Urban agriculture (UA) can be used as an action to promote sustainability in cities and inform public health policies for urban populations. Despite this growing recognition, its implementation still presents challenges in countries in the Global North and Global South. Background: In this context, this systematic review aims to identify the development of frameworks for the implementation of UA as a sustainable action and its main opportunities and shortcomings in meeting urban socio-environmental demands. Methods: In this review, using the PRISMA protocol, we evaluated 26 studies on the interplay between UA and sustainability surveyed on the Web of Science to provide an overview of the state of the art. Conclusions: In summary, it was possible to identify many key challenges in UA adoption, which regard air and soil contamination, availability of green areas, layout of urban infrastructure, food distribution, among others. Due to numerous socio-economic and environmental contextual factors in cities, especially when comparing realities of the Global North and Global South, there is a need to develop a model that can be adaptable to these different contexts. Thus, it is recognized that the concept of sustainability does not present a universal understanding and that in its search it could be argued that one of the most important gaps is still to address social issues in relation to environmental ones. Urban agriculture (UA) movements gained strength from the late 1970s onwards in response to rising poverty and food prices ,3. AlthoIn addition to food and nutritional security, authors argue that UA can provide provisioning, regulation, support, and cultural ecosystem services (ES) , as wellCities have already been recognized as “engines” for sustainable development and climate mitigation ,10,11, wAs such, many authors argue that UA can be implemented to promote sustainability in cities . HoweverYet, a clear and specific definition of economic strategies for UA mainstreaming is still lacking . In thisAlthough UA’s potential to help meet sustainability indicators is recognized, it is essential to have clarity on, after all, what is intended for sustainability and for whom. In this light, this article proposes that for an UA initiative to succeed and be truly sustainable, it must be customized to its socio-environmental context. In this regard, some studies seek to point out an analysis model for UA; however, it is still a challenge to align social and environmental issues. Therefore, the research question that guides this work refers to the identification of opportunities and gaps to situate the UA’s contribution to urban sustainability. The remaining of the article is structured as follows: the next section discusses the concept of sustainability. The third explores examples of how UA is able to help meet sustainability indicators. The fourth discusses the governance challenge. The fifth points out the characteristics of initiatives in the Global North and South. Finally, the need to develop models to evaluate UA is discussed.The concept of sustainability began to be outlined in the 1980s based on the increasing acknowledgement of planetary environmental degradation . It thenIn time, the concept of ecological design came to be associated with sustainable development. Such convergence triggered new ideas and technologies in different fields of activity. Topics such as renewable energy, alternative materials, recycling, agroecological food and environmental footprint were being absorbed by the market and political agendas ,23,24,25In opening up the possibility of a better relationship between development and the environment, such innovations led the way to the emergence of a green economy, with sustainability incorporated as a capitalist value. This, on the one hand, paved the way for political incentives for ‘green’ businesses , but, onAt the beginning of the 2000s it was emphasized that the present distance between the poor and the rich is a limiting factor for reaching and maintaining global stabilities, and the preservation of natural resources . Thus, iIn the last 20 years, there has been a significant development of new tools and approaches that incorporate ecological considerations in a range of fields; however, their uptake is still taking slow steps.We used the PRISMA 2020 framework  to surveIn the second stage, we conducted a systematic literature review by following the PRISMA protocol. The search expression (title or publication title contains the terms (“urban agriculture”) AND (“sustainability”) was used. The articles were organized in two groups: most cited publications in the last 10 years (2012–2022) and publications from the last two years (2021–2022). The aim was to better explore the most relevant and recent trends within the proposed theme. The search took place in March 2022. The initial sample contained 129 documents. After removing duplicates and those meeting the exclusion criteria, a sample of 125 articles was identified. Abstracts were then read by one of the authors and discussed with others in order to identify articles relevant to answering the research question. See After the above step, 28 articles were selected  emissions . In thisnce 1990 . This trnce 1990 . Global nce 1990 . In thisnce 1990 .Covering most empty urban areas with edible green could be a new ecological achievement as such interventions could reduce urban pollution, mitigate, and adapt to climate change by increasing carbon sequestration, water infiltration and retention, and controlling the urban heat island effect ,37. GreeUA is compatible with the proposals of the circular economy movement , where tThe UA benefit most reported by the studies is the food miles. Specht  points oStill on emissions, in UA they are affected mainly by the structure, land use, use of fertilizers and the distribution of their production . It is aIn this sense, Hu et al.  propose Giraud  argues tHowever, a limitation presented for the integration of Nature-based Solutions (NBS) policies is that city master plans do not usually consider food resilience in their guidelines ,54. As sCompared to conventional agriculture, UA is understood to be more resilient due to the shorter production-consumption chain, as well as promoting systems with more diversified production . In thisFinally, it is vital to highlight that UA does not necessarily result in the preservation and regeneration of natural resources . For theThe vulnerability of ecosystems and people regarding the climate crisis significantly differ according to the region of the planet, and this is essentially due to factors such as socio-economic development, inequality, marginalization, unsustainable use of land and oceans, as well as governance . The advThere is a substantial gap in understanding the political economy of urbanization and the roles of governance . In SoutAlthough there is evidence regarding the UA contribution to alleviating social and urban challenges, which include climate change, food security, biodiversity and ES, agricultural intensification, resource efficiency, urban renewal and regeneration, land management, public health, social cohesion, and economic growth , there iAlthough Clinton et al.  have demSome authors postulate that UA presents different approaches between Global North and Global South. First, this division of the world order accepts that the first is composed of countries from North America, Europe, some Asian countries and others located in the southern hemisphere, such as Australia and New Zealand, while the Global South concentrates Latin countries, the African continent, Middle East and parts of Asia. What defines these borders is based on economic, social and political repercussions, representing the division of developed and developing nations . DespiteIn the context of UA, it is observed that while in the Global North countries these initiatives tend to focus on social dimensions and, in some cases, on environmental benefits, in the Global South, UA is primarily focused on food subsistence and income generation ,70.Opitz et al.  point ouThe literature understands green infrastructure initiatives related to UA as reflections of specific needs or problems. In Africa, for example, where food security is an important issue, UA is understood as an answer, while in Asia research on green spaces reflects issues of spatial planning and land distribution in high-density cities. In Latin America and the Caribbean, where there are serious issues of inequality, studies highlight vulnerability and social concerns .Another aspect observed is the difference in governmental action in periods of crisis. While in developed countries it is common to observe the encouragement of activities such as UA , in deveFinally, Dona  argues tUrban food production needs to consider the different dimensions of sustainability; therefore, it must understand the management of environmental challenges, solve or alleviate social problems and promote economic returns .Urban resilience and sustainability depend on the connection between different ES. The provision of ES in cities must seek equality, across socio-economic and demographic regions . The intAccordingly, care must be taken to evaluate the suitability for UA, considering for instance the presence of air pollutants, as well as soil contamination, which expose the health of the local population to risks . The impAn aspect not addressed in the literature is to link the implementation of the green structure of food production to the principles of preservation and regeneration of native species. Cities that consider their native vegetation incorporated into municipal land use plans can promote the activity by encouraging and delimiting cultivated species according to the native profile, for instance restricting the use of non-native species in the territory. Cities such as São Paulo encourage this type of action based on municipal plans such as the Atlantic Forest Municipal Plan . Yet, thBesides, a requalification and assignment of multiple uses of urban green space would address the recommendations of international policies  as a fulThe association of green infrastructure and UA is still lacking, even in countries that already adhere to NBS policies. In the case of flood risk management, Deksissa et al.  argue thRegarding the economic dimension, UA must be incorporated into commercial chains in the city, preferably in its neighborhood, to contemplate aspects of the food miles. In this regard, Sonnino , in an aThe social sphere is perhaps the most fragile to be manipulated since numerous cases of UA implementation are affected by gentrification and mask greenwashing ,87. In aFaced with such challenges, some authors propose strategies for evaluating UA initiatives. Gulya and Edmondson  argue thFollowing what has been observed in the literature, this article defends the need to develop an UA assessment model, especially for countries in the Global South, covering socio-economic and environmental criteria. Among the suggested parameters, it is proposed the evaluation of air pollutants, soil contamination, availability of green areas, layout of urban infrastructure (including proximity to users), the profile of native vegetation, locations with potential for capturing rainwater, strategic locations for the circulation of organic waste, commercial establishments with the potential to establish partnerships with producers, as well as local food demand , 96, 97.The strengthening of sustainable development has promoted the expansion of environmental policies in urban areas, creating opportunities to associate them with food production initiatives, which can not only provide ES to the urban environment but also alleviate social issues related to food and nutrition security. According to the literature, the main obstacle is the association of these different dimensions through solid and active governance, in addition to the fact that it is challenging to stimulate a model for their mainstreaming since the intense socio-economic and environmental particularities of each location imply different implementation needs. In developed countries, UA is not adopted essentially for subsistence, and in some cases it can be a challenge to contemplate populations in food vulnerability, while in developing countries, although very directed towards this population, problems related to local environmental pollution and access to sustainable technologies are often observed in its adoption.This article defends the need to develop transferable models, in which there is a comprehensive inclusion of the socio-economic and environmental characteristics of each locality.Environmental parameters are commonly indicated in the development of UA assessment tools, while social ones are still approached in a restricted way, since they can easily be masked or driven by issues of social injustice and gentrification. Therefore, addressing the social aspects of urban environmental policies is arguably one of the main challenges for UA’s success, which also explains why UA is especially complex in the countries of the Global South.


Hereditary hemorrhagic telangiectasia (HHT) is associated with defective capillary network, leading to dilated superficial vessels and arteriovenous malformations (AVMs) in which arteries connect directly to the veins. Loss or haploinsufficiency of components of TGF-β signaling, ALK1, ENG, SMAD4, and BMP9, have been implicated in the pathogenesis AVMs. Emerging evidence suggests that the inability of endothelial cells to detect, transduce and respond to blood flow, during early development, is an underpinning of AVM pathogenesis. Therefore, components of endothelial flow detection may be instrumental in potentiating TGF-β signaling in perfused blood vessels. Here, we argue that endothelial cilium, a microtubule-based and flow-sensitive organelle, serves as a signaling hub by coupling early flow detection with potentiation of the canonical TGF-β signaling in nascent endothelial cells. Emerging evidence from animal models suggest a role for primary cilia in mediating vascular development. We reason, on recent observations, that endothelial cilia are crucial for vascular development and that embryonic loss of endothelial cilia will curtail TGF-β signaling, leading to associated defects in arteriovenous development and impaired vascular stability. Loss or dysfunction of endothelial primary cilia may be implicated in the genesis of AVMs due, in part, to inhibition of ALK1/SMAD4 signaling. We speculate that AVMs constitute part of the increasing spectrum of ciliopathy-associated vascular defects. Hereditary hemorrhagic telangiectasia (HHT) is characterized by vascular lesions that lack a normal capillary network , leadingEvidence from animal studies suggest that upon activation by circulating growth factors, BMP9 and BMP10, ALK1, through its interaction with its co-receptor ENG, phosphorylates the downstream effectors, SMAD1/5/8, resulting in translocation of the downstream SMAD4 to the nucleus. In brief, both ligands bind to ALK1 and the two type II TGFβ receptors where ENG serves as a co-receptor. Upon dissociation of ENG from the ligand, ALK1 is phosphorylated, and this is followed by phosphorylation of SMAD1, SMAD5, or SMAD9 phosphorylation. In the nucleus, the p-SMAD1/5/8 and SMAD4 complex functions as a transcription factor to regulate the expression of target genes. The ALK1/SMAD4 signaling has been implicated in endothelial cell (EC) quiescence, vascular stabilization, and recruitment of perivascular cells . HoweverThe primary cellular defects underlying AVM genesis are unknown. Animal studies suggest that AVMs form during a period of dynamic vascular remodeling, such as, during developmental angiogenesis or when quiescent ECs are activated in response to wound-induced vascular remodeling or tissue regeneration . The forThe fluid flow that ensues the first cardiac contractions in the fetus provide the hemodynamic force and the growth/humoral factors that contribute to artery-vein specification, establishment of a hierarchically ordered and lumenized vasculature , that eng−/− ECs, unlike their wild-type siblings, assume a disorganized morphology following flow induction and that cessation of flow was sufficient to rescue these abnormal endothelial morphologies in eng−/− ECs  can trigger maladaptive endothelial responses that precipitate conditions for AVM genesis in specific vessel beds . But howIn the following section, we hypothesize, by integrating our recent findings with emerging evidence from the literature, that impaired flow transduction, as a consequence of premature loss or dysfunction of endothelial primary cilium, a microtubule-based flow-sensitive organelle, constitutes one of the earliest steps in the pathogenesis of some forms of AVMs.tunica intima), have multiple flow-sensitive components and membrane invaginations that are crucial for adaptive responses, some of which include the caveolae, membrane-associated mechano-sensitive ion channels, the glycocalyx, components of extracellular matrix, cell-cell junction proteins, G-protein coupled receptors and the primary cilium  exhibit defects in directional migration and display enhanced trans-endothelial permeability in-vitro , Taken together, animal studies suggest that endothelial cilia may have a functional role in mediating several aspects of vascular development in teleosts and mammals, with potential involvement in sprouting angiogenesis, lumenization, recruitment of perivascular cells, and vessel stabilization. Published observations suggest that these morphogenic events are mediated, in part, 1) Endothelial primary cilia membrane harbors components of ALK1 signaling.2) During angiogenesis, tip cells exhibit primary cilia as they migrate and fuse with neighboring sprouts.3) Following tip cell anastomosis, junctional remodeling and lumenization, endothelial primary cilia serve as signaling hubs to increase sensitivity of ECs to BMP9/10 gradients under low shear stress conditions4) Loss or dysfunction of primary cilia  during this stage would result in a concordant reduction in BMP9/10 sensitivity and inhibit cellular processes mediated by the canonical TGF-β signaling in ECs, resulting in misguided angiogenesis of the capillary network.On balance, the model we propose is as follows:1- Improved imaging modalities and post-processing of images to rigorously quantify and colocalize components of ALK1/ENG→SMAD4 signaling are needed to convincingly demonstrate their physical association with the endothelial primary cilium. Specifically, better imaging modalities and image analysis, as well as techniques such as rapid protein proximity labeling can be employed to accurately co-localize primary cilia with components of ALK1/SMAD4 signaling .in-vivo, using transgenic zebrafish reporter lines that our lab had previously generated (Tg(BRE:dsGFP) line, the BMP response element (BRE) derived from mouse Id1 promoter, which includes multiple Smad-binding elements, drives the expression of destabilized GFP, thus enabling in-vivo assessment of the canonical BMP/Smad1/5/8-mediated signaling  would have significantly attenuated ALK1 signaling, as evidenced by reduced phosphorylation rates of SMAD1/5/8. Interestingly, under high shear stress conditions that would otherwise result in deciliation, ECs are still able to display synergistic interaction between shear stress levels and translocation of p-SMAD1/5/8 to the nucleus following exogenous BMP9 supplementation . Howeverenerated . In partignaling . The designaling .3- Similarly, we predict that premature loss or dysfunction of endothelial cilia will impair translocation of p-SMAD1/5/8 and SMAD4 to the nucleus, where they would otherwise induce transcription of genes required for vascular stabilization and EC quiescence . In ECs in-vivo paradigm to study BMP-mediated angiogenesis. By 24 h post fertilization (hpf), zebrafish embryos exhibit the two conserved axial vessels along the medial side of the somites, namely, the dorsal aorta (DA) and the ventrally apposed posterior cardinal vein (PCV) (Tg(kdrl:mCherry-CAAX)y171; (bactin::Arl13b:GFP) line, we have shown that the ECs making up these sprouts manifest primary cilia as they migrate ventrally (iguana (igufo10/fo10) mutants  or ift88, due primarily to “decreased number and activity of venous sprouts” (Tg(fli1:lifeact-mCherry) y137  . The angin (PCV) . In contin (PCV) . Startinin (PCV) . At the in (PCV) . By ∼32 in (PCV) . The forin (PCV) . Despiteentrally . Furtherentrally . However mutants . The igueviously , we haveeviously . Consistsprouts” . More grmCherry) , endothey)y137, number 1:dsRed) .We predict that premature loss of endothelial cilia during development, particularly at a time when immature ECs coalesce to form a newly perfused vascular tube, would curtail transduction of initial flow patterns to ECs. This would result in attenuation of TGF-β signaling and curtailment of downstream EC autonomous processes needed for vascular stabilization . Severalbmp9 were shown to impair CVP formation in embryonic zebrafish, the observed phenotypes are not as severe as those observed in iguana mutants , an inherited ciliopathy condition . Whether


Angiogenesis is a highly regulated multiscale process that involves a plethora of cells, their cellular signal transduction, activation, proliferation, differentiation, as well as their intercellular communication. The coordinated execution and integration of such complex signaling programs is critical for physiological angiogenesis to take place in normal growth, development, exercise, and wound healing, while its dysregulation is critically linked to many major human diseases such as cancer, cardiovascular diseases, and ocular disorders; it is also crucial in regenerative medicine. Although huge efforts have been devoted to drug development for these diseases by investigation of angiogenesis‐targeted therapies, only a few therapeutics and targets have proved effective in humans due to the innate multiscale complexity and nonlinearity in the process of angiogenic signaling. As a promising approach that can help better address this challenge, systems biology modeling allows the integration of knowledge across studies and scales and provides a powerful means to mechanistically elucidate and connect the individual molecular and cellular signaling components that function in concert to regulate angiogenesis. In this review, we summarize and discuss how systems biology modeling studies, at the pathway‐, cell‐, tissue‐, and whole body‐levels, have advanced our understanding of signaling in angiogenesis and thereby delivered new translational insights for human diseases.Cardiovascular Diseases > Computational ModelsCancer > Computational ModelsThis article is categorized under: BioRender.com).Multiscale and multicellular regulation of angiogenesis signaling (created with  A series of computational models have been proposed and analyzed to study HIF stabilization , a class of oxygen‐based cellular metabolic products, can also participate in the regulation of HIFs. Experimental studies have shown that PHDs, FIH, and HIFs can be regulated by ROS through a number of direct and indirect mechanisms  to control angiogenesis  is the predominant producer of nitric oxide (NO), an important vasodilator and regulator of angiogenesis, in endothelial cells. Activation of eNOS is regulated by multiple growth factor‐driven pathways , calcium‐dependent pathways, as well as fluid shear stress  by depleting tetrahydrobiopterin (BH4), an essential cofactor for eNOS. This will shift eNOS from a NO‐producing enzyme to a superoxide‐producing enzyme, which would further potentiate the preexisting cellular oxidative stress and endothelial dysfunction  signaling pathway is a major signaling pathway regulating vascular growth, maintenance, and remodeling. The VEGF signaling pathway also mediates calcium signaling patterns in endothelial cells associated with proliferation and migration /Tie signaling pathway is a major endothelial signaling pathway regulating vascular permeability, stability, and quiescence  signaling pathway, consisting of FGF‐2 and receptors FGFR1‐4, is another important signaling pathway regulating angiogenesis, wound healing, and tissue repair  signaling pathway, has been demonstrated to play an important role in angiogenesis. Its downstream signaling has been demonstrated to be able to stimulate endothelial proliferation, migration, and vascular morphogenesis . Three computational models by Palma et al. , RamirezOur group, through two modeling studies, has developed a novel large‐scale computational systems biology model formulated using mass‐action kinetics‐based ODEs to mechanistically characterize the complex biology of macrophage polarization spanning the M1–M2 spectrum and its potential impact on angiogenesis in health and disease . These cells also actively contribute to angiogenesis in normal physiology as well as in human diseases such as cancer and ischemic diseases , PDGF, N‐cadherin, and transforming growth factor (TGF) pathways, as reviewed in Sweeney and Foldes  built from 11 public data sources and microarray datasets for identifying essential genes associated with angiogenesis in different disease settings , and by systematically analyzing omics data (proteomics and transcriptomics) they were able to show mechanistically that IL‐35 can potently impact ECM remodeling through collagen formation and integrin activation as well as ROS generation in endothelial cells to collectively suppress angiogenesis in the ischemic tissue  during normal development and repair. However, under inflammatory conditions, hypoxia, or aberrant development, ocular neovascularization also takes place, becoming the cause for several ocular diseases, such as diabetic retinopathy, age‐related macular degeneration, retinal vessel occlusion, and retinopathy of prematurity  network of angiogenesis‐related proteins suggested that the therapeutic regulation of multiple targets instead of a single factor like VEGF might be more effective in the treatment of pathological ocular neovascularization ; investigation ; writing – original draft ; writing – review and editing . Hanwen Wang: Investigation ; writing – original draft . Rebeca Hannah M Oliveira: Investigation ; writing – original draft . Chen Zhao: Conceptualization (lead); investigation ; supervision (lead); writing – original draft ; writing – review and editing . Aleksander S Popel: Conceptualization ; funding acquisition (lead); supervision (lead); writing – review and editing .Systems medicine: Evolution of systems biology from bench to bedsideThe macrophage and its role in inflammation and tissue repair: Mathematical and systems biology approachesSystems biology of oxygen homeostasisContext‐dependent regulation of receptor tyrosine kinases: Insights from systems biology approachesSystems biology of pro‐angiogenic therapies targeting the VEGF system


Utricularia (bladderwort) form modified leaves into suction bladder traps. The bladders are metabolically active plant tissue with high rates of mitochondrial respiration (RD). In general, plants possess two mitochondrial electron transport pathways to reduce oxygen to water: cytochrome and an alternative. Due to the high metabolic rate in the bladders, it is tempting to assume that the bladders prefer the cytochrome c oxidative pathway. Surprisingly, we revealed that alternative oxidase (AOX), which yields only a little ATP, is much more abundant in the bladders of Utricularia reflexa in comparison with the shoots. This pattern is similar to the carnivorous plants with passive pitcher traps  and seems to be widespread across many carnivorous taxa. The exact role of AOX in the traps of carnivorous plants remains to be investigated.Carnivorous plants of the genus  Utricularia capture prey using modified leaves as suction bladder traps. The bladders are hollow, water-filled vesicles with flexible lateral walls with an entrance forming a short tube which is rendered watertight by a trapdoor. The trap function is based on generating a negative hydrostatic pressure inside the trap caused by an energy-demanding water pumping process from the trap lumen to the outside. When the trap is stimulated by potential prey, or also spontaneously, the trapdoor abruptly inverts its curvature, the trap walls relax and the bladder sucks water and prey inside.1–3 The captured prey is then digested by an action of commensal microorganisms and endogenous plant-derived digestive enzymes.4–6Carnivorous plants of the genus D). The high RD observed in Utricularia bladders is probably associated with their demanding physiological functions, i.e., relating to ion and water pumping, prey digestion and nutrient absorption.7 Jobson and his colleagues found positively selected aminoacids  in subunit I of cytochrome c oxidase (COX) across all examined Utricularia species.8 This motif lies directly at the docking point of COX helix 3 and cytochrome c, and modeling suggests that can alter COX/cytochrome c dissociation kinetics and thus the RD was adaptively reinforced by these specific amino acid changes. However, plants also have an alternative route for mitochondrial electron transport. Alternative oxidase (AOX) accepts electrons from a ubiquinol pool bypassing the complex III and IV and this dramatically reduces the ATP yield of respiration.9 A recent study showed that carnivorous pitcher plants of the genera Nepenthes and Sarracenia have high abundances of AOX in their pitcher traps with a possible role in botanical carnivory.10 Because pitcher plants, in contrast to Utricularia, usually do not have higher RD in their traps in comparison to the photosynthetic parts of the leaf,11 we were interested in studying if the AOX enzyme is also abundant in metabolically active bladders in unrelated aquatic carnivorous Utricularia.The bladders are active plant tissue with high metabolic rate and a high rate of mitochondrial respiration  in our experiment. U. reflexa produces some of the largest bladder traps within the genus  used as a substrate. The water was considered oligo-mesotrophic and slightly dystrophic. Small zooplankton were added to the water to support plant growth. Adult U. reflexa plants were 20–30 cm long and their largest traps were 4–6 mm long. The 50 mg samples of traps, and shoots without traps, from the mature 3rd–6th leaf nodes were collected separately for Western blotting. The traps were halved to remove the water inside the bladders. Immunodetections of AOX enzyme, subunit II of cytochrome c oxidase (COXII) and light harvesting antennae of photosystem II (LHCB4) were performed as described previously10 with antibodies  purchased from Agrisera . For measurements of RD, a Clark-type oxygen sensor was used for 12–24 separated, halved young traps 3–6 mm large from the mature 3rd–6th leaf nodes and in trap-free shoot segments of the same age.7 Generally, RD was measured in a basic control solution of 0.1 mM NaHCO3 with 50 µM KCl and 25 µM CaCl2 in a 5.3 mL stirred chamber kept at 25.0 ± 0.1°C. The RD was measured in darkness for 12–15 min. For inhibitory studies, the leaf material was blotted dry, placed in 10 ml of the solution with 5 mM SHAM or 0.5 mM KCN alone or in combination in darkness at 25°C for 3 h, and RD was measured in this solution.We used the aquatic carnivorous plant he genus  and was Arabidopsis thaliana (A.t.) for which the epitope of the primary antibody was originally designed. Given that the bladder traps have a significantly lower chlorophyll concentration in comparison to the shoots,7 we also immunodetected chlorophyll-binding protein LHCB4 where we expected the opposite pattern from than in the AOX protein. Indeed, the abundance of LHCB4 in the traps was 50% of that in the shoots . We realize that measurements of oxygen consumption rates after application of respiratory inhibitors is relative and only suitable for estimation of the capacities (maximum electron fluxes) of COX and AOX, and the true activities can only be determined by the oxygen isotope fractionation technique. Moreover, AOX is under strong post-translational control and in this case, the enzyme abundance is not a good predictor of enzyme activity.13The abundance of AOX enzyme was 10 times higher in bladder traps in comparison to the shoots . On the e shoots . These re shoots , in acco tissues . SHAM inhe traps . The comNepenthes.10 Some of them may also hold for Utricularia bladders. For example, Utricularia bladders have also reduced AN in comparison to the shoots7 and the possible imbalance between light and dark reactions of photosynthesis results in increased excitation pressure at photosystem II which may act as a signal for AOX transcription.14 In general, nutrient stress, which is common for all carnivorous plants, may also induce AOX transcription.15 Ammonia, a product of deamination of prey amino acids in the digestive fluid, may lead to a great increase of AOX activity and protein and transcript abundance in contrast to nitrate supply.16 The expression of AOX is also strongly induced by reactive oxygen species (ROS) through mitochondrial retrograde signaling.17 High production of ROS in U. gibba bladders as a result of high energy metabolism was recently documented.12In our recent study, we discussed the possible reasons and consequences of increased AOX content in the pitcher traps of Utricularia have been focused mainly on COX.18 Such studies are reasonable due to the high metabolic and respiratory activities of the Utricularia bladders and the high demand for ATP needed for their functioning.7 Indeed, application of KCN strongly inhibited water exudation and trap function.20 However, our study showed very high abundance of AOX enzyme in the bladders, which is known to compete with the COX for electrons and yield only a little ATP.13 This finding goes against the high energy requirement for Utricularia bladders, but on the other hand, the AOX enzyme may have other important functions in the carnivorous organ. As a higher abundance of AOX enzyme in traps was found across different genera and orders of carnivorous plants, it seems that it is a part of the general carnivorous syndrome like reduced photosynthesis in traps.11 The exact role of AOX and its activation state in the trap organs of carnivorous plants remains to be elucidated.Until now, the studies on respiration of


Recently, symbolic computation and computer algebra systems have been successfully applied in systems biology, especially in chemical reaction network theory. One advantage of symbolic computation is its potential for qualitative answers to biological questions. Qualitative methods analyze dynamical input systems as formal objects, in contrast to investigating only part of the state space, as is the case with numerical simulation. However, corresponding tools and libraries have a different set of requirements for their input data than their numerical counterparts. A common format used in mathematical modeling of biological processes is Systems Biology Markup Language (SBML). We illustrate that the use of SBML data in symbolic computation requires significant pre-processing, incorporating external biological and mathematical expertise. ODEbase provides suitable input data derived from established existing biomodels, covering in particular the BioModels database.https://odebase.org.ODEbase is available free of charge at  Symbolic computation is a well-established field in mathematics and computer science that has a strong community and numerous applications in science. In contrast to numerical computation, which uses approximate floating point numbers, symbolic computation works with exact mathematical expressions.Recently, symbolic computation methods are playing an increasing role in systems biology and mathematical biology. Problems investigated using such methods include sustained oscillations and Hopf bifurcations, multi-stationarity, multi-scale model reduction, dynamical invariants and structural properties of steady state varieties such as, for example, binomiality and toricity; for details see On the one hand, symbolic computation does not utilize the full information contained in SBML models. For instance, SBML was designed with a focus on network simulation and supports corresponding concepts like events and initial assignments, which are not natural from a formal symbolic computation point of view. On the other hand, symbolic computation operates on formal objects like polynomials, rational numbers, matrices and ordinary differential equations (ODEs), which are not readily available in SBML. For instance, ODEs, describing differential network kinetics along with algebraic constraints, such as conservation laws, can be considered either as pieces of code to be used with numerical solvers or as mathematical expressions to be studied with symbolic computation. The genuine difference between dynamic simulation and static formal analysis requires sensitivity to details and rigor in the course of the construction of symbolic computation input from available SBML descriptions. It is noteworthy that existing SBML parsers generate input for numerical simulation, which is not suited for symbolic computation. MathSBML  and SBMLIt is important to understand that the rigorous construction of symbolic computation input poses some substantial problems. Solving, or even recognizing, such problems, requires joint competence and combined efforts not only from biology but also including mathematics and computer science. We give some examples:SBML allows floating-point values for various entities. However, floating-point values exhibit representation errors and computations are prone to rounding errors. This is inadequate for symbolic computation, where exact computations are performed.SBML has liberal naming conventions for species and parameters that interfere with the typically strict rules of symbolic computation software, which are oriented toward mathematical notation. If different users of symbolic computation software rename those identifiers at their own discretion, it becomes cumbersome to compare their results.SBML gives modelers versatile opportunities of expression, such as local parameters, function definitions, rules and initial assignments. For practical reasons, scientific software does not generally support the full SBML feature set. This leads to incompletely imported models or it prohibits the import entirely.Symbolic computation is concerned with mathematical properties like deficiency and linear conservation laws, which are available in SBML only implicitly through computation. Explicit availability is desirable, especially, since some of those computations can become surprisingly time-consuming.Although integration of symbolic computation input into SBML might appear natural, there are obstacles on both sides. On the symbolic computation side, established software is usually general-purpose, and systems biology is not yet a strong focus of the community. Therefore, widespread support of SBML as an input format for symbolic computation software cannot be expected in the near future. On the systems biology side, the SBML standard would need to be extended. Standardization generally requires considerable efforts, and it seems unlikely that this will be pursued before the links between symbolic computation and systems biology have been further strengthened.ODEbase, which collects symbolic computation input for existing SBML models. All our models originate from the BioModels database (https://odebase.org. By doing so, we expect to promote systems biology models to researchers developing general purpose symbolic computation methods and also facilitate the benchmarking of such methods. If models require updates, revised versions will be made available, keeping all previous versions for reference. Data can be extracted in Maple, Reduce, SageMath and LATEX format. We are open to supporting further formats in the future.The interdisciplinary project SYMBIONT brings together researchers from mathematics, computer science, and systems biology (ODE systems referred to in the title.For each model in ODEbase, the following dataset is computed from the original SBML input. The ODEs and the constraints mentioned below together establish the Stoichiometric and kinetic matrices: Stoichiometric and kinetic matrices are made explicit using exact rational numbers.ODEs for species concentrations: These are explicit first-order, non-linear ODEs that are often, but not necessarily, autonomous. Species are named x1, …, nx, following common mathematical notation. If species rate rules are present in the model, the corresponding ODEs are included as well.Parameter values: Our naming of parameters follows common mathematical notation, viz., k1, …, mk. Assignment rules, initial assignments and initial concentrations are taken into consideration.Map between ODEbase names and original model names: A bijective mapping between the mathematical names for species and parameters and their respective SBML names is provided.Constraints: All SBML species assignment rules are converted to formal constraints. Furthermore, linear conservation constraints are computed using an extension of Deficiency: The deficiency is computed from the network’s complexes. This is a measure of how independent the reaction vectors are, given the network’s linkage class structure (Classification: Polynomials and, more generally, rational functions play a crucial role in symbolic computation. We classify whether ODE vector fields and constraints are covered by such expressions. In the polynomial case, we furthermore check if the SBML-specified kinetics differs from the regular mass-action kinetics (All models in ODEbase are a faithful conversion from the respective SBML model. SBML features recognized during the conservation process include species with boundary condition, local parameters, parameter and species assignment rules, parameter and species initial assignments, species rate rules and function definitions. Models containing SBML events or parameter rate rules are not covered. Neither are models with irrational parameter values.ODEbase as a canonical source of symbolic computation input related to existing models of biological processes offers a number of advantages:Interdisciplinary competence: The derivation of adequate ODEs for the kinetics requires combined biological and mathematical expertise. Users can outsource this task to ODEbase.Economic use of human resources: Symbolic computation input has been pre-computed and is directly available.Availability: ODEbase models used and cited in the literature can be conveniently reviewed on the basis of the original data and re-used in follow-up publications.Canonical reference: ODEbase fixes choices for the inevitable renaming of species and parameters to common mathematical notation. This facilitates comparability of results.Benchmarking: ODEbase is perfectly suited to generate benchmark sets for novel algorithms and software in the field.


Organisms respond and adapt to the internal and external environmental changes through various cell signaling. The abnormal alteration of cell-signaling pathways could disrupt cell homeostasis and cause diseases . For insCell Signaling Status Alteration in Development and Disease, we collected studies providing new insights into the roles of cell signaling in development and disease occurrence and progression. A total of 5 articles, including two reviews, two original researches and one method article, were published in this Research Topic. We summarize and discuss the main findings of these studies in this editorial.Although cell signaling can be measured through development of sequencing technologies and the application of effective bioinformatic tools , many quAbreu de Oliveira et al.). Yang et al. comprehensively reviewed the role of cyclic GMP-AMP synthase (cGAS)—a stimulator of the interferon gene (STING) signaling pathway in various diseases, such as acute injury, pneumonopathy and kidney diseases, providing a theoretical basis for immunotherapy targeting the STING signal pathway . Ma et al. found that miR-654-5p overexpresses in activated human hepatic stellate cells and TGFβ-treated human hepatic LX-2 cells augmented liver fibrosis in mice that were intraperitoneally injected with CCl4 by targeting the RXRα receptor . Zhang et al. proposed a robust method to acquire finely resolved transcriptional programs with few cells from snap-frozen or RNAlater-treated clinical tissues that was sufficient enough to resolve even isoforms based on immunofluorescence-guided laser capture microdissection (immuno-LCM-RNAseq). With this method, the researchers were able to analyze transcriptional networks and signaling pathways during development, pathogenesis, and aging of specific cell types within native tissues . Lou et al. integrated both immune and hypoxia signaling to establish reliable prognostic signatures for lung adenocarcinoma (LUAD) across different omics data, and provided a robust prognosis predictor for the LUAD patients .Wnt signaling plays an important role in the mammary gland development and adult homeostasis in virtually all animal species. Willy et al. provided a systematic review on Wnt signaling involved in breast cancer and explored the impact of Wnt signaling alteration on the tumorigenesis and disease occurrence (The studies published in this Research Topic presented a diversity of intriguing and meaningful results covering a range of cell signals, which could facilitate our understanding of development and disease. We hope that this Research Topic will inspire researchers to systematically investigate development and disease progression from the perspective of cell signal in a systematic way.


Exosomes of human cardiosphere-derived cells (CDCs) are very promising for treating cardiovascular disorders. However, the current challenge is inconvenient delivery methods of exosomes for clinical application. The present study aims to explore the potential to enhance the therapeutic effect of exosome (EXO) from human CDCs to myocardial hypertrophy. A heart homing peptide (HHP) was displayed on the surface of exosomes derived from CDCs that were forced to express the HHP fused on the N-terminus of the lysosomal-associated membrane protein 2b (LAMP2b). The cardiomyocyte-targeting capability of exosomes were analyzed and their therapeutic effects were evaluated in a mouse model of myocardial hypertrophy induced by transverse aorta constriction (TAC). The molecular mechanisms of the therapeutic effects were dissected in angiotensin II-induced neonatal rat cardiomyocyte (NRCMs) hypertrophy model using a combination of biochemistry, immunohistochemistry and molecular biology techniques. We found that HHP-exosomes (HHP-EXO) accumulated more in mouse hearts after intravenous delivery and in cultured NRCMs than control exosomes (CON-EXO). Cardiac function of TAC mice was significantly improved with intravenous HHP-EXO administration. Left ventricular hypertrophy was reduced more by HHP-EXO than CON-EXO via inhibition of β-MHC, BNP, GP130, p-STAT3, p-ERK1/2, and p-AKT. Similar results were obtained in angiotensin II-induced hypertrophy of NRCMs, in which the beneficial effects of HHP-EXO were abolished by miRNA-148a inhibition. Our results indicate that HHP-EXO preferentially target the heart and improve the therapeutic effect of CDCs-exosomes on cardiac hypertrophy. The beneficial therapeutic effect is most likely attributed to miRNA-148a-mediated suppression of GP130, which in turn inhibits STAT3/ERK1/2/AKT signaling pathway, leading to improved cardiac function and remodeling.The online version contains supplementary material available at 10.1186/s12951-022-01630-3. Cardiac hypertrophy is initially a compensatory adaptive response to many cardiovascular diseases including chronic hypertension, aortic stenosis, mitral or aortic regurgitation, myocardial infarction, and genetic hypertrophic cardiomyopathy, among others . AlthougExosomes are nano-sized extracellular vesicles secreted from cells with ~ 30 to ~ 200 nm in diameter, and contain various signaling molecules that can be shuttled to recipient cells to modulate the pathophysiology of the latter , 5. Thes, and to target ischemia/reperfusion injured myocardium in vivo, leading to enhanced angiogenesis, decreased apoptosis and fibrosis, and improved cardiac functions [, and their therapeutic effects to myocardial hypertrophy were evaluated in vitro in an Ang II-induced neonatal rat cardiomyocytes (NRCMs) hypertrophy cell model and in vivo in the TAC mouse model. Our results showed that exosomes displaying the HHP preferentially target to cultured NRCMs and accumulate in the hearts of mice upon systemic delivery, which greatly enhance the therapeutic effect of exosomes derived from CDCs to myocardial hypertrophy.Various ligand/homing peptides have been successfully displayed on the surface of exosomes through forced expression of ligand/homing peptides fused in-frame with a transmembrane protein in the parental cells , 14. Heaunctions , 17. To Exosomes can be manipulated to target specific tissues by surface display of a ligand or homing peptide . To targTo demonstrate whether the homing peptide is displayed on the surface of exosomes, exosomes from CDCs expressing FLAG or LAMP were immunoprecipitated with anti-FLAG affinity resin, then immunoblotted with antibodies against exosome markers. As shown in Fig. To demonstrate the targeting capability, HHP-EXO or CON-EXO 10 μg) were labeled with Cell Tracker CM-Dil (in red), which were incubated with NRCMs for 24 h. The cells were fixed and stained with FITC-phalloidin (in green), and nuclei were counterstained with 4′6-diamidino-2-phenylindole (DAPI) (in blue). As shown in Fig. 0 μg wereTo evaluate the cardiac homing capability, exosomes labeled with CM-Dil were administered intravenously in mice (4 mg/kg) through tail-vein, and the animals were sacrificed post 24 h of the injection for collecting heart, liver, spleen, lungs, and kidneys to analyze the exosome retention using IVIS image system  as described previously , 19. TheThe therapeutic potential of HHP-EXO to myocardial hypertrophy was studied in TAC mice with intravenous administration of CON-EXO or HHP-EXO (4 mg/kg) at day 8, 10, 12, 14, 16, 18, and 20 post-TAC  is considered a biomarker for hypertension-induced organ damage . The theSerum levels of Ang II and N-terminal pro B-type natriuretic peptide (NT-proBNP), markers of heart failure and remodeling, were significantly increased in TAC mice treated with PBS Fig. E. No sigThe heart morphology, cross sections, and ventricular histology were analyzed in sham mice, TAC mice with PBS, CON-EXO and HHP-EXO Fig. A–C. The Acta1, Nppa, and Nppb and the Myh7/Myh6 ratio, were significantly increased  in TAC mice with PBS relative to sham mice , whereas the Myh7/Myh6 ratio was decreased only in TAC mice receiving HHP-EXO, but not CON-EXO .Consistent with the results from histology analysis, the average cell surface area increased by 30% in TAC mice treated with PBS relative to sham mice , which was slightly decreased in TAC mice receiving CON-EXO  or CON-EXO   or scramble control  was transfected into HHP-EXO, producing HHP-EXO-miR148i and HHP-EXO-NC respectively, and their effect was evaluated in Ang II-induced NRCMs hypertrophy in vitro. Ang II-induced increase of cell size (surface area) was significantly reduced by HHP-EXO or HHP-EXO-NC, but the effect was abrogated in HHP-EXO-miR148i treatment Fig. B, C. ConIn this study, the HHP was successfully displayed on the surface of exosomes derived from human CDCs, which conferred the exosome capability to target NRCMs in vitro and were selectively enriched in the hearts after systemic delivery. The HHP-EXO ameliorated Ang II-induced cardiomyocyte hypertrophy in vitro and significantly improved cardiac remodeling and functions in the TAC-induced myocardial hypertrophy compared to its non-targeted counterpart. Mechanistically, miRNA-148a, that was selectively encapsulated into CDCs-exosomes mediated the therapeutic effect of HHP-EXO to myocardial hypertrophy via down-regulation of the expression of GP130, leading to inhibition of STAT3, ERK1/2 and AKT signaling pathways.Exosomes that selectively enrich signaling molecules of parental cells can be shuttled to recipient cells through paracrine or hormone-like mechanisms, mediating many pathophysiological processes, such as angiogenesis, proliferation, and apoptosis and inflammation –26, amonNaturally occurring exosomes generally display short half-life and possess very limited organotropism and capability to home to where the parental cells were originated . After smiRNA is one of the most commonly encapsulated signaling molecules in exosomes that modulate the biology of recipient cells . CDCs-exGP130 is a constitutively expressed signaling molecule that forms a receptor complex relaying signals for several cytokines . It playIt is generally recognized that TAC-induced cardiac hypertrophy is associated with increase of artery blood pressure, which is involved in activation of renin-angiotensin system (RAS) , 45. TheThe previous reports demonstrated that biodistribution of exosomes was relatively stable within 24 h after administration , 19. We Collectively, the present study demonstrates that HHP-exosomes preferentially target the heart and enhance the therapeutic effect of CDCs-exosomes on cardiac hypertrophy. The beneficial therapeutic effect is most likely related to miRNA-148a-mediated inhibition of GP130 followed by supressing STAT3/ERK1/2/AKT signaling pathway, leading to improved cardiac function and remodeling.Reagents and antibodies used in this work are listed in Additional file The heart homing peptide  fused in-frame with human Lamp2  between amino acid 31–32 was generated by overlapping polymerase chain reaction (PCR) using primers shown in Additional file 3, which were enzymatically digested and then plated to allow the cardiac explants to grow. After 5–7 days, cells surrounding the explants were harvested and seeded onto poly-D-lysine-coated dishes to allow cardiosphere formation. Two days later, cardiospheres were collected and plated on fibronectin-coated dishes to generate CDCs. The CDCs was expanded to at least passage 4 for downstream experiments.Human atrial specimens were obtained from patients underwent heart surgery at Xiamen Cardiovascular Hospital, Xiamen University. Human cardiosphere-derived cells (CDCs) were isolated and cultured as described previously . BrieflyCDCs of passage 4 were transfected with lentiviral hLAMP2b (LAMP), HHP and FLAG, respectively. The stable cell lines expressing LAMP (LAMP-CDCs), HHP (HHP-CDCs), and FLAG (FLAG-CDCs) were established by sorting green fluorescent protein (GFP) positive cells using flow cytometry. Stable cell lines, LAMP-CDCs and HHP-CDCs were expanded to passage 8 in Iscove's Modified Dulbecco's Media (IMDM) supplemented with 10% FBS. The cells were refreshed with serum-free IMDM and further incubated for 2 weeks. The conditioned medium (CdM) was harvested, filtrated through a 0.45 μm filter, and then stored at − 80 °C. Exosomes from HHP-CDCs and LAMP-CDCs were isolated from the CdM by gradient centrifugation as described previously . Briefly2, NRCMs were subjected to 1 μM Ang II treatment in the presence of 50 μg/ml exosomes or controls for 48 h. H9C2 cardiomyocytes were seeded onto 6-well plates in DMEM supplemented with 10% FBS and penicillin/streptomycin. After 24 h grown at 37 °C with 5% CO2, H9C2 cells were pretreated with 10 μM SC144 for 1 h, and then exposed to 1 μM Ang II with or without 50 μg/ml HHP-EXO for 24 h.Neonatal rat cardiomyocytes (NRCMs) were isolated by collagenase and trypsin enzymatic dissociation from 1–2 days old newborn rat hearts as previously described . NRCMs wTransverse aortic constriction (TAC) surgery was performed on 10-week-old C57BL/6 male mice . BrieflyCardiac function and gross morphology were assessed by echocardiography using Vevo 2100  equipped with a 40-MHz MS550D probe and a high-frequency ultrasound system as described previously . EchocarHearts, lungs and kidneys were harvested after blood pressure measurement, rinsed in saline, and weighed. Lungs were dried in an oven at 60 °C for 5 days and re-weighed as dry weight. Hearts were embedded in optimal cutting temperature (OCT) medium. Frozen sections of 6.0 μm were fixed in 4% paraformaldehyde, and stained with H&E (Hematoxylin-eosinstaining) and WGA (Wheat Germ Agglutnin) WGA and Masson’s trichrome solutions, respectively . Slides Western blot was performed as previously described . BrieflyStatistical analyses were performed using GraphPad Prism 9 software. Unpaired two-tailed Student’s t test was employed to determine the differences between two groups or one-way ANOVA followed by Tukey’s post hoc test was used for comparison among multiple groups. Date were presented as mean ± SEM, and P < 0.05 was considered statistically significant.Additional file 1: Figure S1. Schematic illustration of displaying a homing peptide/FLAG on the surface of exosomes. The coding sequence of HHP/FLAG (red bar) was fused in-frame to the LAMP2b cDNA between the signal peptide (SP) and the N-terminus, which was then cloned into pLVX-IRES-ZsGreen1 expression plasmid. Forced expression of the plasmid in CDCs would display the HHP/FLAG  on the surface of exosomes. Figure S2. Schematic illustration of mice treatment schedule. The TAC mice were randomly divided into 3 groups, PBS control, CON-EXO, and HHP-EXO (n = 12 each). Exosomes (4 mg/kg) or PBS were tail-vein injected on day 8, 10, 12, 14, 16, 18, 20 post-TAC. Echocardiographic studies were performed 3 days (Control) prior to, and on day 7, 14, 21, 28 and 42 after, the TAC. The mean arterial blood pressure was evaluated, serum was collected, and the hearts were harvested on day 42 post-TAC. Figure S3. Cardiac hypertrophy after exosome treatment. A Coronal sections of the hearts among groups by HE staining. B Quantitation of heart weight/body weight (left panel) and heart weight/tibial length (right panel) ratios among groups. Data are presented as ‘Mean ± STDEV’, n = 9-12 animals, *P < 0.05 and **P < 0.01. Figure S4. HHP-EXO and SC144 perform similar effect of inhibiting GP130-STAT pathway. H9C2 cardiomyocytes were pretreated with SC144 (10μM) for 1h, and then exposure to Ang II (1 μM) with or without HHP-EXO (50μg/ml) for 24h, the expression of β-MHC, GP130, p-STAT3, STAT3, p-ERK1/2, ERK, p-AKT and AKT was detected by Western blotting. Table S1. Parameters of cardiac function and related serum kinases levels in TAC mice with different treatments. Table S2. Reagents and antibodies used in the present study. Table S3. Primers for cloning of LAMP2b fusion plasmids used in the present study.


Instead ofIn the published article, there was an error in affiliations 1Department of General Surgery, Institute for Minimally Invasive Surgery, Affiliated ZhongDa Hospital, Medical School, Southeast University, Dhaka, Bangladesh“2Department of Endcrinology, Affiliated ZhongDa Hospital, Medical School, Southeast University, Dhaka, Bangladesh, it should be1Department of General Surgery, Institute for Minimally Invasive Surgery, Affiliated ZhongDa Hospital, Medical School, Southeast University, Nanjing, China“2Department of Endcrinology, Affiliated ZhongDa Hospital, Medical School, Southeast University, Nanjing, China”Delin Liu. As well as having affiliation “1”, they should also have “Department of Endcrinology, Affiliated Zhongda Hospital, Medical School, Southeast University, Nanjing, China”.In the published article, there was an error regarding the affiliation(s) for Results, The endothelial cells of keloid are divided into four subgroups, [176–180]. This sentence previously stated:A correction has been made to “genes upregulated in Endo1 were mainly involved in Osteoclast differentiation, TNF signaling Endo1 upregulated genes were mainly involved in Osteoclast differentiation, TNF signaling pathway, Apoptosis; Endo2 upregulated genes were mainly involved in IL-17 signaling pathway, Fluid shear stress and atherosclerosis, Rheumatoid arthritis; Endo3 upregulated genes were mainly involved in Endo3 upregulated genes are mainly involved in Endocrine resistance, Estrogen signaling pathway, Proteoglycans in cancer and other signaling pathways”The corrected sentence appears below:“genes upregulated in Endo1 were mainly involved in Osteoclast differentiation, TNF signaling pathway, Apoptosis; Endo2 upregulated genes were mainly involved in IL-17 signaling pathway, Fluid shear stress and atherosclerosis, Rheumatoid arthritis; Endo3 upregulated genes were mainly involved in Endocrine resistance, Estrogen signaling pathway, Proteoglycans in cancer and other signaling pathways”The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.


Clinical pregnancies and live births result from a complex interaction of molecular pathways at the level of the female and male gametes during their development and interaction for fecundation, and the subsequent development of the embryo before, during, and after implantation. All these mechanisms interact with the surrounding environment present at the level of the gonads and male and female bodies, and later, at the level of the female genital tract: from tubes to the endometrium and uterus. To date, the knowledge of this molecular biology underlining human fertility has been paramount to understanding physiology and pathology, with the ultimate objective of successfully characterizing and treating female and male infertility . In thisIn this Special Issue, the study by Olszewska et al.  allowed The most relevant pieces of evidence about the transcription factor p63, pivotal in regulating maternal reproduction and genomic integrity as well as epidermal development, were collected in the review by Luan et al. . In partOne of the most common diseases associated with female infertility is endometriosis , althougBesides male and female infertility factors, which are not mutually exclusive to each other, the events at the endometrial–embryonal interface are of paramount importance. Indeed, failure of these events can lead to recurrent implantation failure (RIF) and recurrent pregnancy loss (RPL), regardless of the use of ARTs. Calcium signaling pathways are known to be of vital importance to embryo implantation and pregnancy establishment; anterior gradient protein 3 (AGR3) and S100 calcium-binding protein P (S100P) are involved in these pathways, and they were elegantly investigated by Tempest et al. [When fertility ends, it is time to recall whether some molecular changes may increase the risk of cancer . In thisWe believe that the studies published in the Special Issue “Molecular Biology of Human Fertility” provide cutting-edge research and summarize the most robust pieces of evidence on the molecular aspects of the complex mechanisms of human fertility, representing a starting point for future research on such a relevant aspect of human life.


More than 135,000 people aged under 45 yr are diagnosed with cancer annually in Indonesia. Good detection and management of cancer increase the quality of life.To determine the knowledge, attitudes, and behaviors of practitioners supporting cancer patients in fertility preservation.This cross-sectional study was conducted in 18 type D government hospitals and Dr. Cipto Mangunkusumo Hospital, in Jakarta, Indonesia, between January 2018 and August 2019. This study involved practitioners providing care to cancer patients. Data were described descriptively.Most of the general practitioners, specialists, and subspecialists who participated in this study were aged 26-30 yr (65.4%), 31-35 yr (70.4%), and 31-40 yr (53.0%), respectively. The fertility treatment most known by general practitioners was in vitro fertilization with embryo cryopreservation (12.1%); for specialists it was sperm cryopreservation (24.5%). Meanwhile, subspecialists knew most about in vitro fertilization with embryo cryopreservation and sperm cryopreservation using a GnRH agonist (such as leuprolide injection) pre-cancer treatment (13%). A positive attitude towards fertility preservation as an important priority for cancer patients was shown in 72.0% of general practitioners, 73.3% of specialists, and 100% of subspecialists. General practitioners mostly referred patients to fertility specialists (44.4%). Many specialists (54.9%) and subspecialists (67%) discussed the possible impact of the patient's condition and / or treatment on fertility.The knowledge of and practices related to fertility preservation differed among general practitioners, specialists, and subspecialists. However, positive attitudes among them were similar.  There are more than 135,000 people below 45 yr old who are diagnosed with cancer every year in Indonesia (1). The advancement of technology to screen and treat cancer has increased the survival rate of cancer patients. Unfortunately, long-term cancer therapy, such as chemotherapy and radiotherapy, can have negative psychological, economic, social, sexual, and biological effects (2). The National Comprehensive Cancer Network in 2014 stated that one of the most important concerns among young cancer patients was an option for fertility preservation . One study found that few patients in the study were counselled about fertility preservation. This was due to a lack of knowledge on the optimal time and methods to preserve fertility (5).In Indonesia, based on Riset Kesehatan Dasar 2013The profile of knowledge, attitudes, and practices among specialists treating cancer patients is still varied. Several studies such as those conducted by Adams and colleagues (6) in the UK and Overbeek et al. (7) in the Netherlands have shown that oncologists recognize that fertility preservation is an important issue. However, less than 50% of oncologists in these studies discussed the choices of patients due to lack of time, lack of knowledge, bad patient prognosis, and fertility treatment variable success rate and unaffordable cost. Lack of health providers' knowledge will influence their attitudes and practices.No studies have been carried out about health care providers' knowledge, attitudes, and practices surrounding fertility preservation in cancer patients; therefore, this study aimed to determine the profile of these, focusing on Jakarta, the capital city of Indonesia.This descriptive study with a cross-sectional design was conducted in all type D government hospitals with general practitioners and specialists in Jakarta, and in Dr. Cipto Mangunkusumo Hospital in Jakarta with subspecialists, from January 2018 to August 2019. The participants consisted of general practitioners, pediatricians, subspecialists in hematology-oncology, interns, intern subspecialists in hematology-oncology, general surgeons, oncology surgeons, and radiotherapy specialists.The questionnaire was adapted from a questionnaire by the British Journal of Cancer from 2013 with the title fertility preservation in cancer survivors: A national survey of oncologists' current knowledge, practice, and attitudes. The results of its translation and validation in the Indonesian language have been published by Harzif et al. (8).This study was approved by the Ethics Committee of the Faculty of Medicine, University of Indonesia (Code: 926/UN2.F1/ETIK/2017). Written informed consent was obtained from all participants.The data gathered from the completed questionnaires were described by frequency and percentage. The analysis used the Statistical Package for the Social Sciences (SPSS), version 23.0.Within the 18 type D government hospitals in Jakarta, 133 of the 215 general practitioners (61.9%) fully completed the questionnaire, as did 21 of 40 (52.5%) internists, 18 of 41 (43.9%) pediatricians, 12 of 25 (48.0%) general surgeons, and 20 of 39 (51.3%) obstetricians and gynecologists. In Dr. Cipto Mangunkusumo Hospital in Jakarta, two of the 13 intern subspecialists in hematology-oncology (15%) fully completed the questionnaire, as well as five of the 18 (63%) pediatrician subspecialists in hematology-oncology, two of the six (33%) oncologist surgeons, and six of the 10 (60%) radiotherapy specialists.Around 65.4% of the general practitioners were 26-30 yr old and 46.6% had graduated from Government University. 40.6% were members of Java tribes. Among the specialists, 70.4% were 31-35 yr old and 60.6% had graduated fromUniversitas Indonesia. Meanwhile, all of the subspecialists had graduated fromUniversitas Indonesia with an average age of 31-40 yr (53%).The general practitioners, specialists, and subspecialists most knew about in vitro fertilization (IVF) with embryo cryopreservation (12.1%), sperm cryopreservation (25.4%), and IVF with embryo preservation and sperm cryopreservation using a GnRH agonist pre-cancer treatment (13%), respectively. A positive attitude about fertility preservation as an important priority for cancer patients was shown among 72.0% of general practitioners, 73.3% of specialists, and 100% of subspecialists. The general practitioners often referred patients who had questions about fertility to a fertility specialist (44.4%). The specialists and subspecialists mostly discussed the impact that a patient's condition and/or treatment might have on their future fertility . Table I describes the factors influencing health care providers when initiating a discussion about fertility preservation. Table II depicts comments from health care providers about fertility preservation.Most of the general practitioners had never had patients that were using fertility preservation methods and only a few knew about the choices concerning them. A study conducted in Indonesia by Harzif et al. (9) stated that this is common due to a lack of specialized organizations or local guidance concerning fertility preservation. This lack of general practitioners' knowledge in Indonesia is also seen in the United States where less than 25% of general practitioners participating in one study could present educational material about fertility preservation (10). Around 91% of them needed further information about fertility preservation; only a few had discussed this topic with fertility specialists, given written information about fertility preservation, or considered patients' hopes about their future fertility. This may be because of a lack of knowledge in fertility preservation, newly started fertility preservation facilities in Indonesia, unclear referral schematics, and unaffordable costs which have not been supported by universal health coverage.Among specialists, the response rate was from 43.9% to 52.5%. This response rate was better compared with a study in Hong Kong which had a response rate of 36.5% (11). The three most known methods in our study's specialists were IVF with embryo cryopreservation, sperm cryopreservation, and methods carried out pre-cancer treatment using a GnRH agonist. In the Hong Kong study, the three most familiar fertility preservations were similar: sperm cryopreservation, oocyte cryopreservation, and IVF with embryo cryopreservation (11).Around 74.6% of specialists and 93.0% of subspecialists still needed further information about fertility preservation. In a study conducted in Lebanon, 89% of oncologists agreed that cancer treatment can threaten fertility and 94.4% agreed to discuss fertility issues with patients. Specialists and subspecialists often discussed the impact of a patient's condition on fertility in the future (12). Quinn and colleagues showed that oncologists in their study were 4.9 times more likely to discuss about the influence of cancer treatment on fertility. Meanwhile, oncologist gynecologists or oncologist hematologists were 2.1 times more comfortable in discussing the option of fertility preservation with patients. However, less than 25% referred patients to fertility specialists. This was because fertility preservation services were only newly developed and there was a lack of informational media about these services (10). Other studies have shown that only 47% of oncologists in the United States and less than 20% in Saudi Arabia referred cancer patients to fertility centers .Factors influencing the discussion about fertility preservation included a bad prognosis, a patient being too ill to delay treatment, and being unable to afford to pay for the service. These factors were in accordance with another study which found that challenges in referring to fertility specialists included a high rate of recurrence and a bad prognosis (15-17). Oncologists also said that there was not enough time to perform fertility preservation activities before cancer treatment. Sperm preservation has a higher success rate than ovary preservation (18); therefore, this information should be used in counseling patients. Oncologists believed that the desire to refer depended on the attitudes about fertility preservation. In the Lebanese study, 90% of the oncologists had more than six yr experience; however, the knowledge of choices, success rates, and costs of fertility preservation methods was still limited. Therefore, this issue should be included in the curriculum of oncology training (12).This study had the limitation of non-response bias due to potential differences in those who did not return a complete questionnaire. Apart from that, the data were based on questionnaire choices, so it was impossible for in-depth data to be collected and there was a risk for respondents misunderstanding the instructions.The knowledge of and practices regarding fertility preservation were different among general practitioners, specialists, and subspecialists. Positive attitudes among them were similar.The authors declare that there is no conflict of interest.


It is used to understand how the body contributes to cognition and control of behavior. Its understanding in terms of “offloading” computation from the brain to the body has been criticized as misleading, and it has been suggested that the use of the concept conflates three classes of distinct processes. In fact, these criticisms implicitly hang on accepting a semantic definition of what constitutes computation. Here, I argue that an alternative, mechanistic view on computation offers a significantly different understanding of what morphological computation is. These theoretical considerations are then used to analyze the existing research program in developmental biology, which understands morphogenesis, the process of development of shape in biological systems, as a computational process. This important line of research shows that cognition and intelligence can be found across all scales of life, as the proponents of the basal cognition research program propose. Hence, clarifying the connection between morphological computation and morphogenesis allows for strengthening the role of the former concept in this emerging research field. Artificial Life 19(1)) interested in “unconventional” computing platforms and intersecting with the study of soft robotics. The importance of this concept stems from the fact that it offers an important connection between the popular computationalist view on the nature of the mind and intelligence and the emerging and quickly gaining popularity  anti-computationalist perspective focusing on the embodiment of cognitive systems . Develos . MorphoHowever, together with the increasing popularity of the term “morphological computation”, there has been a growing number of instances where it has been applied only loosely. Those conceptual ambiguities prompted a response from Müller and Hoffmann , who havIn the current paper, I wish to suggest that, similar to how counting on fingers has become a paradigmatic example of embodied cognition in complex (‘higher’) mental phenomena, (see ), “countAs a sidenote, it must be clarified that “counting with cilia” is meant here primarily as a metaphor, as cilia’s involvement in morphogenesis is not fully known, and this phrase does not aim to suggest otherwise. For example, morphogenetic movements use primarily contraction and cell-to-cell adhesion , althougThe goal of the paper is to provide three contributions to the debate on the concept of morphological computation begun by the influential paper of Müller and Hoffmann . First, Müller and Hoffmann  begin thThe semantic view of computation has a long history, building on early work by Hilary Putnam  and hasMüller and Hoffmann  begin thAn abstract initial state computer , p. 9.T refers to a theory of the physical computational device, which encapsulates the correspondences between the abstract computation and the physical computer and a description of the evolution of the physical states. Further, Müller and Hoffmann follow Horsman et al. in specifying that the representation relation they posit is one that a user introduces: “the occurrence of representation is a vital part of physical computing, and computational entities (human or otherwise) are the ones performing it”  evolved” , p. 4. AMorphological computation can play the role of a central conceptual hub relating the research in basal cognition to the investigation of human brains in computational neuroscience. In a way, I want to suggest that it can play a key role in understanding the principles of “scaling up” cognition in its “endless forms most beautiful” and complex .While the brain does not necessarily involve “morphological” computation, the achievements of computational neuroscience  as wellFurthermore, basal cognition draws heavily on the investigations within synthetic biology and soft robotics (e.g., ,76,77,78Importantly, despite the continued tensions between proponents of computationalist and anti-computationalist theories of mind, recently, a middle way has been considered by some researchers. Researchers such as Villalobos and Dewhurst  and KorbAn argument similar in spirit may be found in a paper by Beer and Williams . The autWhile my argument takes the conclusions of Beer and Williams’s work for granted and builds on the commonalities between information theory and dynamical systems theory, the analysis provided here aimed to show that two properties taken to be at odds, autopoiesis and computation, can, in fact, be identified in the same system as interacting and co-supporting. In this way, I suggest regarding morphogenesis—the metaphorical “counting with cilia”—as an initial example of how computational descriptions may be of use for accounting for autopoietic and self-organizing processes.This paper discusses the concept of “morphological computation”, pointing out that the existing critical analysis of Müller and Hoffmann  relies oI further substantiate these claims by analyzing an example of morphological computation that has been overlooked so far in this literature. I refer to studies of developmental and regenerative morphogenesis that have been increasingly regarded as computational in nature, and I point out that the computations in question are, in fact, performed morphologically. This example connects the analysis back to the debates within cognitive science, philosophy of mind, and philosophy of biology, as it is one of the central cases studied under the label of “basal cognition”. Its importance can hardly be overstated, as it puts basal cognition at the center of the stalled debate between computationalists and anti-computationalists, providing important support for a recently proposed “middle-way” approach—computational enactivism—aiming to reconcile insights from these opposite traditions.Hence, this discussion of morphological computation offers the potential of significantly influencing our understanding of cognitive systems and intelligence, helping the project of basal cognition and allowing it to make novel connections to established fields, such as computational neuroscience in particular.


V. vinifera hybrids and different cultivars were subjected to selfing or used in reciprocal crosses by testing them as female parents or male parents. Two cold-resistant and four high-quality cultivars were selected, and the offspring of fourteen crosses and six self-combinations were evaluated. The pollen viability of the six cultivars was determined by TTC staining. Compatibility and the rates of fruit-setting, seediness, germination, emergence, and seedling were measured as parameters that can affect fertility of both hybridization and self-crossing processes. Using principal component analysis, the six fertility indexes were transformed into comprehensive principal components, and the weights of the indexes were determined. Combined with the membership function method, the fertility index was comprehensively evaluated for different crosses to screen for hybrid combinations with higher fertility. The results showed a high positive correlation between the pollen viability of the cultivar subjected to selfing and the fruit-setting rate, seediness rate, and hybrid compatibility index of the cultivar used as the male parent for crossing. Additionally, there was a one-to-one positive correlation between the fruit-setting rate, germination rate, emergence rate, and seedling rate of the selfed cultivar and the fruit-setting rate, germination rate, and seedling rate of the cultivar used as the female parent for crossing. There was some variation in the comprehensive fertility index values for the parents and combinations in different years. The comprehensive fertility index was always the highest for Ecolly as the male parent. The composite fertility index values were relatively high when Dunkelfelder, Cabernet Sauvignon, or Marselan were used as the female parent. The combinations of C1 (Cabernet Sauvignon × Ecolly), C3 (Marselan × Ecolly) and C6 (Dunkelfelder × Ecolly) exhibited relatively high comprehensive fertility indices, and pedigree clustering shows that these three combinations cluster into one class of highly fertile hybrid combinations. This study provides the basis for effective intraspecific hybrid breeding of grape (V. vinifera).The correlations were explored between fertility indicators of intraspecific  V. vinifera, which will limit the acceptance of such cultivars by consumers  and four high-quality wine grape cultivars [Garanior  were randomly selected and measured for each combination. The pollen viability and rates of fruit-setting, seediness, germination, emergence, and seedling were measured and analyzed in two consecutive years.A cold-resistant wine grape cultivars, Ecolly or Meili, was used as one parent and four high-quality wine grape cultivars with relatively weak cold resistance were used in a reciprocal cross test design for a total of 14 hybrid combinations. Additionally, self-crossing was performed with the six cultivars. The hybridization and selfing combinations are presented as Well-developed flower spikes were collected at the beginning of flowering. The pollen was rubbed out, evenly spread on a clean carton, and fully dried under a fluorescent lamp until the pollen was dispersed. After being filtered through a 120-mesh sieve, the pollen was fully ground with a mortar to break the pollen wall, and finally collected in a labeled centrifuge tube indicating the collection date and variety.The pollen viability was determined using the 2,3,5-triphenyltetrazolium chloride (TTC) staining method . BrieflyHybridization experiments were carried out in May 2020 and May 2021 in an experimental vineyard of NWAFU. Emasculation and bagging isolation of grape inflorescences were performed 3 days before flowering. Pollination was done with a brush the next morning after emasculating, with three rounds of pollination on three consecutive days. After pollination, the inflorescences were bagged and the number of flowers was counted. The bagging was removed after 2–3 weeks to allow the fruit to develop naturally.Two months after hybrid pollination, the fruit-setting was determined. After the grapes had fully ripen, they were harvested and the seed setting of the fruit was measured. The compatibility index is equal to the ratio of the number of full mature seeds harvested to the total number of flowers that could have been pollinated.The seed germination and seedling raising experiments were carried out in the research greenhouse of NWAFU. With reference to the method of The pollen viability (%) equals the number of viable pollen divided by the total number of pollen × 100%. The fruit-setting rate (%) equals the number of fruit swelling divided by the number of flowers in the combination × 100%. The seediness rate (%) equals the number of fruits with fully mature seeds divided by the total number of fruits in the combination × 100%. The compatibility index equals the number of harvested full seeds divided by the number of flowers in combination. The germination rate (%) equals the total number of germinated seeds divided by the total number of seeds tested × 100%. The emergence rate (%) equals the number of seedlings (two pieces of cotyledon) divided by the number of seeds sown × 100%. The seedling rate (%) equals the number of surviving seedlings divided by the number of transplanted seedlings × 100%.Evaluation of fertility is based on the evaluation of the various subordinative function indices in the form,.i is a particular parent or combination, j is a particular index, Xij is the testing value of the index j of parent or combination i, Xjmin is the minimum value of index j for all parents or combinations, Xjmax is the maximum value of index j of all parents or combinations, Uij is the subordinative function value of parent or combination i, and index j that relates to fertility.Here, 1Microsoft Excel 2013 was used to record and process the original data and calculate the average and coefficient of variation. Analysis of variance and systematic cluster were performed in SPSS 22.0 statistical software. Heat Map with Dendrogram and Principal component analysis were performed using Origin 9.0 software. Weight coefficient analysis was performed using SPSSAU, an online platform for data analysis.The pollen viability was determined for the six tested cultivars by TTC staining, and the results are shown in The fruit-setting rate, seediness rate, and compatibility index of the six tested parents were investigated and counted, and the results are shown in The germination, emergence, and seedling rates of the inbred seeds were investigated and counted, and the results are shown in The fruit-setting rate, seediness rate, and compatibility index of the six tested parents were investigated and counted, and the results are shown in The germination, emergence, and seedling rates of the hybrid seeds were investigated and counted, and the results are shown in As shown in Principal component analysis of the six fertility indicators was carried out with groups for each cultivar as the male parent, as the female parent, or selfed, and the results are shown in From the load and contribution value of each index determined in the principal component analysis, the effects of the fertility index on the comprehensive fertility of the tested hybrid and selfing combinations were calculated, and the weights were determined. The results are presented as To comprehensively evaluate the fertility of the tested hybrid combinations, it is necessary to combine the contribution rates of the principal components and coordinate the fertility indicators of each principal component. The fertility indicators for cultivars used as male parent or female parent were standardized and quantified by the membership function method. These index values were then multiplied by the membership value and weight of each index and then summed to obtain the comprehensive index of fertility of each parent. The results are shown in The fertility indicators of the 14 hybrid combinations tested were standardized and quantified by the membership function method. These index values were then multiplied by the membership value and weight of each index and then summed to obtain the comprehensive index of fertility of each parent. The results are shown in Systematic cluster analysis was carried out on the comprehensive fertility index values of the 14 tested hybrid combinations for two consecutive years, and the results are shown in V. vinifera, with highly compatible intraspecific hybrids , C3 (MSL × ECL), and C6 (DKF × ECL) were identified as high fertility hybrid combinations that should be preferably selected.V. vinifera to obtain more hybrid populations. Next steps will be to explore the physiological, biochemical, and molecular mechanisms underlying the factors that cause fertility. Future work should also further explore the abortive process that occurs in intraspecific hybridization, in which fruit is produced but germination does not occur.The purpose of this study was to guide intraspecific hybridization in The original contributions presented in this study are included in the article/Z-LW, FY, HW, and HL: conceptualization. Z-LW, YW, XC, and DW: data curation. MH and XH: formal analysis. HW and HL: funding acquisition and project administration. FY and Y-HL: methodology. All authors have read and agreed to the published version of the manuscript.