The ability to adaptively follow conspecific eye movements is crucial for establishing shared attention and survival. Indeed, in humans, interacting with the gaze direction of others causes the reflexive orienting of attention and the faster object detection of the signaled spatial location. The behavioral evidence of this phenomenon is called gaze-cueing. Although this effect can be conceived as automatic and reflexive, gaze-cueing is often susceptible to context. In fact, gaze-cueing was shown to interact with other factors that characterize facial stimulus, such as the kind of cue that induces attention orienting  or the emotional expression conveyed by the gaze cues. Here, we address neuroimaging evidence, investigating the neural bases of gaze-cueing and the perception of gaze direction and how contextual factors interact with the gaze shift of attention. Evidence from neuroimaging, as well as the fields of non-invasive brain stimulation and neurologic patients, highlights the involvement of the amygdala and the superior temporal lobe ) in gaze perception. However, in this review, we also emphasized the discrepancies of the attempts to characterize the distinct functional roles of the regions in the processing of gaze. Finally, we conclude by presenting the notion of invariant representation and underline its value as a conceptual framework for the future characterization of the perceptual processing of gaze within the STS. In any social situation, the direction of one’s gaze serves as a fundamental method of communication through which individuals exchange information. Gaze can express relevant information about the mental states of others, support social control, regulate turn-taking, guide attention and communicate intimacy ,2,3,4. Sgaze-cueing in behavioral studies, the perception of gaze direction and contextual information can interact [Gaze-cueing is considered an involuntary and reflexive effect  What are the neural correlates that mediate gaze-cueing and the perception of gaze direction? (ii) Are the neural bases of gaze-cueing and the perception of gaze direction affected by contextual factors, such as emotional expressions?Potential neural candidates for the visual processing of others’ gaze that could allow for interactions with social factors  are the superior temporal sulcus (STS) and the amygdala see .The STS is part of a distributed neural system for facial information processing, together with the inferior occipital gyri and fusiform gyri . The amyHere, we investigated the close interaction between gaze perception and other changeable features of the face , along with the neural systems underlying gaze-cueing and the processing of gaze direction. Although other areas were found to be implicated in gaze processing , we focused our review on the role of the STS and the amygdala since our main goal was to shed light on their roles in integrating gaze perception and emotional expressions. We concluded our review by showing data of brain-damaged patients and non-invasive brain stimulation evidence, highlighting the crucial roles of the STS and amygdala in gaze perception.The close interaction between eye movement, gaze perception and other changeable features of the face, such as emotional expressions, was demonstrated using neuroimaging and brain stimulation techniques, as well as in studies of brain-damaged patients. In this section, we discuss recent neuroimaging evidence investigating the visual processing of gaze-cueing and gaze direction. As mentioned in the introduction, likely neural candidates for visual processing of others’ gaze direction that could allow for interactions with social factors are the superior temporal sulcus (STS) and the amygdala.Neuroimaging studies showed that amygdala activation is not receptive to gaze direction per se , but insIn terms of a functional difference between the STS and amygdala, it was suggested that the attentional shifting toward a joint object is a critical function of the STS, while the amygdala may appear to be required for combining emotional expression and gaze direction ,50,51 raAn interesting study by Carlin and colleagues  helped tTogether, the studies mentioned here revealed that the STS has a pivotal role in processing the direction of gaze compared to the amygdala, at least when neutral facial expressions are presented.Multiple neuroimaging studies compared the neuroanatomical correlates of joint attention conveyed by gaze shifts to the correlates of attentional shifts induced by other symbolic cues without using face stimuli. These studies addressed the important question of the specificity of the STS to facial stimuli in the context of gaze perception. Previous studies investigated two alternatives: (i) Is the STS specialized for processing social attention (such as gaze cues)? (ii) Is the STS more broadly processing any symbolic cue ? In the following section, we summarize papers that investigated the specificity (or lack thereof) of the STS in the social orienting network. We identified recent studies comparing gaze and symbolic cues in fMRI data ,70,71,72However, in line with the idea of a lack of differences between symbolic and gaze cues in the STS, Sato and co-workers  used fMRIn addition, in 2014, Callejas and colleagues  tackled To conclude, while the STS is sensitive to gaze perception , its rolDuring social communication, emotional expression is useful for communicating the inner state of others and predicting their potential actions. When changes in emotional expression are associated with gaze shifts, the social cues of the other reveal information that guides individuals’ behavior toward or away from other stimuli in the environment. Gaze cues play a significant role when conveying fear, where the meaning of the emotion is ambiguous until the source of the emotional change is determined . The interaction between gaze perception and emotional expression is associated with amygdala and STS activation, which is crucial regarding both facial expression and gaze perception ,65,79. HAlthough it was not the authors’ primary focus of investigation, Hooker and colleagues  employedThe conjoint processing expressions and gaze direction were explicitly studied also in the STS. An experiment was carried out by Engell and Haxby  that aimFurthermore, to investigate whether individual differences in anxiety levels may explain the abovementioned inconsistent findings, Ewbank and colleagues  examinedA potential confounding factor in the abovementioned studies is the use of static stimuli, which may have concealed the role of the amygdala. Therefore, Sato and colleagues  showed dIn another fMRI study using an emotion recognition task , the autOverall, these results indicate a complex pattern of amygdala responses to gaze direction, which depends on individual differences, the type of emotion expressed by the face and gaze direction  was also used to investigate the conjoint processing of emotion and gaze direction . Lachat A subsequent MEG study  focused Speed processing represents a still unexplored element of threat perception. Most of the aforementioned studies ,50,79 emThese results hint at the presence of a fast and reflexive amygdala activation linked to obvious threat and a subsequent reflective activation linked to ambiguous threat . These In the same study, the pSTS showed a different pattern of activation, with stronger responses for the short presentation of averted-gaze fear and the longer presentation of direct-gaze fear. The pSTS was involved in the late stages of longer stimuli presentations, highlighting its potential role as a constituent of the ‘social brain’ . The ‘soIt is still unknown whether previously observed effects of gaze direction on amygdala activation depended to some degree on low-level features in the stimulus display . Therefore, Hardee and colleagues  performeIt is possible to trigger attentional orienting with eye gaze information even when such information is subliminal and participants are not aware of it, as demonstrated by multiple studies ,115,116.Recent growing evidence suggests that non-invasive brain stimulation techniques (NIBS) can be used to induce neuroplasticity in order to modulate cognition and behavior ,122, unvDirect evidence for the roles of the STS and amygdala in gaze processing can also be derived from brain-damaged patients. Two studies published in 2006 ,129 repoAlthough many studies have focused on the critical role of the STS in emotion perception ,135,136,In this review, we addressed the neural bases of the perceptual processing of the direction of another’s eye gaze and the gaze-cued attentional orienting process. In addition, we reviewed modulation by contextual factors on the neural bases of gaze direction and gaze-cueing, such as the kind of cue that induced attention orienting  or the emotional expression conveyed by the gaze cues. We reported many inconsistencies between the reviewed findings, which prompt further research in this area. Such inconsistencies may be explained by the different methods employed, such as task instruction , type of emotional expressions , kind of facial stimuli  and scanning parameters. All these methodological differences represent a limit when results from different studies need to be compared. For example, N’Diaye and colleagues  demonstrFirst, we concluded that although several authors reported a specific function of the STS in processing gaze cues compared to non-symbolic cues ,62,64,70Second, when emotional expressions are presented, the STS seems to have a pivotal role in gaze perception and to be less sensitive to emotions, while the amygdala seems to play an important role in the interaction between gaze and emotional expressions, especially when negative expressions are presented ,33,42,79Finally, few studies have found the amygdala to be activated for the averted gaze, regardless of facial expression , suggestTogether, the available neuroimaging results on the contextual  modulation of gaze, especially the proposed increased invariance to gaze-independent characteristics from posterior to anterior STS , paves t


The application of membrane technologies for wastewater treatment to recover water and nutrients from different types of wastewater can be an effective strategy to mitigate the water shortage and provide resource recovery for sustainable development of industrialisation and urbanisation. Forward osmosis (FO), driven by the osmotic pressure difference between solutions divided by a semi-permeable membrane, has been recognised as a potential energy-efficient filtration process with a low tendency for fouling and a strong ability to filtrate highly polluted wastewater. The application of FO for wastewater treatment has received significant attention in research and attracted technological effort in recent years. In this review, we review the state-of-the-art application of FO technology for sewage concentration and wastewater treatment both as an independent treatment process and in combination with other treatment processes. We also provide an outlook of the future prospects and recommendations for the improvement of membrane performance, fouling control and system optimisation from the perspectives of membrane materials, operating condition optimisation, draw solution selection, and multiple technologies combination. I. I2+-based to N2 . Howevered to N2 . TherefoCurrent studies indicate that both the concentration of feed solutions and the dilution of draw solutions in the FO process can be utilised for wastewater treatment, which expand the application areas of the FO process. Due to advantages such as high selectivity and a low fouling tendency, the FO process has been applied to concentrate various types of wastewater such as sewage, oil sands process-affected water, and radioactive wastewater for the purposes of recovering water, concentrating nitrogen, and extracting dye. On the other hand, by using the dilution effect of the FO process, wastewater/sewage can be used to dilute fertilisers. The FO process also shows good performance in combination with other membrane-based technologies and biological/chemical technologies, such as MBR, AD, and CF to increase the treatment effect. Additionally, the reverse salt diffusion can be applied in a positive way to trigger the phosphorus precipitation and to create a nitrification-denitrification shortcut. However, there are still many challenges in the current FO technology in the areas including membrane materials, draw solution selection, and system optimisation.Although membrane modification by nanomaterials has been reported as an effective way to improve the performance and antifouling properties of FO membranes, most of the previous works were done in lab-scale and rarely in real wastewater treatment. Therefore, the stability and antifouling ability of the nanomaterials-modified FO membranes need more investigation on a large scale or during a long-term operation. There are a few cases associated with surface modification of FO membranes for wastewater treatment, which shows the potential to increase the antifouling property of FO membranes. However, surface modification cannot address the issues caused by ICP. The ICP not only aggravates the membrane fouling but also reduces the efficiency of FO systems, especially when treated with highly polluted feed solution. Current TFC-FO membranes usually apply UF as the substrate, which has a relatively low porosity. Although increasing the porosity of substrates of the TFC-FO membrane can mitigate ICP, the impacts of porous substrates on the formation of selectivity layer of TFC-FO membranes, mechanical, and chemical strengths, especially in highly acidic conditions, need more investigation.A suitable draw solute is very important for both single FO and FO-integrated systems. Some new draw solutes with good osmotic pressure and small reverse solute diffusion have been implemented in cases highlighted in this review. However, a more comprehensive evaluation of these draw solutions or other new draw solutions should be conducted in terms of price, recovery cost, impacts on membrane fouling, and impacts on the chemical stability of the feed solution. Another important consideration is the properties of the feed solution. The different discharge standards of feed solutions should be considered in the design of FO-based wastewater treatment systems. Moreover, system factors such as the temperature, cross-flow velocity, and cleaning process are interactive and work together to determine the efficiency and energy cost of FO systems. Therefore, it is crucial to consider the synergistic effect and trade-offs among these factors. When integrating the FO process with other technologies, there are more interactions among membrane materials, feed solution, draw solution, and system-operating conditions, as summarised in


Acting as the primary link between mother and fetus, the placenta is involved in regulating nutrient, oxygen, and waste exchange; thus, healthy placental development is crucial for a successful pregnancy. In line with the increasing demands of the fetus, the placenta evolves throughout pregnancy, making it a particularly difficult organ to study. Research into placental development and dysfunction poses a unique scientific challenge due to ethical constraints and the differences in morphology and function that exist between species. Recently, there have been increased efforts towards generating in vitro models of the human placenta. Advancements in the differentiation of human induced pluripotent stem cells (hiPSCs), microfluidics, and bioprinting have each contributed to the development of new models, which can be designed to closely match physiological in vivo conditions. By including relevant placental cell types and control over the microenvironment, these new in vitro models promise to reveal clues to the pathogenesis of placental dysfunction and facilitate drug testing across the maternal-fetal interface. In this minireview, we aim to highlight current in vitro placental models and their applications in the study of disease and discuss future avenues for these in vitro models. The human placenta is a crucial organ that supports fetal development throughout gestation. Placental growth and function are precisely regulated to ensure effective circulation of oxygen and nutrients, removal of waste, generation and release of metabolites, and protection against diseases, infections, and xenobiotic transfer to the fetus . ConsideThis minireview aims to: (1) discuss our current understanding of human placentation and highlight areas that require further investigation; (2) discuss current in vitro placental systems, ranging from 2D to 3D models; (3) explore recent applications of these models in studying placental physiology and disorders; and (4) discuss key components to consider when developing or evaluating an in vitro model of the placenta.The placenta, a fetal organ, forms shortly after fertilization and continues to change throughout pregnancy in response to the metabolic demands of the fetus. Placentation begins post-fertilization when the blastocyst attaches to the inner layer (endometrium) of the uterus. The blastocyst then begins to invade the endometrium with the help of its outer layer of cells, termed trophoblasts. This fetal trophoblastic layer is divided into two cell types, an external multinucleated syncytiotrophoblast layer (the invasive trophoblasts) and an inner cytotrophoblast layer. About two weeks after fertilization, the external syncytiotrophoblast forms preliminary fluid-filled villi structures directed outward, towards the decidual layer of the mother’s uterus a. Then, Nutrient exchange between maternal and fetal blood is facilitated largely by the syncytiotrophoblast, which is one continuous multinucleated layer of cells c. The abThe placenta also functions as an immunological barrier, countering the maternal immune response that would normally cause rejection of the fetus, finally leading to spontaneous abortion . Still, In addition to its barrier function, the placenta acts as an endocrine organ. For example, to prevent the progression of the menstrual cycle and the loss of the endometrial lining, the syncytiotrophoblast releases human chorionic gonadotropin (HCG). HCG prolongs the life of the corpus luteum, which is thus able to continue releasing progesterone and promote the healthy function of endometrial vasculature, preventing its deterioration and loss . The plaAlthough much of placental physiology has already been characterized, there are many aspects that are not well understood. For instance, little is known about the cellular mechanisms that drive the programmed events of placental branching angiogenesis, the regulation of the permeability of the maternal-fetal interface, the behavior of extravillous trophoblasts, and the impact of nutrients, hormones, and environmental factors on placental development. In the next section, we discuss the latest in vitro systems that aim to recapitulate important features of the human placenta and eventually provide answers to these questions, with a particular focus on mimicking the maternal-fetal interface and trophoblast invasion.A variety of in vitro models have been developed to study different aspects of placental biology; however, one aspect of particular focus is the maternal-fetal interface as a barrier a. Cells In vitro models of the placental barrier have also recently incorporated 3D vascularized networks. For example, Nishiguchi et al. used a modified transwell system to seed a layer of laminin and collagen-coated trophoblasts (either BeWo or primary cytotrophoblasts) onto a thick layer of self-assembled capillary networks, formed from primary fibroblasts ) and human umbilical vein endothelial cells (HUVECs) in a fibrin hydrogel  Figure c. This mConsidering the multilayered structure and physiologic microenvironment critical to placental barrier function, other groups have also attempted to generate more complex models, including both an endothelial  and trophoblast component. For instance, cocultures of endothelial and trophoblast cells have been combined in sandwiched monolayers on chip, which allow for exposure to fluid flow mimicking the hemodynamic shear stress present in maternal and fetal compartments d. BlundeAnother way to achieve the complex geometry of the placental villous membrane, while bypassing the use of flat cell monolayers, was proposed by Mandt et al., who developed a barrier model using a high-resolution three-dimensional (3D) printing method called two-photon polymerization (2PP) . A villiImproper trophoblast invasion into the endometrial spiral arteries is often associated with pregnancy complications, including pre-eclampsia and fetal growth restriction . Thus, uBioprinting allows for controlled 3D spatial patterning of cells, biomaterials, ECM components, and growth factors in order to generate tissue analogues and has led to the development of a number of physiologically relevant trophoblast invasion assays d. One suBesides bioprinting, microfluidic models have also been useful in tracking and quantifying the dynamics of trophoblast cell migration since they can be designed to generate stable gradients on chip e. As an Besides the defective remodeling of the spiral arteries, many other aspects of placental dysfunction are associated with altered placental development and the onset of pregnancy complications. These events, which include the impairment of villous tree maturation , the detPlasmodium falciparum, all can cross the placenta and cause adverse birth outcomes [Although the placenta acts as a barrier to many pathogens and viruses, rubella virus, cytomegalovirus, herpes simplex virus, Zika virus, and parasites such as outcomes ,49. To doutcomes . PhysiolEscherichia coli was applied to the maternal side of the chip, trophoblast cells triggered an acute inflammatory response by secreting interleukin-1α, IL-1β, and IL-8 cytokines, followed by the adhesion of maternal macrophages. More recently, a microfluidic organ-on-a-chip model comprising the decidua and the fetal chorionic and amnionic membranes was generated to track the propagation of infection and inflammation across the maternal-fetal interface [Microfluidic technologies have also been implemented to explore the impact of pathogenic infections during pregnancy. Zhu et al. generated a multilayered microfluidic placental barrier-on-a-chip model to investigate the placental inflammatory responses to bacterial infection . When Esnterface . This fonterface .It is particularly challenging to study the effects of drugs on the structure and function of the placental barrier since they cannot be tested on pregnant women. The thalidomide disaster of the 1960’s  unveiledOverall, the employment of 3D micro-engineered models creates a suitable and controlled approach towards the understanding of the effects of drug treatments and disease conditions on placental function.Recent bioengineered placental models have enhanced the knowledge in the field; however, there are a number of areas that should be considered to physiologically recapitulate the human placenta in health and disease . The useTogether with the appropriate cell types, an adequate structural and spatial arrangement of the cells  is needed to mimic, on-chip, the in vivo maternal-fetal interface in a more physiologically relevant way. Moreover, normal tissue development and homeostasis are critically regulated by biomechanical cues, such as stretching, compression, and matrix stiffness . To dateDespite the important achievements in the recapitulation of structure and cell composition of the maternal-fetal interface, the presence of perfusable vasculature remains a missing feature of current placental models. Vascular hemodynamics not only are essential to transport nutrients, oxygen, and metabolic waste but also play a key role in placental physiology. Indeed, in vivo, blood flow imparts mechanical stimulation on the endothelial wall of the vessels (shear stress), which is essential to the development and establishment of the uteroplacental and fetoplacental circulations . As repoAnother element commonly missing from current placental models is the inclusion of immune cells, in particular fetal villus macrophages (Hofbauer cells), whose function within the stroma has not yet been fully elucidated . Hofbaue2, 20 mmHg) and increasingly higher oxygen levels in the later stages  [A better understanding of the formation and function of the placenta will be gained by exposing in vitro models to oxygen levels encountered by the tissue in vivo. During pregnancy, placental oxygen concentrations change dramatically, with earlier timepoints (up to 10 weeks) associated with low oxygen (1%–2% Oimester) . Physiolimester)  to date,The incorporation of biological factors present in the bloodstream of patients with pregnancy complications can enhance our knowledge on placental dysfunction. Together with the use of patient-derived primary cells, maternal blood constitutes a valuable resource of factors  that can influence placental function. For instance, the blood composition of patients with pre-eclampsia differs from that of individuals with uncomplicated pregnancies in the levels of sex steroids , pro- anAlthough microfluidic technologies reduce the required materials and costs compared with other culture systems, the use of small volumes could represent a limitation in the detection sensitivity of analytes. To overcome this, the integration of biosensor technologies can enhance sensing capabilities and analysis of real-time responses in on-a-chip placental models, facilitating studies on drug response and placental development . BiosensPlacenta-on-a-chip models have recently contributed enormous progress to our understanding of human placental biology. These models overcome the ethical limitations linked to pregnancy-related studies and can be used to elucidate the pathophysiology of placental disease and act as tools for examining maternal-fetal barrier function and exchange. Biomimetic in vitro systems minimize the need for animal studies, bridge the gap between human and animal physiology, and comply with the 3Rs of research. Recent advances in in vitro approaches have enabled the arrangement of human placenta components with control over geometry and fluidics; however, many challenges are yet to be resolved. Certain aspects of placental physiology  are yet to be considered in the future for the creation of physiologically relevant models. Specifically, recapitulation of the physiological features of the native tissue will help to address several open questions and advance our understanding of the mechanisms underpinning normal and pathological placental development; transport of drugs, immune cells, and hormones across the barrier and the endothelium of fetal vasculature; and response to environmental factors and pathogenic infections.


The current trend for the rapid growth of the global aging population poses substantial challenges for society. The human aging process has been demonstrated to be closely associated with changes in gut microbiota composition, diversity, and functional features. During the first 2 years of life, the gut microbiota undergoes dramatic changes in composition and metabolic functions as it colonizes and develops in the body. Although the gut microbiota is nearly established by the age of three, it continues to mature until adulthood, when it comprises more stable and diverse microbial species. Meanwhile, as the physiological functions of the human body deteriorated with age, which may be a result of immunosenescence and “inflammaging,” the guts of elderly people are generally characterized by an enrichment of pro-inflammatory microbes and a reduced abundance of beneficial species. The gut microbiota affects the development of the brain through a bidirectional communication system, called the brain-gut-microbiota (BGM) axis, and dysregulation of this communication is pivotal in aging-related cognitive impairment. Microbiota-targeted dietary interventions and the intake of probiotics/prebiotics can increase the abundance of beneficial species, boost host immunity, and prevent gut-related diseases. This review summarizes the age-related changes in the human gut microbiota based on recent research developments. Understanding these changes will likely facilitate the design of novel therapeutic strategies to achieve healthy aging. The average human lifespan expectancy in most countries is longer than ever before, benefiting from the achievements of modern medicine and lifestyle improvements. However, this has led to the rapid growth of the world’s aging population (60 and older) . Aging ivia the consumption of host-friendly bacteria found in yogurt  also changes, its diversity and beneficial species are retained , partialongevity . Similarongevity . Eleven position . The typposition . Japanes nations , includi nations . The abu elderly , but was elderly . Meanwhi elderly , whereas elderly .Bacteroides, Eubacterium, and Clostridiaceae. Sequential changes occurred in the relative abundance of Bacteroides, Lachnospiraceae, and Bifidobacteria in the gut microbiota during childhood and adolescence (<20 years old), while Megamonas and Peptoniphilus were relatively enriched in the elderly (>70 years old). Using the same data samples, Lactobacillus, Oscillospira, Oxalobacter, Prevotellaceae, Parascardovia, and Butyrivibrio, increased with age, but decreased in the extremely elderly. In contrast, some taxa that are frequently linked with inflammation and diseases, including Parvimonas, Anaerotruncus, Corynebacterium, Lachnospiraceae, Desulfovibrio, Bilophila wadsworthia, Odoribacter, and Butyricimonas, showed monotonically increasing patterns with respect to aging. Bifidobacterium longum species but an increase in the overall bacterial diversity with aging (0–70 years). However, another study obtained different results from the gut microbiota of more than 1,000 healthy Chinese individuals aged from 3 to over 100 years using PERMANOVA. These authors reported that the gut microbiota differed little among individuals from the ages of 30 to >100 and that the major between-group differences in gut microbiota profiles were found before 20 years of age  and can help mitigate the effects of some inflammatory diseases in humans  axis, which primarily includes neural, immune, metabolic, and endocrine pathways .The brain can directly or indirectly affect the composition and function of the gut microbiota by releasing signal molecules through lamina propria cells  or modulating gastrointestinal motility, secretions, and intestinal permeability . Inversevia neuronal signaling that involves the central nervous system (CNS), autonomic nervous system, and enteric nervous system (ENS), often involving the stimulation of the vagus nerve. The vagus nerve is a bundle of parasympathetic motor and sensory fibers that provide a direct means of neurocommunication between the ENS and the CNS (A receptors and glutamic acid decarboxylase (GAD)-positive cells in the cerebral cortex following stimulation of the peripheral end of the vagus nerve , thereby regulating neurological functions , and obesity, but also in psychiatric and neurological disorders, such as depression, anxiety neurosis, AD, and Parkinson’s disease (PD) ; Table 1Alzheimer’s disease is a progressive neurodegenerative syndrome and the most common cause of dementia. The pathogenesis of AD includes the excessive aggregation of amyloid-β (Aβ) peptides, the presence of neurofibrillary tangles (NFTs) induced by the hyperphosphorylation of tau protein, neuroinflammation, and metabolic disturbances; however, the mechanisms underlying the pathogenesis of AD is not fully understood .Escherichia Shigella, Odoribacter splanchnicus, and Klebsiella pneumonia, and reductions in key butyrate-producing anti-inflammatory species, such as members of the genera Butyrivibrio and Eubacterium, compared with those of non-AD individuals (Bacteroides was proved to be independently associated with the presence of mild cognitive impairment (MCI) in patients without dementia based on graphical modeling and multivariable logistic regression analysis in a cross-sectional study  on the surface of microglia and subsequently exacerbate the inflammatory response in the AD brain  GutAD brain .Bifidobacteria and Lactobacilli decrease, which in turn leads to a decline in GABA levels in the CNS (The gut microbiota is important for the synthesis of brain neurotransmitters (such as GABA and 5-HT), BDNF, and SCFAs, which are all associated with AD . GABA is the CNS . Glutama the CNS . SCFAs a the CNS . Besides the CNS . Given t the CNS .Parkinson’s disease is a long-term degenerative disorder of the CNS, and is characterized by the abnormal aggregation of α-synuclein and the degeneration and necrosis of substantia nigra dopaminergic neurons. The clinical manifestations of PD include both motor symptoms and autonomic non-motor symptoms such as cognitive impairment and sleep disturbance. Several lines of evidence indicate that the gut may be involved in the origin of PD. For instance, gut symptoms appear in the early stages of PD, while α-synuclein misfolding and aggregation also initially occur in the ENS and dorsal motor nucleus of the vagus nerve . FurtherPrevotellaceae in the gut of PD patients was reported to be 77.6% lower than that of healthy controls, and this decline may result in reduced mucin synthesis and a subsequent increase in gut permeability  is a major risk factor for cardiovascular, cerebrovascular, and kidney diseases in the elderly. Longitudinal studies have indicated that HTN during midlife may be a risk factor for subsequent cognitive decline and dementia . HTN maycrobiota . Evidenccrobiota . OverallEnterobacteriaceae and Streptococcus spp., resulting in a less fermentative and more inflammatory gut environment  is one of the most important public health challenges of the 21st century and poses a serious threat to the health of the elderly. Epidemiological studies have shown that diabetic patients are more susceptible to dementia than healthy individuals . Type 2 controls . Additioecreased , Anotherand T2DM . In addipatients . The effpatients . AlthougBifidobacteria and Lactobacilli , and inducible nitric oxide synthase (iNOS), indicating that C29 may ameliorate aging-related memory impairment and inflammation , and is regarded as a medical breakthrough. A recent study reported that transferring the gut microbiota of aged mice to young GF mice promoted inflammation in the small intestine of the latter and enhanced the leakage of inflammatory bacterial components into the systemic circulation  is defined as the transplantation of the functional bacteria present in the feces of healthy people into the gastrointestinal tract of patients to rebuild the gut microbiota and treat both intestinal and extra-intestinal diseases. FMT has been used in the treatment of and exploratory research into various microbiota-related diseases, such as culation . Ridauraculation . In summLactobacillus acidophilus, Lactobacillus casei, Bifidobacterium bifidum, and Lactobacillus fermentum) can positively affect cognitive function and some metabolic statuses in the AD patients through a randomized, double-blind, and controlled clinical trial  disease phenotypes develop spontaneously as they are usually maintained by their owners, (ii) they are not required to be genetically manipulated, and (iii) the long life span and late onset of the conditions is a great parallel to human patients who are also not genetically modified. In addition, the non-human primate is another promising model in investigating human aging and cognitive impairment due to the high similarity to the human brain and nervous system regardless of their high cost and longer research period .On all accounts, insights into the mechanisms involved in how gut microbes affect aging and aging-related cognitive impairment may provide new directions for the diagnosis, treatment, and prevention of aging-related diseases. Gut microbiota can be a promising intervention target for aging and cognitive disorders. The future research based on microbiota-directed interventions require more well-designed, large, randomized, double-blind, and placebo-controlled clinical trials. Moreover, research needs to illustrate the physiological and pathological function of the microbiota that are present and investigate precise mechanisms by which changed microbe composition contributes to the pathophysiology of disease and by which potential probiotic bacteria exert beneficial effects on host health.JN and HQ contributed to organizing this article and revising its content. HL was responsible for writing the manuscript and figure design. All authors read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


A 46-year-old right-handed man with a medical history of refractory stage IIIB, ALK-negative, anaplastic large-cell lymphoma came to our attention. He had previously been treated with several chemotherapy drugs, including brentuximab vedotin. Two weeks after completing salvage chemotherapy, the patient presented with progressive swallowing and speech difficulties. At this stage, he was admitted to our hospital for further diagnostic work-up and clinical management. Neurological examination showed severe dysarthria and bilateral weakness of facial, oromandibular and palatal voluntary movements. The patient could barely open his mouth and protrude his tongue on command. However, reflex movements  and activation of emotional and automatic motor responses  were broadly spared.3). Brain magnetic resonance imaging displayed T1-hypointense, T2-hyperintense abnormalities of the frontal subcortical white matter, also involving the U-fibers and the frontal operculum bilaterally (mainly on the right side). No mass effect or contrast enhancement after gadolinium administration was evident , which was performed simultaneously with a fiberoptic endoscopic evaluation of swallowing (FEES). EES was carried out according to a previously described protocol . BreathiThis patient’s severe dysphagia required nasogastric tube feeding and a percutaneous endoscopic gastrostomy was planned.In view of the patient’s clinical features, combined with the localization of lesions on neuroimaging and the CSF findings, Foix–Chavany–Marie syndrome (FCMS) related to progressive multifocal leukoencephalopathy (PML) was diagnosed.FCMS, also known as opercular syndrome, is a rare neurological entity characterized by voluntary palsy, but preserved reflexive and automatic motor functions of the trigeminal, facial, glossopharyngeal, vagus and hypoglossal nerves. This syndrome is caused by bilateral lesions of the frontal operculum, classically affecting voluntary control of the facial, oromandibular, pharyngeal and laryngeal muscles. The presence of divergent corticobulbar pathways for voluntary and automatic or emotional motor activation of craniofacial muscles is the anatomical basis of FCMS symptoms. For example, opercular neurons, which are responsible for voluntary movements, send supranuclear fibers to the nuclei of the cranial nerves, whereas the automatic or emotional activation of craniofacial muscles depends on another pathway, from the amygdala and hippocampus to the brainstem.The swallowing abnormalities detected in the case here reported are not consistent with the conventional concept of automatic-voluntary movement dissociation in FCMS. We observed not only an impairment of the oral preparatory and propulsive phases but also involvement of the automatic-reflexive mechanisms of the pharyngeal phase of swallowing . The oral phase alterations can be considered unsurprising, being related to ineffective voluntary control of corticobulbar pathways from the opercular cortex. The abnormalities of the pharyngeal phase, on the other hand, were unexpected, given that this phase is classically considered to depend on involuntary activation of the swallowing central pattern generator, which is located in the medulla oblongata. Nevertheless, our findings are in keeping with the role played by the frontal operculum in the control and modulation of the automatic-reflexive mechanisms of swallowing . MoreoveLoss of suprasegmental control from the right opercular cortex may also lead to abnormal respiratory-swallowing coordination , increasing the risk of airway penetration and aspiration. Indeed, breathing is modulated by cortical structures  projecting to limbic areas and connected with medullary cardiorespiratory regulatory centers. This pathway is at least partly shared with networks involved in the swallowing function, and therefore represents a neuronal substrate for respiratory-swallowing coordination .In addition, we hypothesize that the preservation of pharyngeal afferent sensory inputs and of brainstem structures may account for the normal onset timing of LPM and of swallowing apnea observed in this patient.Dysphagia related to FCMS is an uncommon symptom in PML, to our knowledge reported only once in the literature to date . In our


One of the main consequences of industrialization is the development and daily use of plastics, including numerous related additives and contaminants (of emerging concern) that are released in the environment. Many of these chemicals bio-accumulate in biological tissues and can adversely affect human and wildlife health by altering endocrine functions or through other biological mechanisms . TherefoNumerous EDCs have been shown to exert long-term pleiotropic effects on endocrine function and health, and contribute to endocrine-mediated diseases . CompounAn additional urgent and emerging concern is the environmental exposure to plastic debris in the micro and nano-range that enter the food chain. Although the number of studies of micro- and nanoplastics evaluating harmful effects on aquatic and terrestrial organisms remains small, evidence indicates that even remote environments  are contaminated with these pollutants . There aReproduction, fertility and development represent several of the main targets of environmental toxicants, with different outcomes on health depending on dose, timing of exposure, and timing of evaluation . GametogWhile the effects in the exposed adults are often, but not always, transient, gestation and the early postnatal period are critical exposure windows. Importantly, the effects of exposures during early development may not manifest for years, or even decades . The effA large body of experimental evidence from studies using animal models and cell lines continues to reveal adverse effects on reproductive and developmental outcomes after exposure to these compounds. Fully characterizing the effects, and understanding the mechanisms by which EDCs induce harm, indicates the need for further studies in the field, as well as the development of safe alternatives to preserve reproduction, fertility and health in humans. In this Research Topic we present a collection of two original research articles and two review articles.Bottalico et al.) utilized a non-mammalian model  to characterize the effects of BPA, nonylphenol, DEHP and fucosterol - alone or in combination - on metabolomic profiles of midbrain, testis and liver. This seasonal breeder requires specific neuroendocrine signaling to allocate the metabolic resources that sustain growth and reproduction. EDC exposures affected metabolism, but these studies revealed that the mid-recrudescence stage was most vulnerable to metabolic perturbation in male fish. Thus, seasonally driven physiological changes may alter the vulnerability of seasonal breeders to EDCs.The first research article . This study contributes to evidence that BPA disrupts social behaviors . Evidence from human populations suggests that PFAS exposures are associated with effects on fertility, fetal growth, pre-eclampsia and pregnancy-induced hypertension, thyroid hormone levels in pregnant women, and risk of pre-term birth. Importantly, PFAS is a large class of chemicals and most of the evidence accumulated to date comes from studies of PFOA and PFOS; this review also examines the effects of short-chain replacements such as GenX, ADONA, and F53B, which have been detected in the environment but have limited studies from experimental models, and little (or no) evidence from human populations.In the first review article, the peer-reviewed literature on the reproductive effects of PFAS was summarized . Although there are relatively few studies examining the effects of exposures to plastic particles, there is some evidence that plastic particles decrease growth rates, reduce fertility and/or fecundity, and induce other measures of toxicity. The effects of nano- and microplastics can differ depending on their shape, size and composition, and they may also aggravate the effects of other pollutants.The final contribution to this Research Topic examines the evidence that microplastics affect reproductive health, using There is overwhelming evidence, acknowledged by scientific and medical organizations, that EDCs induce harm to humans and wildlife. Effects on reproduction, development and neurobehaviors are well documented and the manuscripts included in this Research Topic add to that growing but convincing body of evidence.


Given the multiscale nature of biological systems, the integration of phenomena at different spatial and temporal scales has emerged to be essential in capturing mechanobiological mechanisms underlying vascular adaptation processes. In this regard, agent-based models have demonstrated to successfully embed the systems biology principles and capture the emergent behavior of cellular systems under different pathophysiological conditions. Furthermore, through their modular structure, agent-based models are suitable to be integrated with continuum-based models within a multiscale framework that can link the molecular pathways to the cell and tissue levels. This can allow improving existing therapies and/or developing new therapeutic strategies. The present review examines the multiscale computational frameworks of vascular adaptation with an emphasis on the integration of agent-based approaches with continuum models to describe vascular pathophysiology in a systems biology perspective. The state-of-the-art highlights the current gaps and limitations in the field, thus shedding light on new areas to be explored that may become the future research focus. The inclusion of molecular intracellular pathways  within the multiscale agent-based modeling frameworks will certainly provide a great contribution to the promising personalized medicine. Efforts will be also needed to address the challenges encountered for the verification, uncertainty quantification, calibration and validation of these multiscale frameworks.The widespread incidence of cardiovascular diseases and associated mortality and morbidity, along with the advent of powerful computational resources, have fostered an extensive research in computational modeling of vascular pathophysiology field and promoted  Equation-based models are continuum models based on systems of ordinary differential equations (ODEs) or partial differential equations (PDEs). ODEs are used to describe the temporal variation of system state variables, while PDEs capture both temporal and spatial-related evolution of said variables. At the molecular level, PDE systems  are broadly implemented in the vascular field to describe the transport of molecular species . In add(Agent-Based Modeling: Promising Tool for a Systems Biology Approach), provides a description of the ABM strategy, focusing on relevant aspects in the context of complex biological systems and multiscale approach. The third section  describes the state-of-the-art of computational multiscale agent-based modeling framework of vascular pathophysiology. Specifically, models of atherosclerosis, in-stent restenosis (ISR) and vein graft adaptation will be detailed, as well as studies focusing on other aspects of vascular remodeling processes. The fourth section  discusses the strengths and limitations of agent-versus continuum-based frameworks. The subsequent section  presents the current challenges of agent-based modeling strategies and future perspectives in the field, while the last section (Conclusion) the concluding remarks.Recently, several multiscale models were proposed to capture the complex nature of vascular pathologies and depict the driving mechanisms of response to endovascular procedures or surgical interventions. The aim of the present review is to point out works on multiscale modeling of vascular remodeling, with special emphasis on those frameworks integrating continuum models and agent-based approaches in a systems biology perspective. Studies that proposed ABMs as the core of said frameworks are reviewed herein, highlighting the potentials of multiscale agent-based modeling methodology in incorporating the systems biology principles and capturing mechanobiological processes in vascular pathophysiology. In detail, the second section ABMs belong to a class of computational models in which the system of interest is replicated with a bottom-up approach, i.e. through the discrete representation of its components, called “agents”, as autonomous decision-making elements . The behin-silico replica for further advancing their research.Considering all the above, ABMs provide a simple but effective and realistic representation of systems composed by heterogeneous populations of active elements, in which the interactions and the spatial-related aspects play a major role. Translating these concepts to biology, ABMs present great potentialities in modeling complex biological processes through an intuitive and flexible framework . Moreovein-vitro and in-vivo experiments, as well as of clinical trials and, more in general, the inter-subject variability encountered in any clinical study. The embedded stochasticity may also lead to unexpected and rare event combinations resulting in an unusual system evolution that, although constituting an outlier from a statistical viewpoint, may highlight counterintuitive and unpredictable processes that may realistically occur. The stochasticity does not necessarily represent a real stochastic event in the biological system  or in the continuum (lattice-free) space, as schematized in ABMs are flexible and modular . Once thMultiscale Models of Atherosclerosis and Multiscale Models of In-Stent Restenosis, respectively. Furthermore, other vascular remodeling processes have been modeled , as reviewed in Multiscale Models of Other Vascular Applications.Multiscale agent-based modeling frameworks of vascular pathophysiology have been developed by several research groups to predict vessel response to the alteration of the environmental and operational conditions and to provide insights into the driving mechanisms of post-intervention vascular remodeling at different temporal and spatial scales. To date, the most relevant applications of these computational frameworks regarded the atherosclerotic plaque development and the processes of restenosis following endovascular procedures and of vein graft neointimal hyperplasia after bypass surgery, as described in detail in, A general computational approach characterizes most of the reviewed studies , based oThe ABM is the core of the multiscale framework. It is initialized with hemodynamic, mechanical or molecular cues and simulates vascular remodeling by implementing cellular behaviors. The morphological and compositional tissue changes, resulting from the ABM simulation, are used to update the tissue and molecular scale configurations, which undergo new simulations to compute the updated conditions for the ABM re-initialization.Atherosclerosis is a multifactorial and inflammatory-driven disease that leads to the narrowing of the arterial lumen due to the formation of a plaque in the arterial wall . The earSome of the aforementioned aspects of pathology initiation and progression were considered in the available multiscale agent-based modeling frameworks of atherosclerosis, as presented in The available multiscale models of atherosclerosis  capturedtrans-endothelial migration, LDL accumulation and, consequently, atherosclerotic plaque progression. Computational fluid dynamics (CFD) simulations were performed to compute the WSS profile, used to initialize the ABM. Given the ABM-simulated changes of luminal geometry occurring during plaque growth, an ABM to CFD coupling was performed to update the WSS distribution, by computing the hemodynamics in the current vessel geometry. The ABM to CFD coupling occurred after significant changes in the luminal geometry rather than at a fixed time. A 3D ABM, constituted by a uniform layer for the arterial wall  covered by a single layer of endothelial cells, was implemented. Leukocytes were the only active agents and specific rules for the endothelial adhesion, the trans-endothelial migration, the chemotactic migration in the arterial wall, the cytokines production, and the lifespan were implemented. In particular, leukocyte adhesion probability was defined as a function of WSS, circulating cytokine and leukocyte concentration, while the trans-endothelial migration as a function of arterial stiffness. Moreover, LDL transport and accumulation in the arterial wall depended on WSS and systemic LDL concentration. LDL diffusion in the arterial wall was modeled through Fick’s law and rules defining LDL oxidation and phagocytosis by monocyte-derived foam cells were applied. Finally, Glagov’s remodeling was implemented, according to which the lumen area was preserved in the initial phases of atherosclerosis thanks to a compensatory outward remodeling  and patient-specific conditions  . Bypass in-vivo measured flow rate. The model finely replicated the experimental intimal area growth over time at different WSS conditions. In this model, the multiscale component was not properly represented, because only events at the cell scale were simulated while the WSS  was analytically computed. In a further evolution  and 2) indicating favorable scaffold characteristics  and possible loading conditions to obtain the desired cell growth. studies . Additio studies . Finallyrvations . The stuMultiscale Agent-Based Modeling Frameworks of Vascular Pathophysiology demonstrated that coupling agent- with continuum-based models allows successfully capturing biological information. The proposed frameworks used each specific model for the task it is most suitable for, thus taking advantages from its strengths and minimizing its limitations. Generally, these frameworks were based on 1) a continuum model for the molecular advection-diffusion-reaction processes, 2) a discrete (agent-based) model at the cellular level and 3) a continuum model for the tissue level mechanics (solid mechanics or hemodynamics). Moreover, for a more exhaustive vision related to the modeling of vascular adaptation, the reader should be directed also to multiscale frameworks entirely based on continuum models (which are not the object of this review), implying that also the cell scale is represented through ODE/PDE systems. Examples can be found in models of atherosclerosis , which thus determined the nature of the multiscale framework to be either hybrid  or fully-continuum. Accordingly, this section will focus on the strengths and weaknesses of adopting agent-based versus continuum-based approaches at the cell scale, within a multiscale framework.Works described in is e.g., , ISR , thus supporting the potentialities of the proposed framework. Another example is offered by the ISR model of Besides the works by The works by Moreover, in ABMs, cellular activities are often modeled through “if-then” rules to describe different behaviors the agents assume according to the specific scenario. This aspect was not included in the aforementioned frameworks based on PDEs. Indeed, although PDEs can embed discontinuous behaviors through properly defined constraints, the individual nonlinearities are more naturally captured through ABM rules . GeneralMultiscale Agent-Based Modeling Frameworks of Vascular Pathophysiology generated multiple solutions, thus reflecting a realistic scenario in which a population of observations is usually obtained in biology-related contexts . An example of multiple outputs obtained from an agent-based modeling framework of atherosclerosis is depicted in Additionally, stochastic ABMs and deterministic continuum models are usually developed, as also reflected by the studies previously reviewed. The stochasticity in ABMs is often introduced by defining probabilistic behavioral rules. This allows embedding a certain degree of randomness resulting in the generation of multiple possible evolution outputs of the system from a given initial condition. Conversely, the implementation of stochastic differential equations is less common, although possible , and, toComputational Speed-Up). The simulation of each agent dynamics is computationally more expensive compared to that of the aggregate population through PDE systems. ABM simulations require hours up to days, while ODE/PDE-based simulations typically run in the order of seconds. For instance, in the work of ABMs to simulate cellular behavior present some weaknesses. The major limitation is related to the computational costs associated with a discrete stochastic model  exploring the mechanobiological processes at a deeper level of details, highlighting the importance of spatial heterogeneity and local morphological peculiarities, 2) capturing emergent properties of the system and 3) including randomness. Moreover, such a hybrid scheme exalted the potentialities of continuum models at the molecular and tissue scales and of ABM at the cell scale. Indeed, 1) PDEs are ideal for modeling the spatio-temporal evolution of concentration profiles of molecules that are transported through diffusion and/or convection in the tissue and are subjected to well-defined reactions, 2) ABMs efficiently describe “active” entities, as cells that proliferate, die or produce and degrade ECM and 3) continuum models are typically adopted at the tissue scale to model solid mechanics and hemodynamics, generally through FEM or finite volume method.The advent of computational modeling in vascular pathologies (and other) have fostered a deep discussion on how much we can rely on the simulation outcome . RecentlModel verification consists in the demonstration that the computational model behaves as expected from the mathematical formulation, implying that there are not implementation errors, the equations are correctly solved and the introduced numerical errors do not significantly affect the solution . ValidatAll these processes are challenging, yet fundamental phases of the modeling activity. When dealing with multiscale frameworks integrating individual sub-models, it is good practice to verify, analyze and validate each module first, and then proceed with the whole multiscale framework . This inA strict definition of what the ABM verification implies, and which are the suitable methods for this purpose, is lacking. While verification methods for deterministic and continuum models (based on ODE/PDE systems) are well documented, the literature lacks rigorous methods for ABMs. A rare example of model verification workflow for ABMs was proposed by Multiscale Agent-Based Modeling Frameworks of Vascular Pathophysiology, a certain number of repetitions must be performed to account for the aleatory uncertainty, typically as many as to bring the standard deviation to a stable plateau. Consequently, these tasks may become extremely time-consuming and almost unfeasible. This roadblock can be addressed by either employing ABM-suitable computational languages that speed up the simulations, or by resorting to surrogate models (or metamodels) that drastically reduce the model complexity, as discussed in Computational Speed-Up. Most of the studies reviewed in Multiscale Agent-Based Modeling Frameworks of Vascular Pathophysiology analyzed the response of the model to the variation of certain parameters  to explore the model behavior under specific conditions, which can be easily linked to meaningful considerations from a clinical/biological viewpoint. For example, tuning the stent-related parameters highlighted the potentiality of the model in providing a tool for testing the arterial response to different stent designs. However, a robust uncertainty quantification or sensitivity analysis is generally lacking. Some contribution in this context derived from Hoekstra’s research group  experimental data used for model calibration and validation are often obtained from retrospective analyses of experiments that were not specifically designed to support the computational modeling process, and 2) most of the in-vitro studies refer to normal cells and not pathological ones. Consequently, also for idealized models, the availability of the data required to calibrate and validate the model is not granted. The advantage of the ABMs reviewed herein is that, since they replicate cellular behavior under specific conditions, they can be more easily related to in-vitro or in-vivo experiments. In this context, the work by Uncertainty and sensitivity analyses can also be performed to identify the most influencing parameters that drive the model response, whose accurate estimation would result in a great improvement of the model prediction reliability and associated uncertainty reduction . Indeed,In summary, the field of multiscale agent-based modeling of vascular adaptation still presents challenges in the area of verification, uncertainty quantification, calibration and validation that need to be fully addressed. Although these processes are fundamental for the achievement of model credibility and its potential application in the pre-clinical or clinical decisional phase, they have been poorly explored for multiscale agent-based modeling frameworks. Future works in this area will be of great impact, since they will add value to this promising approach for the study of vascular adaptation.for and while loops that scan the entire grid and evaluate each agent dynamics in response to environmental conditions and mutual interactions with other agents. Programming languages widely used in academia, such as Matlab (MathWorks), NetLogo , Repastge.net/, ) etc., o runtime . NeverthSurrogate models mimic the behavior of the original computational model, by providing an estimation of the outputs of interest, while getting rid of the original model complexity and being computationally cheaper. They behave as a black-box replicating only the input-output response of the original model, without any detail of the inner system dynamics and working mechanisms. Once validated, the surrogate model can replace the original one thus allowing performing a huge number of simulations at a lower computational cost. This is useful in tasks that require the collection of an elevated quantity of outputs or model evaluations, as in sensitivity analysis, uncertainty quantification, or model calibration. An example of the latter is offered by the work of Other research groups focused more on code parallelization combined with the use of supercomputers with a huge number of central processing units (CPUs) and/or graphics processing units (GPUs). In this direction, In the emerging field of personalized medicine, the so-called omics sciences, including genomics, proteomics, transcriptomics and metabolomics, are recently receiving great interest. The omics data allow identifying patient-specific pathophysiological pathways, thus providing insights into the patient’s disease mechanisms, and potentially leading to the development of tailored therapies. The integration of multi-omics data in multiscale models of vascular adaptation is thought to provide a remarkable contribution in the understanding of cardiovascular diseases  and, as consequence, in the disease prevention, diagnosis and treatment  . For insAlthough continuum models of gene-protein networks were successfully combined with ABMs of cellular behavior in the context of cancer modeling , to the In this review, the state-of-the-art of computational multiscale agent-based modeling frameworks of vascular adaptation was presented, demonstrating that coupling continuum- with agent-based models is a successful approach for simulating the behavior of complex biological systems, and especially for capturing the mechanobiological mechanisms underlying vascular response to biological, chemical and mechanical stimuli. First, a multiscale model is deemed fundamental, being the nature of the system inherently multiscale: the tissue/organ response is just the tip of the iceberg, resulting from the complex network of interactions across different spatio-temporal scales. Then, each scale presents peculiar features, making it more suitable for either a continuum or discrete model. Specifically, while the extracellular molecular transport and the solid mechanics or hemodynamics at the tissue scale are well described by continuum models (ODE/PDE systems), cellular behaviors are more naturally and effectively replicated by ABMs, which, through a bottom-up and systems biology approach, allow capturing the emergent behavior of the system arising from the action and interaction of individual entities .To the authors’ opinion, the inclusion of cell-scale ABMs in a multiscale framework of vascular adaptation, compared to fully-continuum frameworks, adds value to the description of the biological system by providing greater details on morphological-related features, tissue heterogeneity and by capturing the intrinsic randomness. However, this approach is not without limitations, which are mainly related to the high computational costs, and challenges, as those regarding the processes of verification, uncertainty quantification, sensitivity analysis, calibration and validation, for which robust and efficient methods need to be developed. In fact, most of the studies presented herein provided sophisticated methodologies to model vascular adaptation processes but lacked in calibration and validation. The assessment of the credibility of these models is an essential requirement that should be addressed before they can be used as a practical tool for the improvement of current therapeutical approaches in vascular medicine and the development of new ones. For example, the computational frameworks discussed herein might be used to test drugs acting on specific pathological processes, or different stent designs  or deployment procedure  either on idealized cases, as a preliminary study to exclude the worst solutions and drive further experimental research on the most promising ones, or on patient-specific cases, to optimize the personalized therapy.Finally, the present review, by addressing the state-of-the-art of multiscale agent-based modeling frameworks of vascular mechanobiological processes, aimed to inspire researchers for future investigations of novel and unexplored scenarios within the cardiovascular field. Multi-omics data, defining patients’ molecular signature, were never explicitly included in multiscale agent-based model frameworks of vascular pathophysiology. The integration of these data into the models could markedly increase the understanding of vascular diseases and improve the diagnosis, prognosis and treatment in the context of personalized medicine, which is expected to revolutionize the approach to cardiovascular diseases in the near future.


The use of non-invasive ventilation (NIV) devices such as continuous positive airway pressure and bi-level positive airway pressure machines have been associated with an increased incidence of dry eye disease (DED). To understand how the use of these ventilation masks impacts the eyes, a review of the pathophysiology of DED and an evaluation of recent studies investigating the effects of NIV use on the severity and incidence of this condition were performed. It was found that the use of face masks associated with the ventilation devices exhibited a positive correlation to the incidence and severity of numerous ocular pathologies. However, the benefits of non-invasive mechanical ventilation are undeniable in treating conditions such as obstructive sleep apnea, chronic obstructive pulmonary disease, and respiratory failure; therefore, proper education, behavioral modifications, and treatment can help reduce or prevent the adverse effects that NIV have on the eyes. Non-invasive ventilation (NIV) was initially used to treat patients with acute respiratory failure in the early 1940s; however, in the last two to three decades, substantial evidence on the efficacy of NIV in treating severe obstructive sleep apnea (OSA) and exacerbations of chronic obstructive pulmonary disease (COPD), congestive heart failure (CHF) induced pulmonary edema, and acute and chronic hypoxic and hypercapnic respiratory failure has been documented .However, there are side effects associated with the long-term use of these devices, which have largely contributed to the low patient compliance in CPAP therapy. The overall rate of CPAP non-adherence based on seven hours of sleep a night has been reported to be as high as 34.1% . While tPathophysiology of keratoconjunctivitis sicca (dry eye disease)DED is a multifactorial disorder of the tear film and ocular surface that can be divided into two categories: aqueous deficient DED and hyper-evaporative DED. Aqueous deficient DED is due to decreased tear production, and evaporative DED is due to abnormal meibomian gland physiology. Although one may predominate, the combination of the two along with other external factors disturbs the microenvironment and disrupts homeostasis of the ocular surface .The lacrimal functional unit includes the ocular surface, meibomian glands, the main lacrimal gland, and the nerves that innervate them . ContinuDamage to the ocular surface can cause significant distress as it is extremely uncomfortable, affecting one’s quality of life, and may hinder daily activities . DED hasLiterature reviewGlobally, the prevalence of DED has been measured to be 5-50%, with as many as 16 million people affected in the United States alone ,10,11. TWhile CPAP remains the treatment of choice for patients with OSA , many paHayirci et al.  evaluateNIV is also commonly used to manage acute and acute-on-chronic respiratory failure due to COPD and decompensated CHF. In a prospective, cross-sectional study, Smith et al.  observedMatossian et al.  found thOne study showed patients who received NIV therapy in the ICU for acute pulmonary exacerbation experienced ocular dryness leading to irritation as a complication, among other more common side effects such as discomfort, pressure ulcers, and mouth dryness. Yesilbalkan and Ozbudak  utilizedIn a two-phase prospective cohort study, Kousha et al.  studied NIV usage subjects the unprotected eye to mechanically generated air. The physical insult of excessive drying disrupts the eye’s natural tear film, which acts as a barrier against pathogenic infection . Some paThe etiology of keratoconjunctivitis sicca (DED) is multifactorial, but research has shown that the use of NIV in treating OSA, COPD exacerbation, and respiratory failure has contributed to an increased incidence. Prolonged use of improperly fitted masks accompanying NIV devices accelerates ocular drying, causing irritation and inflammation and increasing the risk of infection and other ocular pathologies. The adverse effects of NIV use in causing dry eye symptoms and the development of DED may cause patient dissatisfaction leading to possible noncompliance with home NIV therapy. The use of NIV is an important part of treatment for many respiratory pathologies; therefore, so patient compliance is paramount. Thus, proper patient education, implementation of behavioral modifications, and proper eye care protocols, as discussed above, can help reduce the undesirable effect of dryness and its subsequent effects. Future studies can be focused on different preventative measures and therapies that can decrease the occurrence of dry eye symptoms during NIV usage, accessing the success rates of each remedy introduced while on NIV therapy.


Here complexity, though grounded in features that are conceived as individual and cohesive, is most prominently recognized to arise from interactions at the intersections among systems forming wider ensembles or diverse consortia. On this basis, individuality and identity of wholes are understood as affected and/or constituted by interactive dynamics with other systems and the environment.The complexity of life, mind and society seems to be an endless source of challenges for philosophy and science, which keep exploring them under ever-new lenses. In order to explain or describe these domains, systemic approaches investigate how parts are dynamically organized and integrated, Classical approaches often comprise individualistic assumptions that neglect interactions and collective phenomena related to identity. Naturalist accounts have to confront significant trouble in conceptualizing identity and individuality, since the massive interconnectivity and/or heterogeneity among components intrinsic to complex organizations entail remarkable difficulties in determining primitive systems or starting points. Currently, new modeling and explanatory approaches engage in studying a variety of processes, such as metabolic interactions giving rise to the first living cells, their evolution through lateral transfer of genes, the emergence of multicellular organisms, the intersubjective participation in sense-making or in the generation of cognitive meaning, social interplay as a source of autonomous decision-making, and technologically mediated interrelation in social groups and network dynamics.in context. This perspective excludes the possibility of conceiving such entities as independent individuals, and requires to consider them as entangled. When defining the title of this Research Topic, we coined the term “inter-identities” to refer to these kinds of interactions and, more precisely, to indicate what emerges from these interactive processes and cannot be found in the interactors, when taken separately. We introduced the notion of inter-identities with a programmatic aim: promoting the exploration of new strategies to study and conceptualize these forms of complex interaction.Rather than focusing on substantial identities, these endeavors examine how the entities involved in those processes appear, change and act The articles gathered in this Research Topic (RT) propose inquiries convergent to that goal. They are based on multiple transdisciplinary approaches aiming at describing complex interactive processes belonging to the living, the cognitive and the social domains.A central feature of the systems populating these three domains, typically captured through the notion of autonomy, is the capability of coupling with the environment and other systems. An autonomous system cannot be interpreted as fully determined by internal, localized elements, like genes, nor by external factors. The property of autonomy entails systems whose dynamics of self-production are based on interactions between the systems as wholes, their components and their environments. Hence, these systems' autonomous behavior is deeply grounded in interactive dynamics, so that the autonomy involves normative assessments of the environment, in such a way that other systems and situations are perceived and cognized according to those interactive norms, as well in normative constraints prompted from the environment.autonomy and the notion of inter-identity are deeply interconnected: they actually articulate a tension between, on one side, the self-determined character of these systems' dynamics of self-production and generation of behavior, and, on the other side, the multiple connections influencing these processes.In this sense, for living, cognitive and social systems the notion of This tension travels across the articles contributing to the RT. The related problems concern different scientific and philosophical aspects in the three target domains of life, mind and society, or more transversal, epistemological dimensions of inter-identities, and the research challenges they involve.origins of life, Ruiz-Mirazo et al., suggest that the first living cells already comprise an irreducible collective dimension, both in ecological and evolutionary terms, necessary to explain how several bottlenecks of the process of biogenesis are overcome. About the organization of the motility of eukaryote cells in interaction with the environment, Militello argues that its emergence involves a strict control of the motile abilities of their constituting entities, such as organelles of endosymbiotic origin  and flagella, although it does not necessarily entail a complete loss of the agential capacities of the individual parts. Expanding the discussion toward other complex collectivities, Canciani et al., build an organizational account of eusociality which emphasizes the regulatory control relationships involved in some insect colonies , involving a hierarchically organized network of interactions.(a) Life and Biology. An important fraction of the articles engages with inter-identities in this realm. In the field of the synthetic biologyBich takes a complementary view on the problem of “inter-identity” by studying the ways in which models and realizations of that field can contribute to discover the interactive dimension of minimal life and cognition. In particular, the article discusses how concepts such as control, cognition, communication can characterize those interactions.Looking at examples in evolutionary processes for which interactions are decisive. Hernández and Vecchi investigate how biological autonomy is compatible with evolutionary processes by which living organisms capture and integrate environmental ingredients directly within their own dynamic organization; they analyse, in particular, biotic entrenchment emphasizing the interactive aspects of the construction of the individual. Also within this line, an illustrative case of the evolutionary relevance of interactions of interspecific individuals is offered by Suarez and Triviño on the sanguivory diet of vampire bats as an adaptation occurring at the level of the holobiont, the host–microbiome multispecies systems. Besides, Nuño de la Rosa et al. consider the evolution of eutherian pregnancy as the relational emergence of the pregnant female a new kind of historical individual, in contrast with prevalent dualistic conceptions often based on conflict models about the relationship between mothers and embryos.Other papers explore (b) Minds and psychology. A second group of articles examines issues related to cognitive agency and identity in interactions.James and Loaiza characterize inter-personal identities as collections of entangled stabilities that emerge in recurrent social interaction, and emphasize how sense-making, at the personal level, is a manifestation of histories of acting together. Another focus of interest is the role of social interactions in non-heterosexual personal identity; Collado and Besoain introduce a processual theory to examine the suffering associated with the influence of prevalent heteronormative environments on identities. In order to overcome standard monologic accounts, they consider how multiple effects or self-states can be produced, recurrently unified to create identities inherently susceptible to transformation, for example through performance art. Addressing pregnancy from an agential perspective, Martínez Quintero and De Jaegher converge in prospecting the interactive developmental organization of mother-baby relations, and stress the importance of taking into account the two inter-connected agencies, as well as how maternal agency changes while pregnancy advances.On personal identity in social interaction from an enactive standpoint, education is the topic explored by Pérez-Izaguirre in the context of a Basque secondary school in which adolescent students, coming from diverse ethnic backgrounds, meet and tend to construct their identity through transgression. Arrieta's article concerns the domain of bioethics in medicine. Based on the discussion of patients' decisional, executive, and narrative capacities, the author proposes a characterization of the patient's autonomy in the case of poor treatment adherence, and examines what appropriate actions may contribute to increase adherence rates. The collective dimension of social and political forms of organization is explored by Barandiaran et al., within the framework of networked digital interactions. By means of a detailed and critical exploration of different theoretical views of identity, they characterize collective identities as recurrent, cohesive, and coordinated communicative interaction networks, following a technical graph–theoretical approach.(c) Societies, education, bioethics. This group of articles offers specific and insightful examples of inter-identities. Inter-identities in Epistemic dimensions of interidentities. Although all the articles contribute to the study of interidentities, some of them are particularly dedicated to more general epistemic matters. Thus, Gómez-Marin and Arnau examine the epistemological changes required to conceptualize inter-identities, which should be rather thought, according to their Whiteheadian  account, as “intra-identities.” They criticize not only reductionist, but also emergentist positions, arguing in favor of a general shift of perspective toward process ontology to overcome difficulties attributed to the -simple location- assumption, which gives the false impression that enduring substances exist. Through the analysis of some experimental and modeling practices of biologists, Montevil and Mossio explore the way in which historical and relational approaches interpret the identity of organisms. The acknowledgment of a complementary relation between these views leads the authors to promote a compelling convergence of these perspectives in a hybrid construct. Also within philosophy of biology, Ferreira-Ruiz and Umerez discuss interactionism with regard to gene-centrism and the nature-nurture problem. They criticize the vagueness that general interactionist accounts tend to show, and propose examining more carefully the causation behind complexity in order to clarify the interactionist claims  supporting deflationary positions with respect to genetics.(d) inter-identities—emerge.In general, the contributions gathered in this RT tackle, from different perspectives, two main sides of a common issue: how do complex  systems construct their identities? And also: how do science and philosophy conceptualize and methodologically explore interactivities? We believe that the answers they propose constitute a remarkably diverse and thought-provoking body of research, delineating new approaches to describe the processes of interaction in which complex identities—All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Although there have been significant advances in our ability to accurately identify infertile and moderate to severely subfertile breeding males, our ability to accurately identify highly fertile males continues to be quite challenging. Apart from motility and kinetic parameter analysis, a number of studies investigating the impact on fertility outcomes of spermatozoa radical oxidative stress (ROS), Total Antioxidant Capacity (TAC), DNA fragmentation, membrane status , and capacitation-like status have been conducted. However, there is still a lack of a complete definition of the components of semen, not only the spermatozoa itself but also seminal plasma components that affect fertility outcomes. Thus, the development of new analytical tools to accurately define sperm quality is critical.Anel-López et al. compared the effects on sperm quality and fertility outcomes of use of three commonly used antibiotics in ram semen extenders. Using computer assisted sperm analysis, sperm motility parameters were significantly lower for semen extended with gentamycin. Further, it was shown that there were no significant differences in fertility outcomes between semen extended without an antibiotic vs. semen treated with penicillin-streptomycin, globally the most commonly used extender antibiotic. This finding was consistent with immediate post-thaw results of simultaneous flow cytometric assessment of sperm viability  and prompts the question, “in the absence of venereal pathogens is the antibiotic treatment of semen necessary”. In a larger study examining the relationship between a range of conventional and new post-thaw laboratory measures of ram sperm quality, Mendoza et al. demonstrated that the percentage of intact membrane, non-capacitated (IM-NC) spermatozoa  in extended chilled semen used for cervical artificial insemination was positively correlated with fertility outcomes.When the analysis was restricted to insemination conducted during the breeding season, an additional three new measures of sperm quality  were significantly correlated with fertility outcomes. Modeling indicated that the use of semen with higher percentages of IM-NC and DNA-intact sperm would result in fertility outcomes greater than the population mean.In the first paper, Sobeh et al. reported the findings of a study investigating the impact on sperm quality of addition of a polyphenol-rich extract, derived from the bark of Entada abyssinica, to a standard semen extender. It was concluded that the extracts's potent antioxidant capacity contributed to the observed improvement in sperm progressive motility and plasma membrane integrity. Greco et al. investigated the effect of administration of Tetrahydrocannabinol (THC), maca , and their combination on testicular tissue and semen parameters in mice. The natural anti-oxidant properties of maca have been shown to protect testicular cell membranes and mitochondria from oxidative stress. Overall, administration of maca, reduced the deleterious effect of THC on testicular parenchyma and semen production. Mao et al. tested the effect of dietary Echinacea purpurea (EPE) treatment on the reproductive function of streptozotocin-nicotinamide-induced diabetic rats. EPE treatment significantly increased sperm progressive motility and decreased the percentage of sperm abnormalities. Interestingly, they demonstrated that feeding of EPE increased sperm enzymatic antioxidants , whereas proinflammatory cytokines, such as NO, IL-1b, and TNF-a were decreased.Three papers examined the impact on sperm quality of direct or indirect administration of plant derived medicinal substances. Suwimonteerabutr et al. investigated the impact on sperm quality of the addition of butaphosphan and cyanocobalamin to a standard semen extender for chilled boar semen. Overall, supplementation of the semen extender resulted in significant improvements in progressive motility, sperm viability and plasma membrane integrity through to Day 7 of chilled storage. Using a unique approach Wang et al. investigated the molecular mechanisms of sperm cryoinjury and cryoresistance by comparing the piRNA profiles of boar sperm with that of Giant Panda sperm, the latter being known to be quite cryotolerant. They concluded that observed species difference in the profiles involved in the cAMP signaling pathway may be responsible for the difference in cryotolerance of boar and Giant Panda sperm. Continuing in this theme O'Brien et al. investigated whether domestication of ungulates is likely to have altered the sensitivity of their sperm to laboratory manipulation and chilled storage. Using principal components analysis they showed that mitochondrial membrane integrity, oxidative stress level (percentage of low levels of reactive oxidative species) and curvilinear velocity of sperm after chilled storage were the most important biomarkers defining differences between the sperm of domesticated and wild species of pigs, sheep, and goats, respectively.Three papers examined the impact of chilled and frozen semen storage on sperm quality. Gacem et al., using a computer-aided sperm motility analysis system recording sequences at high frequency (250 frames per second), compared the kinematics of sub-populations of spermatozoa from two different horse breeds with that of donkeys. Three distinct sub-populations of motile spermatozoa were defined for both species. The predominant subpopulation consisted of spermatozoa with very fast velocity characteristics and a linear trajectory with a high beat frequency.It is now recognized that instead of semen containing a homogenous population of spermatozoa, it consists of subpopulations of spermatozoa related to period of spermatogenesis and spermatozoal maturation. Khan et al. focused on how studies using OMICS technologies (proteomics and transcriptomics) can improve our understanding of the mechanisms of cryo-injury and cryo-tolerance. Systematic application of these technologies could contribute to the optimization of current farm animal cryopreservation protocols. The ultimate goal is the identification of biomarkers that accurately predict spermatozoa freezability. Continuing this focus, Evans et al. examined how lipidomics technologies could be applied to accurately characterize the fatty acid composition and their biological roles in ejaculated, stored, and cryopreserved spermatozoa. Özbek et al. reviewed how OMICS technologies have been and further could be applied to improve identification and selection of more fertile bulls. The final review focused on the critical issue of the level of agreement between laboratories, specifically for the assessment of the percentage of morphologically normal spermatozoa (Perry). A programme to support standardized examination of fixed samples of bull semen by a network of commercial laboratories is described, together with the standardized reporting of specific abnormalities and the maximum percentages of each, based on published reports of their impact on fertility.In the first of the four reviews, HR-M, MM, SN, and MA-R contributed to the conceptualization, writing of the original draft, and review and editing. All authors approved the final version of this editorial.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. 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Purgatorius from early Palaeocene (early Puercan) age deposits in northeastern Montana that represent the earliest dated occurrences of plesiadapiforms. We constrain the age of these earliest purgatoriids to magnetochron C29R and most likely to within 105–139 thousand years post-K/Pg boundary. Given the occurrence of at least two species, Purgatorius janisae and a new species, at the locality, we provide the strongest support to date that purgatoriids and, by extension, Pan-Primates, Euarchonta and Placentalia probably originated by the Late Cretaceous. Within 1 million years of their arrival in northeastern Montana, plesiadapiforms outstripped archaic ungulates in numerical abundance and dominated the arboreal omnivore–frugivore niche in mammalian local faunas.Plesiadapiform mammals, as stem primates, are key to understanding the evolutionary and ecological origins of Pan-Primates and Euarchonta. The Purgatoriidae, as the geologically oldest and most primitive known plesiadapiforms and one of the oldest known placental groups, are also central to the evolutionary radiation of placentals and the Cretaceous-Palaeogene biotic recovery on land. Here, we report new dental fossils of  PlesiadPurgatorius and Ursolestes, and seven named species )Click here for additional data file.