical mechanisms involved in cancer progression, immunosuppression and drug resistance. Several of the proteins involved in organising the F-actin architecture of podosomes, such as WASP  and the Podia are tubular membrane projections formed by protrusive activity and sustained by integrins and CD44 mediated adhesions that are observed in haematopoietic stem cells ,137 as wChemotactic and EMT promoting signals such as SDF1-α induce podia formation in leukaemia  and haemIn summary, the possible connection between the formation of podia, invasive focal contacts or podosomes and the EMT phenotype in haematological malignancies remains to be elucidated. This is an emerging field of research in haematological tumours with significant potential to identify critical signalling nodes involved in invasive migration, metastatic behaviour, and drug resistance.In epithelial tumours, the upregulation of the core EMT TFs  and the intermediate filament vimentin are related to the development of different types of invasive adhesions such as degradative focal contacts, invadopodia and microtentacles. In haematological tumours, it remains largely unknown whether the expression of EMT TFs and the development of cytoskeletal and adhesive structures are coordinated similarly to epithelial tumours; or whether the expression changes are constrained in distinctive combinations according to the microenvironment and/or the type of haematological cancer. Notably, the formation of particular invasive adhesions associated with EMT remain largely unstudied in haematological cancers. Given the substantial evidence indicating that the development of EMT signatures correlates with poor prognosis in leukaemia, lymphoma and multiple myeloma, it will be critical in the coming years to determine the adhesions and cytoskeletal organisation associated with this phenotype. Several drugs that may interfere with the signalosomes at adhesion sites and/or cytoskeletal -remodelling are already available and could be used as migrastatics: compounds interfering with the migration of invasive cancers ,142,143 Determining the composition and regulation of EMT-associated adhesions in haematological malignancies will improve our understanding of the development not only of invasive migration but also the mechanisms leading to drug resistance and immunosuppression. It is anticipated that this research will result in the identification of new therapeutic targets that alone or in combination with cytotoxic therapies will allow for the treatment of patients refractory to current therapies.


The probability of developing invasive breast cancer increases progressively with age, but it raises sharply in women aged 45-55 years, concomitantly with the stop of the ovarian activity and the fall in the production of sex steroids hormones, especially estrogens. Apparently, in contrast with the decline of circulating estrogens, over 70% of primary breast cancer in postmenopausal patients express estrogen receptor (ER) and proliferate in response to the stimulatory effect of estrogens produced in extra-ovary districts. These extragonadal sites include the adrenal gland, which produces androgen precursors such as testosterone and androstenedione, and the adipose tissue, where the aromatase enzyme converts androgen precursors to bioactive estrogens.Compared with the circulating estrogens produced by the ovaries, those synthesized in the adipose tissue reach a local concentration high enough to exert a significant paracrine activity on neighboring tissues. Considering that, in the mammary gland, the fat tissue may represent up to 80% of the entire volume, it is not surprising that the estrogens, locally produced, provide the suitable microenvironment for the initiation and progression of ER-positive breast cancer.In vitro/in vivo studies demonstrated that alterations in the tissue level of leptin can disrupt the correct structural and functional organization of normal epithelial cells, the so-called cell polarity, leading to tumor initiation [For a long considered a simple fat depot, adipose tissue is now emerging as an active tissue. Indeed, in addition to the production of estrogens by the aromatization of androgenic precursors, adipocytes produce specific growth factors, termed adipokines, which can influence neighboring cells’ behavior. For example, in the breast, leptin, and adiponectin, the two main adipokines synthesized and released by mature adipocytes, act in a tightly balanced manner during mammary gland remodeling . Howeveritiation . Besidesitiation  which caCells polarity is an essential property required for the correct alignment of cells during epithelial tissue organization and consists of the asymmetric distribution of intracellular components along the apical-basal axis. Under the control of three molecular apparatus dynamically interplaying, intracellular components compartmentalize to define an apical domain, directly in contact with the luminal space, and a basal–lateral domain in contact with adjacent cells and basement membrane. Of the three molecular apparatus governing cell polarity, the domain-identity machinery plays a crucial role in establishing the so-called apical junctional complex, which includes tight and adherens junctions, and whose correct assembly requires the interplay of three specific evolutionarily conserved multiprotein structures, termed PAR, CRB, and SCRIB polarity complexes. PAR and CRB localize at the apical domain, whereas SCRIB localizes at the basal–lateral domain.Given the complexity of the process that regulates cell polarity establishment and maintenance, it is not surprising that disruption of the interaction among the three polarity complexes can lead to apical-basal polarity lost, alteration in the structural and functional compartmentalization of intracellular components, misregulation of tissue organization, and cancer initiation .GGT1, the gene encoding γ-glutamyl transferase enzyme, a marker of cell distress and membrane disruption; 2. this negative correlation progressively decreased in histologically normal and cancerous tissue.A recent study , aimed aADIPOR2, one of the genes coding for the adiponectin receptor expressed by epithelial cells, and all genes involved in cell polarity and apical junction complex establishment. Already found in the tissue surrounding the tumor and histologically classified as normal, this loss of correlation suggests that the downregulation of ADIPOR2 could represent an early step in the process leading to a decreased uptake of adiponectin, an unbalanced leptin stimulatory activity, and cell polarity disruption.Of particular interest was the dramatic decrease of the correlation between ADIPOR2 downregulation, can disrupt the correct structural and functional organization in the normal epithelial tissue and trigger tumor initiation, which is promoted and sustained by the bioactive estrogens produced by aromatization of androgenic precursors.This finding is of great clinical relevance considering the role played by weight gain/obesity in breast cancer etiology. Postmenopause is frequently associated with weight gain, mainly due to the accumulation of adipose tissue promoted by testosterone no longer balanced by ovarian estrogens . The inc


Immune surveillance is an essential process that safeguards the homeostasis of a healthy brain. Among the increasing diversity of immune cells present in the central nervous system (CNS), microglia have emerged as a prominent leukocyte subset with key roles in the support of brain function and in the control of neuroinflammation. In fact, impaired microglial function is associated with the development of neurodegenerative diseases, including Alzheimer’s disease (AD) and Parkinson’s disease (PD). Interestingly, these pathologies are also typified by protein aggregation and proteostasis dysfunction at the level of the endoplasmic reticulum (ER). These processes trigger activation of the unfolded protein response (UPR), which is a conserved signaling network that maintains the fidelity of the cellular proteome. Remarkably, beyond its role in protein folding, the UPR has also emerged as a key regulator of the development and function of immune cells. However, despite this evidence, the contribution of the UPR to immune cell homeostasis, immune surveillance, and neuro-inflammatory processes remains largely unexplored. In this review, we discuss the potential contribution of the UPR in brain-associated immune cells in the context of neurodegenerative diseases. Protein homeostasis, also known as “proteostasis,” is a set of coordinated processes that govern synthesis, quality, control and localization of cellular proteins. Up to a third of protein biosynthesis takes place in the endoplasmic reticulum , which favors selective translation of mRNAs coding for proteins involved in cell survival, ER homeostasis, and antioxidant responses , a signal transduction pathway that maintains the balance between the folding capacity and the secretory demand of the cell. The UPR is integrated by three ER transmembrane sensors: Inositol-Requiring Enzyme (lRE1), Protein kinase R-like ER Kinase (PERK), and Activating Transcription Factor-6 (ATF6), which are triggered by the accumulation of misfolded proteins in the ER lumen . The UPRvia mobilization of ER Ca2+ , monocytes, T cells, Natural Killer (NK) cells, NKT cells, dendritic cells (DCs), and B cells  is an ER-resident chaperone that regulates IRE1 function  cells, delaying the onset of EAE signs (Brucklacher-Waldert et al., Perhaps the best-documented link between the UPR and neuroinflammation is in MS (Stone and Lin, C. elegans (Taylor and Dillin, The UPR is a central proteostatic pathway coordinating immunity and inflammation, emerging as a novel therapeutic option for neurodegenerative diseases. Despite the promising advances in the field, the interplay between the UPR and immune cells in the CNS remains to be fully uncovered. Relevant questions should aim to reveal the contribution of UPR transducers and regulators in microglia and additional immune cells contributing to neuroinflammation. Consideration should be given to the aging process, which is regulated by XBP1s in DF, AG, JB, AL, and FO provided scientific input and wrote the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Nutrition and intestinal function are strictly interrelated. The main role of the gut is to digest and absorb nutrients in order to maintain life and well-being. Consequently, chronic gastrointestinal disease commonly results in malnutrition and increased morbidity and mortality. Furthermore, chronic malnutrition impairs digestive and absorptive function because food and nutrients are not only the major trophic factors in the gut but also contribute to the structure and functioning of digestive enzymes and absorptive cells. Finally, specific nutrients can induce or prevent gastrointestinal disease . In conclusion, nutrition has both a supportive and therapeutic role in the management of many gastrointestinal diseases. All these aspects are highly relevant during infancy and childhood, dynamic phases of life characterized by rapid growth, development and developmental plasticity, in which adequate amounts and compositions of substrates both in health and disease are fundamental for growth, functional outcomes and long-term health.Nutrients, “Nutrition and Pediatric Gastroenterology”, contains three original publications and five reviews investigating the specific aspects of nutrition that could play a role in gastrointestinal disease in infancy and childhood, both functional and nonfunctional.This Special Issue of The first review published in this Special Issue provides a comprehensive overview of the possible role of diet in the pathogenesis and management of the most common gastrointestinal chronic diseases, both organic  and functional  . MoreoveNutritional status and its modifications are pointed out by two review papers ,3. The rTwo papers focus on celiac disease (CD) ,5. The iTM). The CoMiSSTM is a symptom-based score aimed at evaluating evolution during a therapeutic intervention (awareness tool). The study found an excellent agreement between CoMiSSTM in presumed healthy infants provided by a pediatrician or parents, without the need to provide any special training to the parents.Contributions related to both immunoglobulin E (IgE)-mediated and non-IgE-mediated gastrointestinal food allergic disorders have been provided ,7. One rLactobacillus reuteri DSM 17938), a prebiotic (agave inulin) and a synbiotic on the stool characteristics in 37 children with cerebral palsy and chronic constipation [p = 0.014). Stool consistency improved in the prebiotic group (p = 0.008). The probiotic, prebiotic and synbiotic groups showed a significant improvement in the history of excessive stool retention, the presence of fecal mass in the rectum and the history of painful defecation. It was therefore concluded that children with cerebral palsy and chronic constipation may benefit from the use of Lactobacillus reuteri DSM 17938 and/or agave inulin in terms of stool characteristics compared to placebo.The Special Issue also includes the results of a double-blind, randomized placebo-controlled clinical trial, which evaluated the efficacy of a probiotic (The present Special Issue provides a summary of the progress in many pediatric gastrointestinal diseases and the importance of nutritional assessment. This is of interest from a clinical and public health perspective. Nevertheless, more studies with larger samples and comparable methods are warranted to understand the actual role of macro- and micronutrients in disease development and health maintenance.


Friction stir welding (FSW) and friction stir spot welding (FSSW) techniques are becoming widely popular joining techniques because of their increasing potential applications in automotive, aerospace, and other structural industries. These techniques have not only successfully joined similar and dissimilar metal and polymer parts but have also successfully developed polymer-metallic hybrid joints. This study classifies the literature available on the FSW and FSSW of thermoplastic polymers and polymer composites on the basis of joining materials (similar or dissimilar), joint configurations, tooling conditions, medium conditions, and study types. It provides a state-of-the-art and detailed review of the experimental studies available on the FSW and FSSW between similar thermoplastics. The mechanical properties of FSW (butt- and lap-joint configurations) and FSSW weld joints depend on various factors. These factors include the welding process parameters , base material, tool geometry  and tool material, and medium conditions . Because of the dependence on many factors, it is difficult to optimize the welding conditions to obtain a high-quality weld joint with superior mechanical properties. The general guidelines are established by reviewing the available literature. These guidelines, if followed, will help to achieve high-quality weld joints with least defects and superior mechanical properties. Apart from parametric-based studies, the statistical-based studies -based studies) are covered, which helps with the determination of the influential parameters that affect the FSW and FSSW weld joint strength. Also, the optimal ranges of the most influential process parameters for different thermoplastic materials are established. The current work on the development of general guidelines and determination of influential parameters and their operating ranges from published literature can help with designing smart future experimental studies for obtaining the global optimum welding conditions. The gaps in the available literature and recommendations for future studies are also discussed. Thermoplastics and their composites are becoming popular due to their high stiffness and strength-to-weight ratio. They have many industrial applications, like in automotive industries , to reduFriction stir welding (FSW), a comparatively new joining technique, was patented by The Welding Institute (TWI) in 1991 . In thisSeveral review articles, overview articles, and book chapters have been written on the FSW of thermoplastic polymers and polymer composites, and their research highlights are summarized in Apart from FSW and FSSW, new variants of these techniques have also been developed for joining thermoplastic materials. The friction stir processing (FSP) technique is used for welding and processing of thermoplastics by reinforcing the weld zone (processing zone) with particulates to develop composite weld joints ,47, whicAccording to the best of the authors’ knowledge, there is no detailed review article available in the published literature on the determination and optimization of the welding conditions for maximizing joint strength of FSW and FSSW of similar thermoplastic materials. The present study covers the literature on the experimental investigations of FSW and FSSW of similar thermoplastic sheets and pipes. A detailed comparison of the process parameters, tooling conditions, and medium conditions from the available studies has been presented for optimizing the welding conditions. As a result, general guidelines are developed, most significant parameters are determined, and narrow optimal operating ranges of the significant process parameters are established, which will help with developing superior quality and strength thermoplastic weld joints using FSW and FSSW techniques.The literature available on the FSW and FSSW of thermoplastic materials is vast and can be divided into several classes, as shown in Many studies have analyzed the effects of process parameters, tooling , and medium conditions on the weld strength and quality. However, few of the studies have investigated the CFD  modeling  and flowMany studies have investigated the welding of similar thermoplastic materials. However, there are several studies available which have investigated the FSW and FSSW techniques, and other variants of these techniques, for joining dissimilar materials. Some studies have investigated the welding between dissimilar thermoplastic materials. They include FSW of PE-PP , ABS-PC This study will focus only on the review of the process optimization of the FSW and FSSW between similar thermoplastic polymers and polymer composites. The effect of different process parameters, tooling, and medium conditions on the weld joint mechanical properties will be covered in detail.Many studies are available on continuous and spot-welding forms of FSW. Both butt and lap configurations have been studied for continuous FSW. The FSSW is like resistance spot welding, which is a very widely used welding technique in the automotive industry and has many other promising applications. Most of the studies have optimized the welding conditions for maximizing the weld strength, as the structural components often fail at the weld joint.The quality and strength of the butt-joint configuration weldments are assessed using joint tensile strength. Because of the large number of studies available on the butt-joint FSW, it is further categorized into three parts. First, we will investigate the studies which only consider the FSW process parameters. Then, we will study the combined effects of process parameters and tool geometry (pin profile and size). Finally, we will study the effects of external heat assistance along with process parameters and tooling conditions on the weld joint strength.There are several studies available that have performed the butt-joint FSW of thermoplastic polymer and polymer composite sheets using a plain cylindrical pin profile tool. These studies help to only examine the parametric effects on the weld strength. Several thermoplastic sheets have been investigated, and their operating ranges and optimal values of the process parameters are summarized in Many studies have also investigated the effects of pin profiles, along with processing parameters, on the joint mechanical properties of FSW of thermoplastic materials. The geometric profile of the tool pin is changed from plain cylindrical profile to further improve its overall mixing ability of the molten polymer material. Several thermoplastic sheets have been investigated using threaded cylindrical pin tools, which include HDPE  FSW technique should be used as it improves mechanical properties and reduces thermal residual stresses.The square pin, convex pin, tapered pin with groove, or threaded-tapered pin with a chamfer should be used instead of the plain cylindrical pin because of their better mixing ability of molten polymer material and for achieving better weld joint strengths.The stationary shoulder tool should be used as it provides better quality welds.For threaded pin profile, the tool should be designed such that thread flute and pin rotation are not in the same directions, so for a right-hand threaded pin with clockwise rotation or a left-hand threaded pin with anticlockwise rotation, to obtain better weld joint with better properties and less defects.The above-detailed discussions suggest that the weld joint strength and quality of butt-joint FSW of thermoplastics depends on process parameters, tooling conditions , and medium conditions. Because of its dependence on many factors, only a few of them are considered in a single study. The available studies provide only the local optimum welding conditions, which is limited to the factors and their ranges considered. To determine the global optimum welding conditions, a smart and detailed experimentation plan needs to be devised . The plaThe FSW depends on many process parameters. However, as will be discussed in the later section, the rotational and traverse speeds are the most important parameters that affect the joint tensile strength. The range and average optimal rotational and traverse speeds for achieving maximum joint tensile strength from the There are very few studies available on FSW of pipes, because unlike other types of welding, there is complexity involved to move the high-speed rotating FSW tool along the curved path. Muñoz  has studMosavvar et al.  have stuThere are few studies available on FSW of thermoplastic polymer and polymer composite sheets in lap-joint configuration, and they are summarized in The submerged (underwater) FSW technique should be used as it provides better joint strength than conventional FSW.The threaded cylindrical-conical pin and cone frustum pin profiles should be used as they provide better weld joint strength.Based on the above discussions, general guidelines can be developed which will help with achieving high-quality lap-joints with superior mechanical properties and less defects through friction stir welding of thermoplastic polymers and polymer composites. The guidelines are:The lap-joint FSW depends on many process parameters. However, as will be discussed in a later section, the most significant parameters that affect the joint strength are traverse and rotational speeds. The optimal traverse and rotational speeds for achieving maximum joint strength from The widespread use of the modern thermoplastic structures requires detailed investigation not for only butt- and lap-joints, but also for other types of joints, like T-joint. Most studies are available on butt-joints while few are on lap-joints, however, the studies on other types of joints are lacking. This research gap needs to be filled as other types of joints are also useful in automotive and other structural industries. Elyasi and Derazkola  have stuSeveral studies are available on FSSW of thermoplastic polymers and polymer composites. These studies investigate the parametric and tool geometry effects on the joint strength. The joint strength for this category of weldments is assessed using lap-shear tensile force, which is obtained through lap-shear tests. Some studies have not varied the tool pin profiles to only investigate the parametric effects on the weld strength. Lambiase et al. ,156 haveSeveral studies have varied pin profiles and materials to investigate their effects and to determine the best pin profile and material which maximizes the joint strength. Yan et al.  have stuThe welding should be performed with longer dwell times as it improves joint strength.The effect of plunge rate should not be investigated in future studies, as it is not a significant parameter and has negligible effect on the weld joint strength.Tapered cylindrical and tapered threaded pin profiles should be used as they provide better weld joint strength.The tool should be made of pure copper material as it provides better results than aluminum and steel alloys.Based on the above discussions, general guidelines can be developed which will help with achieving high-quality joints with superior mechanical properties and less defects through FSSW of thermoplastic materials. The guidelines are:The FSSW of thermoplastic materials depends on many process parameters. However, as will be discussed in the next section, the dwell time and rotational speed are the most important parameters that affect the joint strength. The optimal dwell time and rotational speeds for achieving maximum joint strength from the Several studies have conducted statistical analysis, like analysis of variance (ANOVA), for determining the most significant parameters that affect the weld joint mechanical properties. As different studies have conducted investigations on different sets of parameters in different operation ranges, there is expected variation in the results. This is because one of the parameters might be significant in a specified set of parameters and operation ranges, and it might be insignificant in another set of parameters and operation ranges. Apart from mechanical property optimization-based studies , the staThe ANOVA results of all the studies are summarized in Very limited statistical studies are available on the FSW of thermoplastic sheets in lap-joint configuration. Ahmadi et al.  have invLimited statistical studies are available on the FSSW of thermoplastic sheets. Bilici et al.  have stuFor optimization of FSSW of thermoplastics polymers, the machine learning techniques like artificial neural networks (ANN) have also been utilized. Kurtulmuş and Kiraz  have devFSW is a greener welding technique because of its low power consumption with no harmful welding byproducts, like greenhouse gases and toxic fumes. This technique can help automotive and other industries to cut down on their carbon footprint from their manufacturing chains. Apart from automotive industries, it has broad applications in other structural industries, like aerospace and marine industries. It is a unique welding technique that is widely popular among both metallic-based and polymeric-based industries. It has not only successfully joined similar and dissimilar metal and polymer parts but has also successfully developed polymer-metallic hybrid joints. FSW has the potential to compete and excel other metallic-based and polymeric-based welding techniques. It requires no preparation of parts, less processing time, no consumables, low-cost equipment, ability to join difficult to weld materials, and simple processing steps which can be easily automated for mass manufacturing. The technique is already in use in major car industries like Mazda and aerospace industries like Boeing. However, the large-scale, cost-effective, robotic FSW could be the answer to the next generation of flexible manufacturing in automotive, shipbuilding, and aerospace industries.For thermoplastic polymers and their composites, the FSW technique is still in the development phase because most of the research is focused on butt- and lap-joint configurations. There is a serious need to transfer knowledge to other types of joints (like T-joint), and especially pipe and tube welding, which will create widespread applications and can also greatly help to cater to the already established piping, tubing, and tank construction industries. Also, apart from a few studies which have been focused on the development of specialized automated and robotic platforms to perform FSW of thermoplastics, most of them are focused towards using milling machines with fixtures. Further research into the development of low-cost, lightweight, and specialized platforms can also create extensive applications for the process because of the portability to use in field areas.The literature available on the FSW and FSSW of thermoplastic polymers and polymer composites is vast and has been classified into several classes in this study. The main classifications include the thermoplastic materials used (similar and dissimilar thermoplastic polymers and polymer composites), joint configuration , tooling conditions , medium conditions , and study types . Further, a detailed review focusing on the FSW and FSSW between similar thermoplastic polymers and polymer composites has been carried out. The effect of different process parameters, tooling, and medium conditions on the mechanical properties of the weld joint were covered in detail.For the butt-joint, general guidelines have been developed that suggest that the double-side cooling-assisted (weld nugget cooling) FSW technique should be carried out using PTFE-coated and heat-assisted stationary shoulder tool. The welding sheets should be pre-heated, and the tool pin should be either a square pin, convex pin, tapered pin with groove, or threaded-tapered pin with a chamfer. These guidelines ensure a butt-joint weld with superior mechanical properties and less defects.There are few studies available on the FSW of thermoplastics in lap configuration. However, the developed guidelines suggest that the better joint mechanical properties are achieved under submerged conditions. Also, the threaded cylindrical-conical pin and cone frustum pin profiles should be used for better weld joint strength.There are also limited studies available on FSSW of thermoplastic polymers and polymer composites. The general guidelines suggest that welding should be performed with longer dwell times using tools made of pure copper material with tapered cylindrical and tapered threaded pin profiles. The available studies have also suggested that the plunge rate does not affect the weld joint strength, so it should not be investigated further in future parametric-based studies.The statistical-based studies like ANOVA have helped with the determination of significant parameters for FSW and FSSW of thermoplastic polymers and polymer composites. For butt-joint configuration FSW, the most influential parameters are the rotational and traverse speeds that affect joint tensile strength and other mechanical properties. Other influential parameters are axial force, tool diameter, tilt angle, and tool temperature. For FSW of lap-joints, the most influential parameters are the traverse and rotational speeds, as their contribution on joint strength is reported to be around 91.35–95.86%. For FSSW, the most influential parameter for weld joint strength is the dwell time. Other influential parameters are rotational speed, plunge depth, and heat transfer coefficient of the tool material.In a nutshell, the optimum welding conditions for FSW and FSSW of thermoplastic materials need to be determined for achieving high-quality joints with superior mechanical properties. The optimization of these welding conditions is a challenging task, as FSW and FSSW of thermoplastics depends on many factors. The available studies have only determined the local optimum conditions for the FSW of thermoplastics. There is a lack of detailed study for establishing the global optimal welding conditions. The developed general guidelines and the most influential parameters determined, and their operating ranges established from previous studies, can help with the development of a smart and extensive experimentation plan for future studies to determine the global optimum conditions.There are two main areas related to FSW of thermoplastics with very few available studies. These two areas need to be studied in detail in the future to close the research gaps. Firstly, there are very few studies available on the FSW of thermoplastic pipes. In the future, the existing knowledge for thermoplastic sheets needs to be transferred for piping, tubing, and tank construction, as the thermoplastic-based materials have huge applications in these industrial areas. Secondly, there are also very few studies available that have focused on the development of a FE-based model for FSW of thermoplastic materials. Nowadays, the availability of low-cost yet powerful computational resources is paving the way for simulation and optimization of physical phenomena. The FE-based models are becoming widely popular as the cost is greatly reduced by performing less experimentations, required only for model verification purposes. The future studies should be focused on the development of comprehensive FE-based models of FSW that can help with maximizing the weld strength by the consideration of a greater number of process parameters along wide operating ranges. Such a model can lower the cost burden of large numbers of experimentations, as the model can be validated using a few experimental cases of the FSW of thermoplastics.


Oxidative stress is an imbalance between the production of free radicals and their neutralization by the antioxidants’ defenses . A low aIn livestock, there is a well-defined correlation between the onset of some diseases and a reduction in the antioxidant status . OxidatiAntioxidants entitled “Antioxidants in Animal Nutrition” is to publish papers and reviews on the effects of feed antioxidants on animal performance and health and product quality. It comprises five reviews and eleven original research papers.The aim of this Special Issue of Firstly, dietary challenge models, including oxidized fats and oils, heavy metal exposure, soybean meal, protein or amino acids, and diets contaminated with mycotoxins are reviewed. These models facilitate our understanding of the physiological mechanisms involved and the most suitable antioxidants that can mitigate oxidative stress in poultry, swine, and fish . Consumers tend to focus on safe and natural products of animal origin, and thus it is important to substitute synthetic substances with natural ones. There have been several recent studies on plant feed additives used as natural alternatives to synthetic antioxidants. In fact, natural extracts, essential oils, and by-products from plants contain bioactive compounds that are strong natural antioxidants. The effects of natural extracts on product quality, oxidative stability, and shelf life in ruminants, swine, and rabbits have been reviewed. The authors reported that the effects of plant additives are different but similar to synthetic vitamin E, thus suggesting their role as possible natural substitutes . The impSalix spp. bark in heat-stressed broilers reduced oxidative stress markers and enteric pathogenic bacteria, thus improving growth performance [The effects of heat stress on broiler antioxidant status and inflammatory responses have also been analyzed because such stress is an important problem in the poultry sector. The authors highlighted that some studies have reported that dietary supplementation with extracts of formance .TM). To the best of our knowledge, this is the first study to assess the antioxidant reserves in animal nutrition. Antioxidant reserves help identify the amount of antioxidants stored in the organism, which can be released to reduce oxidative stress. Boswellia and plant extract mixtures were found to sustain blood antioxidant status, while Uncaria and Tanacetum extracts are mainly converted in blood reserves in the form of glucuronides, sulphates, and glucosides. It is thus interesting that different phenolic compounds play a different role in the organism, and this should be related to the phenolic metabolism and their relationship with the intestinal microbiome [In this Special Issue, four original research papers deal with the study of plant feed additives as natural alternatives to the use of synthetic antioxidants. The first of these four papers reports that dietary supplementation with natural extracts containing polyphenols in gestating sows increased the number of piglets born alive and the litter weight, decreasing the presence of low-birth-weight piglets. In addition, piglets born from sows receiving polyphenols had a higher antioxidant status and tended to have a higher weaning weight than controls . These dcrobiome . Phaffia rhodozyma yeast, improved the antioxidant status, immune response, and meat quality [Another study, conducted on broilers exposed to heat stress, showed that dietary supplementation with astaxanthin, a carotenoid derived from  quality . In the  quality .The effects of different feed ingredients, selenium form and rumen-protected amino acids, on antioxidant status in ruminants were evaluated in four experimental trials. In the first one, the administration of fresh or dry forage affected the oxidative stress index in lactating goats. The effects of forage polyphenols on the antioxidant status of lactating goats are not conclusive, and thus further studies are needed . In anotAmino acids are involved in the cellular oxidative balance, and the effects of dietary rumen-protected methionine and lysine, alone or in combination, were evaluated in early lactating ewes. The results showed that methionine improved the antioxidant status and, in contrast, lysine reduce milk oxidative stability. The authors reported that attention should be given not only to the dietary amount but also to the amino acid effects in order to prevent physiological imbalance and oxidative stress .Lactobacillus delbrueckii in piglets, challenged with lipopolysaccharide, improved the intestinal structure and tight junctions and enhanced antioxidant functions, upregulating the nuclear factor erythroid 2-related factor (Nrf2) signaling pathway [Lactobacillus plantarum postbiotics RG14 in post-weaning lambs was investigated. Dietary postbiotic increased serum and ruminal fluid antioxidant activity and reduced serum lipid peroxidation, and the upregulation of hepatic antioxidant enzymes and ruminal barrier function was also observed [In addition, dietary probiotics and postbiotics have been shown to be a good approach to counteract the oxidative stress involved in the onset of several enteric pathologies. This was analyzed in two other original research papers. In the first, dietary supplementation with  pathway . In the observed . An in vitro study analyzed the effects of N-acetyl serotonin, a metabolite of L-tryptophan, on porcine enterocytes submitted to oxidative stress with 4-hydroxy-2-nonenalon. The data showed that N-acetyl serotonin attenuated oxidative stress in porcine enterocytes by regulating Nrf2 signaling. These findings provide new insights into the efficient role of N-acetyl serotonin in preserving the intestinal homeostasis .In conclusion, this Special Issue adds new evidence to the field of the dietary supplementation of antioxidants in livestock, supporting their beneficial role in enhancing antioxidant status and animal health. The product quality was also enhanced by protecting against oxidation and improving their nutritional value. Further studies are needed to better understand the health benefits of dietary antioxidants in livestock and to identify the correct dosage to prevent antioxidative stress.


Background. Interpersonal distance (IPD) plays a critical role in a human being’s social life, especially during interpersonal interaction, and IPD is non-verbal social information and not only provides silent cues but also provides a secure space for personal relationships. IPD has been a research field of neural studies from the recent decade, researches had provided behavior and neural correlates of IPD. Objectives. This review aims to summarize the experimental paradigms of IPD-neural research, to reveal the neural activity processes associated with it, and to explore the correlation between IPD-neural activity and IPD-behavior. Methods. We conducted a standardized systematic review procedure, including the formal search method be adopted to seek out any type of studies related to IPD and brain, then devised them into categories to make a systematic review. Results. 17 articles met the inclusion criteria of the review, 5 event-related potential (ERP) studies measured the amplitude and latencies of ERPs, and 12 functional magnetic resonance imaging (fMRI) studies provided the neural activation during IPD tasks. In addition, the passive IPD experimental paradigm is the main experimental paradigm for exploring neural activity in IPD cognition, with the parietal lobe, motor areas, prefrontal lobe, and amygdala being the main brain areas involved. Functional connections between the identified brain regions were found and have a moderate correlation with IPD behavior. Conclusions. This review provides the neural activity of the IPD interaction process. However, the insufficient ecological validity of IPD tasks and ignore the initiative of people in IPD interaction. Therefore, there is a large research space on this topic. The work of the current systematic review contributed to linking the external performance and inner neural activities of IPD. Interpersonal distance (IPD), a silent space and interaction zone, is a physical distance that individuals choose to maintain between themselves and others while interacting . IPD conAs we mentioned before, IPD is one of the key psychological capabilities. IPD not only helps to establish interpersonal boundaries and private space but also guides us to create a good enough space for interaction with others. From the perspective of human development, IPD begins with the integration of mother and infants without distance. Infants and toddlers are embraced by their mothers, skin to skin, and they do not have the concept of personal boundaries and personal distance. They believe that they and their mother are one. As children grow up, they gradually learn that they are themselves and their mother is their mother. The growth is from the transitional space to the independent IPD. Thus, studies on IPD are important for understanding human social behavior and development. IPD is a complex social behavior, a body of researches has focused on this field. It was found in the early stages of IPD studies that demographic variables influence the IPD, the personal distance of men is larger than that of women ,14,15, TWith the evolution of cognitive neuroscience, neuroscientists paid attention to the neural correlates of IPD both in non-human and human areas in recent decades. From the view of space protection and survival, initial evidence of the neural basis of IPD was coming from animal experiments. Electrical stimulation of the ventral intraparietal area (VIP) and the precentral gyrus (PZ) in the monkey’s brain evoked spatial defense responses, such as head retraction and hand movement to the outer space . It suggThe application of functional brain imaging and technology is crucial in the field of IPD as brain and behavioral changes are concomitant with each other. On the one hand, the study of the effects of brain lesions on IPD can be a reference for the neurophysiological basis of IPD. In an amygdala lesion case study of IPD, the patient keeps a close IPD during the stop-distance task, indicating the loss of IPD sense with the dysfunction of the amygdala . That isIPD is a complex and integrated social behavior, an in-depth understanding of the neural mechanisms associated with it is a vast and complicated task. How are the neural activity processes of IPD recorded and which brain regions are involved in the cognitive process of IPD? What are the connections between these brain regions? Are the neural IPD studies qualified to reflect the IPD behavioral processes? Hence, the current systematical review is to answer these questions. Besides, there were no articles that have systematically reviewed the neural mechanism of IPD. Thus, the present systematic review was focus on this topic, to sort out all the scientific publications related to neural correlates of IPD. This review introduced the experimental paradigms of IPD and explored the strengths and weaknesses between them. As well, this article focused on summarized the brain activation in IPD, functional connectivity, and correlation between IPD and neural activities. Furthermore, based on a systematic review of the researches, we discussed the limitations of previous studies and proposes the challenges and opportunities in the field of IPD neuroscience. This systematic review contributes to the construction of a standard, ecologically validated experimental research paradigm for IPD, helps to comprehend the neural basis of IPD in a multifaceted way, and provides a reference for subsequent studies. This systematic review was registered in INPLASY (registration number: INPLASY202170074); It was conducted and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement .This review aims to investigate the neural mechanisms related to IPD, eligible studies included those which conduct the IPD evaluation or cognition under neural methods, like functional magnetic resonance imaging (fMRI), ERP.IPD studies mainly adopted within-subjects or between-within subjects design to ensure that factors like age, gender, culture, height, and personal character were equivalent across experimental conditions. Therefore, this review included any types of evidence that related to the IPD neural process.IPD paradigm must have met the physical distance between subjects and others. In addition, the experimental procedure must include the process of interpersonal distance assessment or interpersonal distance recognition.If the IPD paradigm of studies included components other than IPD cognition  were excluded.Eligible studies included healthy subjects who self-report or were screened by the researchers, without physical illnesses, mental disorders, psychiatric, or neurological.Eligible studies also included patients , to study the effect of brain function variation on IPD.Animal studies were excluded.The outcomes of the studies have to contain neural results, especially the functional neural changes during the IPD-tasks. The studies, which only collect the neural structure in the brain were excluded. Outcomes of neural alterations must be recorded through devices used in neuroscience research, such as fMRI and electroencephalograph (EEG).Database searching was completed on 2 April 2021 and included searches of Ovid . Publication dates or language were no a limitation for search.The search terms were entered into the database as follows:  AND .This systematic review adopted a modified version of the Newcastle-Ottawa Quality Assessment Scale (NOS) . The NOS17 articles that met the requirements were included in this review; they were selected from 2796 results. The flow diagram  is illusAll articles included in the systematic review passed the quality assessment . Most ofFrom The approaching and withdrawal task (9 studies) ,50,52,54In this section, we showed findings from fMRI findings firstly, as the majority of studies have focused on the changes of brain regions. Then, we turn to present findings from the EEG during the IPD processing, followed by findings from the correlation of neural activation and IPD.As shown in IPD is not only a motion modulation of the human being but also a complicated social behavior. 8 of 12 results of the included fMRI studies pointed out the activities in the frontal area of the brain during the IPD-tasks ,49,50,52Additionally, the changes of the motor cortex were found in 7 studies ,46,48,50Furthermore, the emotional state has an impact on the neural changes of IPD cognition. 4 studies observed increased activation in the amygdala ,46,47,54Six out of the 12 fMRI studies tried to find the functional connectivity response to IPD tasks, while 5 studies had significant results associated with the IPD-tasks ,49,50,51According to Although changes in brain activity in the IPD neural task were discussed, does the founded brain activity reflect IPD in real contexts? In this literature review, the IPD-neural task showed medium significant correlations with the ecological IPD task, including positive and negative correlations.Interestingly, the enhanced functional connectivity of the brain was accompanied by a decrease in IPD, implying the more active the functional connections, the shorter the IPD. It was reported that greater DIPS-PMv connectivity related to a smaller personal space size . EnhanceIPD expands along with the activation of some brain activities. Greater activation of the right amygdala was found to have a relationship with the increase in preferred distances accompanying negative expressions . The amyTo sum up the above, findings in the neural-IPD generally indicate that the parietal lobe, prefrontal area, motor cortex, and amygdala may play an important role during the IPD processing. Although there was some exploration of the found neural areas, little is known specifically about the connectivity of these regions. Besides, the neural activities of computerized-IPD have a moderate correlation with IPD behavior. Hence, it will be significant to investigate the neural connectivity of the brain area. And, Neural IPD experimental paradigms with better ecological validity and reproduction of real IPD interaction processes will be critical to deeply understand IPD brain activity.IPD is a hot topic in the fields of sociology and psychology, but it has been combined with neuroscience in the past ten years. The earliest literature we included was a study published in 2013. Although the similarity concepts like peripersonal space and near-body space were discussed by researchers, peripersonal space links to the space around the body, with which “near” or arm’s length of the body, while the space occupied by the body is called the near-body space . StudiesThis systematic review examined the IPD processing neural basis. Overall, the passive experiment paradigm is the main methodology of neural IPD exploration. And, The findings from the current review pointed out the parietal and motor lobe may be mainly related to IPD regulation processes, while the prefrontal lobe may be responsible for IPD changes with different social relationships, such as between acquaintances and strangers, in addition, the amygdala was thought to be associated with emotion-related IPD changes. Furthermore, evidence from fMRI and EEG indicates a medium effect between neural changes and IPD behavior. It is vital to further discuss the findings. Above all, it is very clear that neural changes in IPD cognition are an integrated and complex process that involves not only spatial cognition and motor adjustment but also is influenced by social factors and emotions. Substantial evidence of the complexity of neural activity in the cognitive processes of IPD. Multiple EEG components and amplitudes, like N1 and P1 changes during IPD, and evidence from fMRI suggests that these diverse neural changes are complicated, and both the region of interest (ROI) analysis and the whole brain analysis reveal multiple brain regions that were activated and connected during the IPD processing.Additionally, current studies on the analysis of functional connectivity between brain regions involved in IPD processes are insufficient. Only a small number of studies have addressed the exploration of functional connectivity associated with IPD stimulation. Furthermore, the focus of these studies has primarily been on understanding functional connectivity between the DIPS and PMv, dorsal striatum as a seed connected with occipital lobe and other areas, midbrain periaqueductal grey (PAG) as a seed correlated with premotor cortex and dorsolateral prefrontal cortex, and the connectivity between AMY -DIPS, and AMY-FFA. These results suggested the high involvement of the DIPS region in functional connectivity in response to IPD stimuli, though more research is required. The neural activity of the IPD process does not work in isolation, so it is necessary to build systematic neural networks to understand the neural functions that collaborate.Furthermore, there appears to be a passive model of IPD processing which has been a longstanding paradigm in IPD fMRI studies. The passive experimental paradigm includes a large number of looming faces tasks and a few IPD-tasks, such as computerized CID tasks and interpersonal space tasks. Although these experimental tasks are passive IPD paradigms, computerized-CID has processes of IPD assessment and selection of acquaintances and strangers, whereas looming faces tasks are completely passive in the presentation of receptive stimuli. Thus, relatively active PFC activity was observed in the computerized-CID task, whereas brain areas in the looming faces tasks presented more movement-related brain activity changes. However, these types of IPD-tasks cannot fully reveal the neural processing of IPD. In essence, IPD is a reciprocal social behavior in which we both actively approach others and are approached by others. In the behavioral study of IPD based on Virtual Reality (VR) technology, we can find the experimental paradigms of active approach and passive approach ,75,76. DHeterogeneity between studies is influenced by a variety of factors, which makes the results inconsistent between studies and the work of comparing studies difficult. First, the functional brain techniques of EEG and fMRI have different focuses and advantages, and the analysis of data from EEG or fMRI, with inconsistent ROIs between studies, yields inconsistent results. For example, one EEG focuses on observing N1 , while aPrevious studies have explored the neural activity mechanisms of IPD in interpersonal states, however, the following gaps exist. IPD is a complex and integrated process that includes the adjustment of body space and is also influenced by a combination of social factors, as well as the active participation of the individual. Therefore, the experimental paradigms in this systematic review didn’t present the process of IPD completely and systematically. Although passive IPD research provides a way to understand social behavior, a paradigm closely related to personal defenses and private space, active IPD participation is key to building interpersonal distance. Therefore, we suggest that a standard IPD-neural experimental paradigm requires both active and passive interpersonal distance interaction processes. In addition, IPD interactions include many cognitive and behavioral processes, such as active thinking, evaluation, and adjustment of the IPD of individuals. Future experimental designs can consider the above aspects and try to measure the thinking process, action process, and adjustment process of IPD separately during the interpersonal interaction experiments, providing discussion and exploration of neural mechanisms in different IPD interaction stages. Furthermore, the observed correlation between brain activity and IPD behavior was a moderate level, while some studies reported weak or no correlation between them. Computerized IPD tasks may not effectively respond to real IPD processing and may not be a valid reflection of real IPD processing. Therefore, flexible, convenient, and interference-resistant brain activity acquisition devices, such as functional near-infrared spectroscopy (fNIRS), are needed for future studies. fNIRS is a brain activity recording tool developed in the last two decades, with good resistance to interference and good spatial and temporal separation rates. fNIRS is particularly suitable for experiments in natural contexts, and this feature of fNIRS provides the possibility of active IPD-evaluation, where subjects can wear NIRS devices on their heads and take real action to assess IPD with others . In addiAlthough this review has initially sorted out the neural mechanisms of IPD, it still has limitations. The current review did not select a specific population as the subject of the study, and the results included both healthy people and people with mental disorders or traits. Moreover, the studies included in this review used different IPD experimental paradigms and considered different emphases. Besides, most of the studies had small sample sizes and no sample size estimation was performed before the experiments were implemented. Therefore, this will provide important information for future studies on this topic that need to consider the experimental paradigm and how to compare the differences between groups.This systematic review explored the neural changes during the IPD task and the correlation with physical interpersonal distance. This review provides the neural activity of the IPD interaction process. Additionally, factors affecting real IPD interaction that act on the neuroactive processes of IPD and show consistent results. However, due to the complicated nature of IPD, the ecological validity of the neural-IPD tasks was insufficient, and the tasks require further attention towards the activity of human beings during IPD interaction. Therefore, the neural exploration of IPD is looking forward to multiple IPD research topics and high ecological and valid neural-IPD paradigms.


Brain edema is a severe stroke complication that is associated with prolonged hospitalization and poor outcomes. Swollen tissues in the brain compromise cerebral perfusion and may also result in transtentorial herniation. As a physical and biochemical barrier between the peripheral circulation and the central nervous system (CNS), the blood–brain barrier (BBB) plays a vital role in maintaining the stable microenvironment of the CNS. Under pathological conditions, such as ischemic stroke, the dysfunction of the BBB results in increased paracellular permeability, directly contributing to the extravasation of blood components into the brain and causing cerebral vasogenic edema. Recent studies have led to the discovery of the glymphatic system and meningeal lymphatic vessels, which provide a channel for cerebrospinal fluid (CSF) to enter the brain and drain to nearby lymph nodes and communicate with the peripheral immune system, modulating immune surveillance and brain responses. A deeper understanding of the function of the cerebral lymphatic system calls into question the known mechanisms of cerebral edema after stroke. In this review, we first discuss how BBB disruption after stroke can cause or contribute to cerebral edema from the perspective of molecular and cellular pathophysiology. Finally, we discuss how the cerebral lymphatic system participates in the formation of cerebral edema after stroke and summarize the pathophysiological process of cerebral edema formation after stroke from the two directions of the BBB and cerebral lymphatic system. Worldwide, stroke is the leading cause of adult disability and the second main cause of death after coronary heart disease, affecting more than 13.7 million patients every year . Stroke Cerebral edema occurs in three distinct phases that mature separately over time and space: the early cytotoxic edema phase, the subsequent ionic edema phase, and the most severe vasogenic edema phase . CytotoxThe water source of ionic brain edema can only come from blood and CSF . The hypSeveral fundamental pathophysiologic processes contribute to cerebral edema development after stroke, including the disruption of TJs, the loss of homeostatic ionic gradients, inflammatory responses, and the activated glymphatic system. After the disruption of TJs, inflammatory responses and the activation of ion channels can be considered to promote the occurrence of cerebral edema by exerting an influence on the permeability of BBB. We summarize these aspects into only one part: the increase of BBB permeability to promote cerebral edema. However, the influence of the CNS lymphatic system on the occurrence and progression of cerebral edema induced by stroke has not been reviewed. Therefore, this article summarizes the various pathophysiologic processes that affect the permeability of the BBB to promote the occurrence of cerebral edema and focuses on the effect of the CNS lymphatic system on the development of cerebral edema after stroke.BBB dysfunction that occurs during cerebral ischemia enables considerable vascular fluid to pass through microvascular endothelium into the brain interstitial compartment and eventually leads to vasogenic edema formation . Any disThe concept of BBB was first proposed in the early 20th century . Today, de novo expression of ion transporters serve as drivers of ionic edema after stroke , which act as the first line of defense in the innermost layer of the BBB, are differentiated from common ECs by a lack of fenestrations, minimal pinocytotic activity, and the presence of extensive TJs and numerous mitochondria . Notablyr stroke . Severalr stroke .Pericyte is a mesenchymal cell type located in the endothelial basement membrane of the capillaries and microvessels . AstrocyEndothelial cell junctions include TJs and adherens junctions (AJs) . TJs betVasogenic edema is characterized by increased paracellular permeability of the BBB, which is mainly caused by TJ disruption . TherefoThe NVU, which emphasizes cell–cell and cell–matrix interactions in the brain, provides a more integrative answer to BBB disruption after stroke . The perAs a first-line defense located between the blood plasma and interstitium, the continuous endothelium is essential for physiologic homeostasis and directly reacts to harmful substances from the periphery. Under the pressure of ischemia and hypoxia after stroke, actin polymerization elicits stress fibers and concomitant endothelial cell contraction mediated by zipper-interacting protein kinase (ZIPK) through the phosphorylation of the myosin light chain . FollowiActivated pericytes and astrocytes also contribute to the breakdown of BBB and promote cerebral edema formation after stroke. Pericytes migrate from the brain microvascular wall in a rat MCAO model, and the detachment increases the permeability of the BBB to water and tracers . StimulaAfter stroke onset, circulating leukocytes adhere, migrate, and eventually accumulate in the lesion site and then release inflammatory factors to cause secondary BBB disruption. Neutrophils are the earliest leukocyte subtype that infiltrates an ischemic brain and contribute to the breakdown of BBB by secreting MMP-9, neutrophil elastase, and reactive oxygen species (ROS) . In a stMast cells, as resident cells in the brain and meninges, also promote BBB damage and edema formation by releasing their granule contents, such as histamine, TNF-α, proteases, heparin, and various chemoattractants . Rats trMacrophages, which can be transformed from brain-inhabited microglia or differentiated from peripheral monocyte, also promote neuroinflammation and blood vessel disintegration after ischemic stroke . Both miVarious chemical factors, such as cytokines, chemokines, ROS, MMPs, and VEGF, secreted from the periphery and resident immune cells and glial cells play a key role in the regulation of BBB disruption in ischemic stroke . Among tThe depletion of intracellular ATP leads to the cytotoxic edema of all CNS cell types after ischemic stroke, of which astrocytes are particularly prominent; cytotoxic edema ultimately provides the driving force for ionic edema, vasogenic edema, and complete hemorrhagic conversion . The mecde novo expression of the sulfonylurea receptor 1–transient receptor potential 4 channel (SUR1-TRPM4) in all cells of the NVU and contributes to the formation of ionic edema (Na + –K + –2Cl -cotransporter (NKCC) is expressed the astrocytes, neurons, and ECs of the brain , and resic edema . The bloic edema . In the ic edema . The recic edema .+–Ca2+ exchanger (NCX) in astrocytes is also involved in Ca2 + induced ROS production, DNA ladder formation, and nuclear condensation -1β, IL-6, TNF-α, and MMP-9 . The phaensation . Microglensation . By contensation . The phaensation . NCX1-meensation . Calciumensation .At the periphery, impaired lymphatic system function is one of the common causes of edema and leads to the pathologic accumulation of protein-rich lymphatic fluid in the intercellular interstitium . Acquirein vivo two-photon imaging and other techniques, the movement of a fluorescent tracer injected in the subarachnoid compartment flowing into and through the brain interstitium was depicted to represent the exchange of CSF and ISF. In the initial segments of the pathway, flux fluid and macromolecules from the subarachnoid space rapidly enter the brain by bulk flow through paravascular spaces called Virchow Robinson spaces, which exist around vascular SMCs and perivascular astrocytic endfeet  . Howeverancement . TherefoMeningeal lymphatic vessels were discovered by chance after whole-mount mouse brain meninges stained by immunohistochemistry for different cells were used to determine the gateways responsible for T cells into and out of the meninges . They foMore than two decades ago, some researchers have systematically studied the effects of cervical lymphatic blockade (CLB) in conditions such as ischemic stroke and SAH; the specific mechanisms by which CLB exerts an influence on stroke lesions remain unclear . Before In an ischemic stroke model, Many experiments have directly expounded the important role of the meningeal lymphatic system in the post-stroke activation of the processes of brain drainage and edema clearing . The incIn addition to cerebral hemorrhage and SAH, meningeal lymphatic drainage also plays a role in the pathophysiology of ischemic stroke . Pavel YIn general, the meningeal lymphatic system plays a neuroprotective function after stroke and promotes the resolution of edema. Its function may mainly depend on two aspects. On the one hand, in the early stage of stroke, the activation of meningeal lymphatic drainage function can remove excess fluid in the skull; on the other hand, meningeal lymphatic vessels directly invade the injured brain parenchyma to resolve edema. The augmentation of lymphogenesis by treatment with VEGF-C improves heart function following myocardial infarct in mice . VEGF-C The discovery of meningeal lymphatic vessels has led to a collapse of dogma that the brain was an “immune-privileged” site, and its function to carry both fluid and immune cells from the CSF to the deep CLNs sets off an upsurge of how lymph nodes participate in the CNS immune response . NeuroinTraditionally, the occurrence of cerebral edema can be divided into three distinct phases: an early cytotoxic phase, a middle ionic phase, and a later vasogenic phase. Cytotoxic edema occurs within minutes after ischemic insult and ionic edema is the form of cerebral edema which forms immediately following cytotoxic edema and before barrier breakdown not occurring until 4–6 h after the onset of ischemia. Vasogenic edema, which is characterized by the breakdown of the BBB, manifests hours after the initial insult. However, the discovery of the glymphatic system and meningeal lymphatic vessels adds new content to each phase. Ion transporter dysfunction at the NVU lays the foundation for cytotoxic edema and ionic edema, and GSF, which flows rapidly into brain parenchyma through the glymphatic system within minutes after insult, also acts as the source of edema fluid. As the primary initial event driving tissue swelling, the glymphatic inflow of CSF may provide a basis for the treatment of cerebral edema after stroke. The breakdown of the BBB, which results in vasogenic edema formation, involves many joint effects, including the destruction of TJs, imbalance of the NVU, damage of inflammatory response, and activation of ion channels. Inflammation is a key element among many factors that lead to the progression of BBB damage in stroke. The glymphatic system plays a dual role in the process of cerebral edema after stroke with a harmful role in the early stage of edema formation and plays a beneficial role during edema subsidence. The function of glymphatic system is supported by astrocytic AQP4. AQP4 can not only control water flux across the BBB, but also facilitate the circulation of CSF, and drive the clearance of bulk interstitial solutes from the brain parenchyma. Therefore, in the earlier phases of cerebral edema (cytotoxic and ionic edema), the up-regulation of AQP4 can aggravate brain edema formation, while in the vasogenic edema phases, AQP4 may play a key role in the elimination of water of vasogenic origin. The activation of meningeal lymphatic drainage function and the ingrown of meningeal lymphatic vessels into the injured brain parenchyma promote the resolution of edema after stroke. Consequently, the rigorous dissection of the pathophysiology of the cerebral lymphatic system may eventually lead us to novel mechanisms and targets for cerebral edema after stroke.SC and LM collected information and drafted and revised the manuscript. LS contributed to collecting information and editing the manuscript. LM directed the work and finalized the manuscript. All authors agreed to be accountable for the content of the work.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.