Epithelial tissues are the most rapidly dividing tissues in the body, holding a natural ability for renewal and regeneration. This ability is crucial for survival as epithelia are essential to provide the ultimate barrier against the external environment, protecting the underlying tissues. Tissue stem and progenitor cells are responsible for self-renewal and repair during homeostasis and following injury. Upon wounding, epithelial tissues undergo different phases of haemostasis, inflammation, proliferation and remodelling, often resulting in fibrosis and scarring. In this review, we explore the phenotypic differences between the skin, the oesophagus and the oral mucosa. We discuss the plasticity of these epithelial stem cells and contribution of different fibroblast subpopulations for tissue regeneration and wound healing. While these epithelial tissues share global mechanisms of stem cell behaviour for tissue renewal and regeneration, the oral mucosa is known for its outstanding healing potential with minimal scarring. We aim to provide an updated review of recent studies that combined cell therapy with bioengineering exporting the unique scarless properties of the oral mucosa to improve skin and oesophageal wound healing and to reduce fibrotic tissue formation. These advances open new avenues toward the ultimate goal of achieving scarless wound healing. Epithelial tissues provide the body’s first line of protection from physical, chemical and biological damage. Mammalian epithelia vary in structure throughout the body according to their function and microenvironment. Skin is considered the largest organ of our body; however, it is not the only epithelium exposed to the external environment. The airways, digestive tract, as well as the urinary and reproductive systems, are all exposed to external stress and are lined by an epithelium, sharing some important structural and functional features.In this review, we focus on three stratified squamous epithelial tissues – the skin, the oesophagus and the oral mucosa – and provide a comparative analysis of the architecture, cell composition and behaviour of these three different tissues during homeostasis and wound healing. We discuss the outstanding regenerative potential of the oral mucosa and how its scarless wound healing properties can be applied to the other tissues.Adult epithelia harbour resident stem cells (SCs) responsible for homeostasis and tissue repair. The epithelial lining of the skin develops from the ectoderm, the oesophageal epithelium derives from the endoderm, while the oral epithelium derives both from ectoderm and endoderm . Skin, oThe skin is comprised of three different layers: epidermis, dermis and hypodermis, and harbours additional appendages, such as hair follicles, nails, sweat and sebaceous glands . The intThe dermis is the connective tissue layer that provides skin elasticity and tensile strength  and it i+CD39+FAP+ in human; (2) the reticular layer, with lower cell density but rich in connective tissue and expressing FAP–CD90+ in human (and CD36+ for the lower reticular); and (3) the hypodermis which consists mainly of adipose tissue, loose connective tissue and is highly vascularised and rich in hormones and growth factors and expressing CD90+CD36+ in human  progenitors, primarily distributed in the reticular dermis, was shown to robustly contribute to regenerate injured dermis and to populate neogenic hair follicles in adult mice  the papillary layer, closest to the epidermis with a high cell density and loose connective tissue and expressing CD90in human . Anotherin human . Severalin human  as well in human  and respin human . Papillain human  and morein human . Reticulin human . Accorditor Lef1 . More reult mice . As for ult mice .A recent study has identified an additional fibroblast subpopulation below the hypodermis called the fascia that contribute to skin scar formation  and the underlying lamina propria, which is rich in connective tissue, fibroblasts, nerves, minor salivary glands and blood vessels .vs. non-keratinised oral epithelia in The non-keratinised oral epithelia comprise basal, spinous, intermediate and superficial layers, while the keratinised oral epithelia resemble the skin epidermis and include basal, spinous, granular and cornified layers  fibroblasts are known to resemble foetal skin regenerative potential, namely on their migratory capacity through production of MSF, a migration stimulating factor not present in adult skin .Engrailed1-lineage-positive somitic origin, the oral mucosa lamina propria and cranial skin dermis originates from Wnt1-lineage-positive neural crest cells  this layer separates the oral mucosa from the bone or muscle below , while rth-6th suprabasal layers  and Krt14 . Krt15 iThe heterogeneity of oral epithelia is reflected in its suprabasal keratin expression. The non-keratinised lining mucosa shares the expression of Krt4 and Krt13 , whereasWith more similarities with oral than with skin epithelia, the oesophageal epithelium expresses Krt4 and Krt13 on the suprabasal layers . The mou+ cells are present in oral mucosa and skin epithelial basal layer while Sox2 is in oesophageal and oral epithelia, including tongue taste bud cells  . The EPU+Krt14+ epidermal SCs : one α6briCD71dim is a putative oesophageal SC population, the α6briCD71bri represents the transient amplifying cell population and the third population α6dim which is a population of early differentiating cells  and β4 integrin  in Sox2+ basal cells, combined with CD73 and Krt14, Krt13and Krt4 revealed three different basal subpopulations: Itgα6/Itgβ4HighCD73+ is a SC population, the faster dividing Itgα6/Itgβ4HighCD73– is a transient-amplifying population and Itgα6/Itgβ4Low represented the more differentiated basal cell population  , defendiBesides intrinsic ability for division, the factors that drive basal cells to make the decision to proliferate or differentiate were not yet disclosed. For instance, upon skin wounding different SC populations were shown to contribute to different compartments and change their behaviour in order to increase proliferation over differentiation until complete wound closure, only then reverting to homeostasis . This hi+Krt5+Trp63+Sox2Low maintain the physiology of filiform and fungiform papillae, circumvallate papilla and soft palate, and the other is located outside the taste buds and is a Krt14+Krt5+Trp63+Sox2+ population of bipotential progenitor cells which give rise to both taste pore keratinocytes and receptor cells of the taste buds Environment: the oral mucosa comes in contact with a very different environment compared to skin. The external factors such as saliva and the oral microbiota have been shown to play a role in oral wound healing . The ora(2)+ regulatory T cells Angiogenesis: reduced angiogenesis could be expected to impair healing, though some studies have proven that inhibition of the angiogenic response in oral wounds is linked to reduced scar formation . Angioge(4)Keratinocyte proliferation: the oral epithelia present faster re-epithelialisation . Oral ke(5)Engrailed1-lineage-positive fibroblast subpopulation, the study from Rinkevich and colleagues reports a Wnt1-lineage-positive population in the oral dermis tightly linked to the non-fibrotic healing that characterises the oral mucosa. A reciprocal transplantation of these oral mucosal- and skin-derived fibroblast populations performed in mice revealed that these mimic the response of the tissue of origin. Thus, the grafting of Wnt1-lineage-positive oral fibroblasts in skin resulted in decreased scar tissue formation while skin fibroblasts contributed for a scar-like tissue formation in the oral wound site, proving that the oral fibroblast lineage is determinant for the scarless healing of the oral mucosa  using oral mucosa (without fascia) showed that swarming is absent and N-cadherin is minimally expressed, agreeing with its typical scarless healing phenotype  in these cells. Oral fibroblasts were shown not only to express higher basal levels of αSMA but also have higher number of αSMA-positive myofibroblasts in oral mucosal wounds . However(6)ECM: compared to cutaneous wounds, the ECM composition of oral wounds diverges and is a key determinant for the scarless phenotype. Oral wounds showed increased expression of hyaluronic acid, tenascin and fibronectin and decreased expression of elastin . Also, t(7)Molecular cues: transcriptomic analysis have uncovered the molecular differences between skin and oral mucosal wound healing . HealthyTo conclude, the ability of the oral mucosa to heal without scarring cannot be attributed to a single feature but to key extrinsic and intrinsic factors present in all stages of the wound healing process, which are crucial to the final improved outcome.Improving wound healing in skin is an unmet need. Chronic skin wounds have devastating consequences for patients and treating chronic wounds costs the UK National Health Service £5 billion per annum . DevelopReconstruction of skin or oral mucosal tissues using tissue-engineering methods resembles wound healing processes. It requires active SCs, epithelial proliferation, epithelial and fibroblast cell migration and ECM production, all processes coordinated to regenerate the new 3D tissue with similar properties and functions.laminin 332 usually expressed in skin’s basement membrane . While surgical reconstruction of the oral cavity with skin grafts has been easily and routinely accomplished for a long time, particularly after tumour resection, the clinical application of oral mucosa grafts into skin has been less explored . HoweverIn vitro studies have demonstrated the potential of oral mucosal fibroblasts, to improve wound healing after biostimulation with low-level laser therapy , the recipient organ keeps characteristics of the donor tissue , there iications . Whetherications . This heTechniques to improve skin wound healing are currently under development and are an unmet need, particularly following large burns and war injuries, where treatment is still primarily performed by split-thickness skin grafting and accompanied by problems associated with limited donor tissue, pain and scarring .Mounting evidence over the last two decades has demonstrated a remarkable plasticity in adult epithelial cell fate while in in different niches, leaving behind the concept of strict SC fates . While eIn this review, we elucidate the intrinsic properties that prime the oral mucosa with scarless wound healing response. Lessons should be learned from the oral mucosa to apply on other tissues, exploring these unique properties in future innovative therapies combining cell therapy with bioengineering to prevent pathologies associated with impaired wound healing and scar formation in both skin and oesophagus.DP and IS: conceptualisation, writing, editing, and figures. Both authors contributed to the article and approved the submitted version.IS is a consultant for L’Oréal Research and Innovation. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.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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Advanced glycation end products (AGEs), a heterogenous group of products formed by the reaction between protein and reducing sugars, can form endogenously due to non-enzymatic reactions or by exogenous sources such as diet where considerable increase in AGEs is observed due to the modification of food mainly by thermal processing. Recent studies have suggested that AGEs could impact, via inducing inflammation and oxidative stress, the reproductive health and fertility in both males and females. This review presents a summary of recently published data pertaining to the pathogenesis of dietary AGEs and their receptors as well as their potential impact on female reproductive health. More specifically, it will present data pertaining to dietary AGEs’ involvement in the mechanistic pathogenesis of polycystic ovary syndrome, ovarian dysfunction, as well as the AGEs’ effect perinatally on the female offspring reproduction. Understanding the mechanistic impact of dietary AGEs on female reproduction can help contribute to the development of targeted pharmacological therapies that will help curb rising female infertility. The Maillard reaction was first reported in 1912 by French scientist Louis Camille Maillard ,4. This AGEs are stable non-enzymatically catalyzed compounds which are formed by condensation of the amino groups of protein, lipid, amino acid and nucleic acid with the aldehyde group of reducing carbohydrate . This noAGEs can be formed either endogenously by the body or from exogenous sources . EndogenReceptor for Advanced Glycation End product) which is member of the immunoglobulin superfamily [Dietary AGEs bind to several types of receptors . First, erfamily . The experfamily ,33.RAGE has a triple domain: transmembrane, a cytosolic and an extracellular , is exprAfter binding to RAGE, there is an activation of several intracellular inflammatory signaling pathways that include mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase1/2 (ERK1/2), protein kinase C (PKC) and nuclear factor kappa B (NF-κB) ,38. The Second, RAGEs have been found to have multiple soluble forms detected mainly in body fluids and blood. The two most common forms are: sRAGE (soluble fragment of RAGE) and esRAGE (endogenous secretory RAGE). The sRAGE is produced by hydrolysis  of tDietary AGEs are orally absorbed , with apPCOS is arguably the most common endocrinopathy in reproductive-aged women ,56. It iWhen quantified at the ovarian tissue level by immunohistochemistry, RAGE and AGE-modified proteins are expressed in women with or without PCOS, though at much different concentrations . There aOther studies have demonstrated that women with PCOS given isocaloric diets high in AGEs for 2 months had significantly higher testosterone, free androgen index, and androstendione levels compared to women with PCOS on two-months low-AGE isocaloric diet . Animal At the cellular level, AGEs cause alterations in lysyl oxidase (LOX), which play a significant role in the regulation of ovarian follicular extracellular matrix organization and can explain some of the changes observed in PCOS . In factStAR mRNA expression levels. They also showed significant alterations in genes involved in folliculogenesis, in particular an increase in growth differentiation factor 9 (Gdf-9) and follicular stimulating hormone (FSH) receptor (FSH-r) mRNA levels. Mouse macrophage marker F4/80 mRNA expression was upregulated in mice on a high-AGE diet. These results indicate that folliculogenesis and steroidogenesis could be disrupted by a high-AGE diet, leading to abnormal reproduction in female animals  and proper ovulation . One stuThe effect of AGEs on pathways (such as Smad 1/5/8) and expression of genes  involved in ovarian follicular development was studied in human luteinized granulosa cells of women who underwent oocyte collection for in vitro fertilization . The AMHIt is well known that maternal nutrition and the intrauterine environment are crucial in determining susceptibility to reproductive and metabolic disturbances later in life ,82. For Amh and Amhr2, and steroidogenesis such as Cyp19a1 (aromatase enzyme). These results indicate that perinatal exposure to a diet elevated in AGEs causes deficits in perinatal growth, pubertal onset, and reproductive organ development in female mice.In a recent study , seven wF4/80 expression [With the common ingestion of diets high in AGEs, reproductive-aged women might face more metabolic and reproductive complications. The reproductive function and body energy hemostasis are closely linked at the level of the brain, in particular the hypothalamus, and the ovaries; thus, future studies focusing on the neuroendocrine axis are necessary to further define the mechanisms by which dietary AGEs influence female reproduction. The ingestion of diets high in AGEs causes a systemic state of chronic inflammation, as shown by upregulation of ovarian macrophage marker pression , which mThis review underscores a critical need to unveil, in greater depth, the mechanistic pathways of AGEs, which are molecules present in high amounts in the daily Western diet. Cutting down on the ingestion of AGEs could be demanding and might not be maintainable, thus there is a need to promote therapies targeting AGEs and their intracellular signaling pathways in order to improve ovarian health not only now but in the future generations, since AGEs seem to have transgenerational effects on female reproduction.


Advanced wastewater treatment processes are required to implement wastewater reuse in agriculture or industry, the efficient removal of targeted priority and emerging organic & inorganic pollutants being compulsory . Various processes such as membrane separations, adsorption, advanced oxidation, filtration, disinfection may be used in combination with one or more conventional treatment stages, but technical and environmental criteria are important to assess their application. Natural and synthetic polyelectrolytes combined with some inorganic materials or other organic or inorganic polymers create new materials (composites) that are currently used in sorption of toxic pollutants. The recent developments on the synthesis and characterization of composites based on polyelectrolytes, divided according to their macroscopic shape—beads, core-shell, gels, nanofibers, membranes—are discussed, and a correlation of their actual structure and properties with the adsorption mechanisms and removal efficiencies of various pollutants in aqueous media (priority and emerging pollutants or other model pollutants) are presented. Municipal wastewater treatment plants (MWWTPs) face great challenges in optimizing technologies to avoid ecological and human health problems and to ensure environmental sustainability, in direct correlation with the increased pollution due to economic and social growth, wastewater quality discharged into surface waters and climate changes. Industrial activities are responsible for the discharge of effluents with a wide range of inorganic and organic compounds that belong to the priority (PPs) and emerging pollutants (EPs) classes, pharmaceuticals and personal care products, pesticides, heavy metals, detergents, flame-retardants being only few examples of such pollutants. Through their presence, eco-toxicological and human health effects, bio-accumulative and degradation characteristics may influence aquatic biota and the performances and costs of water and wastewater treatment technologies . MoreoveMWWTPs collecting wastewater from combined sewers usually remove solids of different sizes, biodegradable organic and inorganic compounds based on conventional processes such as the following: mechanical , biological (suspended or attached growth) and tertiary  treatment. The implementation of wastewater reuse in agriculture or industry requires the elimination of targeted priority and emerging organic & inorganic pollutants, microorganisms  by means of advanced wastewater treatment (AWWT) , that complete the conventional treatment as presented in Although, inorganic and organic pollutants classified as PPs or EPs are detected in wastewater at low concentrations (few micrograms/milligrams per liter), they are toxic, bio-accumulative, low biodegradable and very difficult to remove in terms of technological, energy and environmental efforts. In the European Union, both PPs and EPs are monitored in surface water ,5,6, but2, TiO2, graphene oxide, Fe3O4, clays, zeolites etc.) or other organic polymers , etc.) to create new materials (composite type) as perfect candidates for sorption of toxic pollutants such as pharmaceuticals and heavy metal ions g-polyacrrin  to the cellulose acetate membrane extended the membrane lifetime in water cleaning, and the LbL deposition method increased the polymer amount, therefore increasing the heavy metal sorption capacity [2+ sorption capacity increased by 50%. The reusability test with EDTA-2Na demonstrated that after four sorption/desorption cycles, the composite membrane maintained the capacity for heavy metal ions sorption with only 8% reduction.The composite membranes can be fabricated by deposition  of organic/inorganic components onto an unmodified membrane ,144,145.capacity . To imprDue to the low manufacture costs and easy chemistry modification, the composite polymer membranes are popular and frequently used in the water treatment technologies. Such composite membranes still lack some properties required in membrane processes, such as high selectivity towards low solutes. In this way, many studies have been carried out for enhancement of sorption/separation performance of composite membranes. The creation of membranes with high permeability and selectivity, rejection and sorption capacities, antifouling properties are the biggest issues among researchers all over the world who work in the development of membrane materials.In summary, this study discussed about the multiple synthesis approaches utilized in creation of different types of composite materials based on polyelectrolytes with subsequent application in pollutants removal from synthetic/waste/surface waters.2+, Cd2+, Co2+, Ni2+, Pb2+, As3+/5+, Fe2+/3+, Zn2+, Cr3+/6+, Hg2+, UO22+, Mn2+, F−) and/or organic  pollutants. The new materials, created by smartly introducing the inorganic materials in polymeric part or polymer chains onto inorganic part, have overcome the main drawbacks of polyelectrolyte chains, i.e., the “softness”  and the high solubility in water.Throughout this review paper, it has been shown the tremendous potential ability of composite polyelectrolytes in sorption/desorption of inorganic . Using “soft” polyelectrolytes, with high and diverse number of functional groups, in combination with “hard” inorganic components could results in an “upgraded” composite material with synergic properties in pollutant retention. All pollutants sorption processes could be modeled, mostly by Langmuir and Freundlich isotherms, pseudo-first or pseudo-second order rate. The composites based on polyelectrolytes have been characterized by different solid-state analysis methods, including the following: scanning electron microscopy, Fourier transform infrared spectroscopy, X-ray photoelectron spectrometry, X-ray diffraction, thermogravimetry analysis, dynamic light scattering, transmission electron microscopy, BET analysis. The obtained data provide physico-chemical information about the composite state before and after interaction with different types of pollutants. It can be summarized that composite polyelectrolytes are promising adsorbents for the elimination of inorganic and organic pollutants from wastewater, both in batch and dynamic experimental set-up. There is extensive work done testing these materials using heavy metal ions and dyes as models for the inorganic and organic pollutants, respectively. Only few studies were found to discuss the removal of EPs, such as pharmaceuticals.the individual removal of EPs or PPs compounds and not their simultaneous removal, in adsorption columns, the latter being a solution for both the complex nature of wastewater matrix and the operational requirements;usually, a combination of two or three AWWT processes might be needed to remove both inorganic and organic PPs/EPs;when a combination of sorption is made with processes that are not selective (such as AOPs), intermediates that could be more toxic than the initial compounds could be generated in the final effluent;phase transfer of pollutants on solid surfaces  and further regeneration might also contribute to supplementary environmental impacts;the technical assessments are used frequently to evaluate the feasibility of sorption or combined processes; there are only few studies that consider the sustainability assessments  to design specific functionalized materials.The current limitations/challenges of pollutants removal by means of sorption processes using composite polyelectrolytes refer to the following:Overall, this paper could be a starting point in the identification of old “partners/components”, but new by combination methods and different techniques in achieving versatile materials with adaptive behavior for the present demands of wastewater treatment.


Arabidopsis thaliana to tuberization in potato or autumn growth cessation in trees. Strikingly, many of the processes affected by photoperiod employ similar gene networks to respond to changes in the length of light/dark cycles. In this review, we have focused on developmental processes affected by photoperiod that share similar genes and gene regulatory networks.Fluctuations in environmental conditions greatly influence life on earth. Plants, as sessile organisms, have developed molecular mechanisms to adapt their development to changes in daylength, or photoperiod. One of the first plant features that comes to mind as affected by the duration of the day is flowering time; we all bring up a clear image of spring blossom. However, for many plants flowering happens at other times of the year, and many other developmental aspects are also affected by changes in daylength, which range from hypocotyl elongation in  Long Days (LDs) in spring and hot summer, and Short Days (SDs) in autumn and cold winter.The Earth’s rotation on its axis and revolution around the sun create cycles of day and night with a 24-h period as well as changes in temperature and humidity with a 365-day period. These periodic alterations in environmental conditions  are modest in tropical and subtropical regions, where changes in precipitation determine the two main seasons , but are considerable in temperate regions, where changes in the length of the day and ambient temperature determine the four seasons – photoperiod, regulates many aspects of plant growth. For example, trees stop growing when days shorten in autumn foreseeing the arrival of cold winter. There are more examples of developmental traits regulated by changes in photoperiod, some discussed in this review. Their importance in plant development and plant adaptation to specific habitats promoted scientific research about the molecular mechanisms underlying photoperiodic response.Compared to temperature, daylight is a more predictable external cue that enables organisms to anticipate seasonal changes and modulate their biological function consequently. The length of the light period over 24 h, also named circadian clock, defined as the internal timer synchronized with solar time that oscillates with a stable phase of approximately 24 h.Light/dark cycles and hot/cold cycles entrain the Light is perceived by photoreceptors that sense different wavelengths of the natural sunlight spectrum  represent the major photoreceptors that sense red and far-red light . PhytochPRR1/TIMING OF CAB EXPRESSION 1 (TOC1) at the beginning of the light period  and LATE ELONGATED HYPOCOTYL (LHY) are expressed at dawn . CCA1 ant period . Other P at dusk ,b. Durin and LHY .ELF4 , because some plants growing in temperate regions flower when days are long whereas other plants growing in tropical regions prefer SD or even neutral days (12 h light/12 h dark) to develop reproductive structures. Hence, photoperiod controls several developmental stages throughout the plant life cycle.In plants, photoperiod integrates the circadian clock output information and the light perception to regulate plant adaptation to different light regimes. Accordingly, plants modulate their growth in response to seasonal changes and synchronize key developmental transitions with favorable conditions to sustain their ecological fitness . Different photoperiods regulate different developmental transitions; for example, in poplar trees LDs trigger vegetative growth in spring while SDs promote growth cessation in autumn. On the other hand, the same developmental process could be regulated by different photoperiods in different plants; a good example is the transition from the vegetative to reproductive phase  rather than those that are regulated by completely different mechanisms or without detailed molecular/genetic studies.Upon seed germination, the elongation of the hypocotyl  is one of the earliest processes affected by photoperiod. Molecular mechanisms underlying this developmental step have been extensively studied in Arabidopsis, which displays short hypocotyls when grown under LDs but long hypocotyls under SDs.The regulation of hypocotyl growth relies on the activity of PIF4 and PIF5, two basic helix-loop-helix (bHLH) transcription factors which protein abundance is controlled by the photoreceptor phyB that mediates PIFs degradation during the day through the 26S proteasome . SeveralYUCCA8 (YUC8), an important auxin biosynthetic gene  through the degradation of DELLA proteins, negative regulators of growth able to interact with PIFs. During the light period, DELLA protein levels are high and sequester PIFs: the formation of inactive complexes hinders PIF binding to target genes. During the dark period, GA accumulation triggers DELLA degradation, allowing the release of PIFs. Thus, PIFs accumulate in the nucleus at night and activate downstream genes involved in hypocotyl growth before dawn .Besides germination and seedling establishment, the transition from the vegetative to the reproductive phase represents a critical step for the reproductive success of flowering plants. Floral induction must occur at the most favorable season to guarantee the highest production of seeds and survival of the offspring. This phase change is economically relevant in seed crops as it determines grain yield, an important agronomic trait. Accordingly, both precocious and delayed flowering should be avoided as they might cause yield losses. Early flowering plants fail to store enough energy for seed development due to insufficient growth of photosynthetic organs; conversely, late flowering plants are vigorous, but fertility can be affected if seed maturation takes place in adverse weather conditions. Therefore, plants should synchronize leaf and flower development with environmental conditions to optimize the timing of the formation of reproductive organs.Multiple genetic determinants control the switch from vegetative to reproductive growth by integrating external cues and internal signals. Before floral transition, the plant undergoes the juvenile-to-adult transition when it reaches the competence to flower in response to inductive environmental conditions. Although photoperiod is one of the major environmental stimuli, others such as ambient/seasonal temperatures together with endogenous conditions  contribute to finely tune the floral induction.Arabidopsis thaliana. Nevertheless, research conducted in many other species - including monocotyledonous plants - has shown that GRNs controlling the floral transition are mostly conserved, albeit with some variations that account for the peculiarities of the different plant species examined.Control of flowering time has been massively studied in Arabidopsis is a facultative LD plant, meaning that although it can bloom in SDs it flowers much more rapidly when days are long . The length of the day is sensed in the leaf, but the floral induction takes place in the shoot apex (reviewed by CONSTANS (CO) is one of the most studied regulators acting in photoperiodic flowering. The expression of the CO gene oscillates with the circadian rhythm and is activated in the leaf upon LD perception  positively regulate flowering mostly by preventing the action of repressors on  at dusk .GI expression, ELF3 promotes GI degradation, and ELF4 removes GI from the CO promoter  Zinc Finger transcription factor whose activity is also regulated by protein-protein interactions with other circadian regulated BBX proteins. For example, BBX19 interacts with CO and depletes the active CO pool  in leaf vascular tissue in LDs (CO and FT confers very early flowering phenotype while their loss of function causes extremely late flowering (but only in LDs) suggested that these two genes might control the first moments of the floral induction in response to photoperiod  family (Florigen Activation Complex (FAC) – first activates SUPPRESSOR OF OVEREXPRESSION OF CO 1 (SOC1) and APETALA1 (AP1), two genes of the MADS-box family involved in floral meristem identity, by directly binding their promoters  is activated by CO and the encoded protein acts as a long-range signal traveling to the SAM where it also interacts with FD (The ) family . As FT i) family , and thi) family . The forromoters . Similar with FD .Bioactive GAs act as another signal that affects flowering under LDs, but it is under non-inductive SDs that they play a more evident role in floral induction  when CO FT expression  has the same effect on flowering as the removal of the floral repressors TEM (in loss of function mutants), obtaining a precocious flowering phenotype. In the same way, plants with reduced levels of both CO and TEM flower at the same time as wild type plants  proteins, which bind CCAAT sequences present in the FT promoter. This binding results in a chromatin loop that brings enhancers present in distal elements close to two CO Responsive Elements (CORE1 and 2) found near the transcription start site of FT  is another important floral repressor . At low  of TEM2  as well FLOWERING LOCUS T repression is mediated by SVP-FLC during the vernalization process  (GA3OXIDASE1 (GA3OX1) and GA3OX2   while TEd GA3OX2 .AP2-like genes is regulated by microRNA172 (miR172), which independently controls the juvenile to adult transition (Other key regulators of the photoperiod pathway are APETALA2 (AP2) and AP2-related proteins – SCHLAFMUTZE (SMZ), SCHNARCHZAPFEN (SNZ) and TARGET OF EARLY ACTIVATION TAGGED 1 (TOE1), TOE2, and TOE3 – that negatively regulate the floral transition by interacting with TPL . The expansition  and the ansition .miR172 relies on five MIR172 genes (A to E), recently shown to play common and divergent roles under different conditions  have been subjected to natural variation in order to adapt to the environment .Stomata are specialized cell structures that control gas exchange  needed for photosynthesis . Stomata+-ATPase) that generates osmotic pressure in the guard cells: stomata open when guard cells swell due to water intake and close when guard cells shrink due to water loss. Mutations in genes associated with the circadian clock (such as CCA1) affect stomata opening/closing cycle, making loss of function mutants unable to anticipate the day/night changes , the close homolog of FT, not only promotes flowering redundantly with FT, but also stomata opening, as mutations in TSF impair stomatal responses  locus in rice (DAYS TO ANTHESIS 8 (DTA8) locus corresponding to ZEA CENTRORADIALIS 8 (ZCN8) in maize (VERNALIZATION 3 (VRN3) loci corresponding to HvFT1 and TaFT in barley and wheat . To date, major factors found to control circadian rhythms and photoperiodic flowering in cereals contain the CCT domain – a conserved sequence of 41–43 amino acids named after CONSTANS, CO-like, and TOC1 proteins previously characterized in Arabidopsis. These regulatory proteins can be divided into three main families: COL (CO-like), also having one or two Zinc Finger BBX at the N-terminus; PRR, also having a pseudo receiver domain at the N-terminus; CMF (CCT Motif Family), only having a CCT domain at the C-terminus  and Asian rice (Oryza sativa), derive from wild species grown more than 9000 years ago in tropical and subtropical regions. Precisely, maize was domesticated from Zea mays ssp. parviglumis  in central Mexico , which encodes a B-type response regulator that activates the florigen in the leaf  – promotes flowering under inductive SDs but delays it under LDs . In non-the leaf . Ghd7 althe leaf . Likewisoduction .Hd3a  and DTA10 loci, two of the most important QTLs controlling flowering time in this cereal crop  and wheat (Triticum aestivum), the founders of agriculture in the old world, derive from wild ancestors grown 10,000 years ago in the middle east  responsible for amino acid changes in conserved domains that impair Ppd-H1 protein function, including the SNP79  differentially express HvFT1 in response to daylength, leading to accelerated flowering under LD but delayed flowering under SD  flower late even when grown under LD, because of reduced expression of CO-like genes and HvFT1  predominates in Southern Europe, characterized by a short growing season; in these regions, cultivars accelerate flower development in spring and seeds reach maturity before terminal drought in summer. By contrast, the non-functional ppd-H1 allele (C- > T SNP48) predominates at Northern latitudes, characterized by a long growing season; in these regions, accessions with prolonged vegetative phase also show increased biomass accumulation and higher grain yield at harvesting. Thus, polymorphisms at Ppd-H1 underly adaptation to different environmental conditions and largely explain latitude-dependent geographical distribution of barley varieties, at least in Europe.In European barley accessions, the frequency of two alleles at SNP48  were identified and Ppd-D1 shown to have the greatest contribution to the regulation of flowering .Ppd-D1 converts a LD plant into a day neutral plant by altering the diurnal expression pattern of Ppd-D1. Under SD, the peak of Ppd-D1 transcription shifts from the light to dark phase, causing induction of the florigen TaFT1 and promotion of flowering regardless of daylength (Ppd-D1 were identified in a panel of 500 common wheat varieties cultivated worldwide (Ppd-D1 expression (under LD) flower earlier than those with lower Ppd-D1 expression. Similar to barley, photoperiod sensitive accessions delay flowering under SD while photoperiod insensitive varieties initiate the reproductive phase regardless of daylength , two FT-like genes have been identified: PtFT1 and PtFT2  resulted in different phenotypes, pointing to a possible sub-functionalization of FT-like genes (FT1 (but not FT2) under SD at low temperature promotes the formation of reproductive structures within 1 month from the heat treatment (FT2 (but not FT1) promotes vegetative growth under LD and inhibits growth cessation under SD. These findings indicate that FT1 activation in winter is required for the onset of reproductive structures whereas FT2 activation in spring promotes vegetative growth  reinforces a diverged regulatory function in annual cycles of vegetative and reproductive growth  and Like AP1 (LAP1) genes also show continuous upregulation during bud development , crown buds  show downregulation of a FT-like gene and induction of DORMANCY ASSOCIATED MADS-BOX (DAM) genes  genes , which sike gene .Picea abies (Norway spruce) uncovered the presence of two genes encoding PEBP proteins that share similarities with the Arabidopsis florigen FT and the anti-florigen TERMINAL FLOWER 1  clinal variation in the photoperiodic control of growth cessation associates with genetic variation in n spruce , 2014.To conclude, FT/TFL1-like proteins might have retained a general function as growth regulators in gymnosperm and acquired a specific function as flowering time regulators in angiosperms. The knowledge about these mechanisms will be very useful in the years to come. With shifting seasons and climate conditions, new breeding programs need to be launched to develop species adapted to changing conditions and to keep up with the increasing demand on forest resources.Solanum tuberosum), the most important non-cereal crop for direct human consumption, and strawberry (Fragaria x ananassa), one of the most widely consumed berry crops in the world. In commercial plant varieties, asexual reproduction through vegetative structures represents an essential propagation strategy that allows producing identical daughter plants that keep the desirable characteristics of the mother plant.In addition to flowering in annual plants and growth habit in perennial plants, photoperiod also controls vegetative propagation in relevant food plants such as potato (Solanum tuberosum) is the fourth most cultivated food plant globally after maize, rice and wheat (FAO 20191). Its domestication from wild Solanum species started 8,000–10,000 years ago in the Andean highlands, an arid region 3,000–4,500 m above sea level characterized by cold temperatures, saline soils, and high solar radiation (Potato (adiation .Solanum tuberosum group Andigena (Solanum tuberosum group Chilotanum diversified from its upland progenitors to adapt to LD conditions (Diploid landraces (2n = 24) underwent autopolyploidization and gave origin to the cultivated tetraploids (2n = 48) belonging to the Andigena . Later, nditions . Togethenditions .tubers, storage organs growing in the soil that also bear vegetative buds for the following season. Potato plants can use asexual reproduction via tuberization as well as sexual reproduction through flowering. Nevertheless, tuber initiation and flower development seem to be antagonistic processes , named after the tomato florigen SELF-PRUNING (homolog of FT).The link between potato tuberization and daylength was described almost a century ago  but the FT-like genes  were identified in the potato genome  whereas the related StSP3D as regulator of flowering . Supportormation .StSP6A silencing lines display decreased tuberization but increased flower bud development when grown under SDs  identified in the potato genome  in its regulatory regions. Upon activation, StSP5G represses tuberization under non-inductive conditions by negatively regulating StSP6A transcription. Thus, the two FT paralogues StSP6A and StSP5G act antagonistically during tuber formation in potato. As supporting evidence, RNAi lines downregulating StSP5G showed StSP6A upregulation in leaves and accelerated tuberization under LD  that encode deleted versions lacking part of the C-terminus  and activating the tuber inducer StSP6A  carried out on a pool of 83 potato cultivars reinforced the correlation between polymorphisms at henotype . Likewisproteins . This diBesides components of the photoperiodic pathway, gibberellins also have a role in the formation of tubers. Treatments with exogenous GA promote stolon elongation but inhibit tuberization . ConversStPHYB or StPHYF caused tuberization in LD in a graft-transmissible manner  or a runner, horizontal elongated stem that grows above the ground . This meIn general, conditions that promote flowering decrease the number of runners, and many strawberry cultivars develop runners under LDs when flowering is not induced .Strawberry varieties can be classified in two groups depending on their photoperiodic behavior: most are seasonal SD-flowering plants that readily produce runners in LDs, while others are ever-flowering plants that develop reproductive structures preferentially under LDs but produce very few runners or are completely runnerless .Given the agronomic relevance of runner formation for asexual reproduction of commercial strawberries , moleculFragaria genus and vary in their ploidy, ranging from diploid to decaploid (Fragaria x ananassa) makes genetic analysis impractical, research has been performed mostly in diploid woodland strawberry (Fragaria vesca).Strawberry species belong to the ecaploid . Since tFvGA20ox4, which is mostly expressed in axillary meristems and developing runners (Suppressor of Runnerless (SRL)  , which wormation . A laterarieties .Runner formation in strawberry also shares crucial components with the photoperiodic pathway that control flowering in Arabidopsis.FvFT1 . Instead, the diversification phase relied on the selection of novel varieties that better adapted to new agroecosystems. Noteworthy, genetic diversity in loci encoding circadian clock proteins largely accounts for phenotypic diversity in plant response to photoperiod, which has contributed to adjust the reproductive phase to different environmental conditions and ultimately has favored the cultivation of cereals outside their area of domestication. In fact, the huge genetic variability underlying photoperiod sensitivity has facilitated the reproductive success of cultivated cereals in tropical, subtropical and temperate regions. As the regulation of the floral transition in cereals has influenced both grain yield and adaptive growth, it can be considered one of the most important agronomic traits to obtain improved varieties adapted to stressful conditions arising from changing climates.In the same manner, selection of allelic variants in the genes responsible for photoperiodic control of potato tuberization has allowed its widespread cultivation at different latitudes and climates, releasing productivity from the constraints of its genetic adaptation to its natural environment. Strawberry is yet another example of a crop in which classical breeding has been based on the alteration of similar GRNs controlling photoperiodic responses, prior to any knowledge of the molecular interactions between its components.FT-like genes.In perennials, changes in photoperiod regulate the critical growth status for tree survival: active growth in warm LDs and growth cessation in cold SDs. The onset of both, to grow and stop growing, is controlled by In other non-woody perennials, FT orthologs also regulate growth and dormancy; as their role in the control of vegetative development may precede their involvement in floral induction, flowering could also be perceived as a growing period.In the face of climate change, it’s extremely important to increase our knowledge on the interaction between the photoperiod pathway and other environmental conditions such as ambient temperature or water availability.FT (It is well established that plants alter their developmental processes to adapt to fluctuating temperatures. For example, hypocotyl elongation and flowering time in Arabidopsis are controlled by the photoperiod but are also greatly influenced by ambient temperatures. Indeed, warmer temperatures promote hypocotyl growth and accelerate flowering. Also, low watering conditions promote precocious flowering, mainly through anticipated activation of the florigen FT .StSP6A in transgenic potato has been used to increase tuber production under drought and heat stress conditions that are known to negatively impact tuber yield and quality (Interestingly, overexpression of the main tuberigen  quality .Altogether, these studies further highlight the connection between photoperiod responses and other environmental factors as well as the potential of components of the photoperiod pathway as targets for genetic improvement in important plant species.All authors contributed to the article and approved the submitted manuscript. PN and UC prepared the table. MO, IC, and UC ideated figures. MO and SP designed the structure of the review.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Reactive oxygen species (ROS) such as hydrogen peroxide and superoxide are produced in plants in response to many biotic and abiotic stressors, and they can enhance stress adaptation in certain circumstances or mediate symptom development in others. The roles of ROS in plant-pathogen interactions have been extensively studied, but far less is known about their involvement in plant-insect interactions. A growing body of evidence, however, indicates that ROS accumulate in response to aphids, an economically damaging group of phloem-feeding insects. This review will cover the current state of knowledge about when, where, and how ROS accumulate in response to aphids, which salivary effectors modify ROS levels in plants, and how microbial associates influence ROS induction by aphids. We will also explore the potential adaptive significance of intra- and extracellular oxidative responses to aphid infestation in compatible and incompatible interactions and highlight knowledge gaps that deserve further exploration. They are generated as a byproduct of aerobic metabolic processes such as photosynthesis, and their accumulation is carefully limited by enzymatic and non-enzymatic antioxidants  is a critical aspect of how plants adapt to environmental and biotic stresses . ROS sucoxidants . Stress oxidants . In addioalexins . All throalexins . On one oalexins . On the oalexins . For exaoalexins , and is oalexins . In addioalexins . Therefooalexins .Alternaria brassicicola, Rhizoctonia solani, and Botrytis cinerea  also perform frequent, damaging intracellular probes (Aphids (Hemiptera:Aphididae) are a large family of sap-feeding herbivorous insects that have many commonalities with plant pathogens . They har probes .Schizaphis graminum) have a more “burnt-earth” approach, causing extensive necrosis and even death of the plant within a relatively short time frame  and the spotted alfalfa aphid (Therioaphis trifolii maculata) can generate H2O2in vitro when provided with catechin as a substrate  damage-associated molecular patterns (DAMPs) that result from cleavage of plant molecules by the invader; (2) widely-conserved molecular patterns that occur in invading organisms but not in plants; or (3) specific effector proteins found in some but not all species and isolates of invader [reviewed in neration . In addiesponses . Thus, t2O2 induction in response to aphid infestation . Pea aphids without S. symbiotica induce ROS, whereas pea aphids with S. symbiotica do not; moreover, silencing ApHRC expression in aphids with S. symbiotica results in ROS induction, and overexpression of ApHRC in plant tissues reverses this effect  plants actively generate ROS in response to aphids; (2) certain aphid effectors trigger the ROS response while other effectors inhibit it; and (3) aphid symbionts can influence ROS induction by producing MAMPs and also by influencing the expression of aphid-encoded effectors.Medicago sativum) challenged with the spotted alfalfa aphid suggested that aphids induce O2– based on the ability of leaf extracts to reduce cytochrome c , as well as in at least four families of angiosperms , perhaps because the relatively long half-life and lower toxicity of this ROS allow higher titers and longer persistence, facilitating detection. Aphid-responsive H2O2 accumulation has been demonstrated in at least 22 plant species in eight plant families, including both monocots and dicots  to species that cause strong phytotoxic effects such galling , leaf rolling (D. noxia), malformation of new growth (Brachycorynella asparagi), discoloration, necrosis, or even in some cases death of the entire plant . Thus, it is clear that aphids can induce O2– and H2O2, and that ROS induction is a widely conserved response in both compatible and incompatible interactions with a diverse array of aphids  abundance in pea plants (1O2) accumulation in Arabidopsis  by the cypress pine aphid (Cinara tujafilina) persisted even at 2 weeks after infestation , and the poplar spiral gall aphid (Pemphigus spyrothecae) that induce marked phytotoxic symptoms (M. sacchari), aphid challenge on resistant plants induced an earlier oxidative response that peaked at 3 days and then declined, whereas H2O2 levels in the susceptible cultivar initially decreased in response to aphids and then increased at 12 days post-infestation, when extensive aphid damage was present , Arabidopsis, and corn (Zea mays), supporting the hypothesis that NADPH oxidases mediate extracellular ROS accumulation in response to aphids   also upregulates expression of a peroxisomal catalase and a chloroplastic SOD, suggesting an impact of aphids on intracellular redox balance  . Althougroplasts . The timroplasts . M. pers balance . Moreovein wheat .2O2 was detected in the cell walls of aphid-infested asparagus  at early time points and low infestation levels, whereas it appeared to have a primarily cytosolic location at later time points and in samples that had higher ROS levels and more extensive symptom development due to the use of higher infestation levels or more susceptible life stages of the host plant  of the interaction that are being sampled. This can limit signal strength, increase random sample-to-sample variation, and make it difficult to pinpoint the timing of transient responses.We propose that a finer-scale kinetic analysis of aphid-responsive ROS accumulation is warranted, especially since the timing and localization of oxidative responses impact their potential contributions to defense. Highly sensitive luminescent probes for ROS detection could potentially be applied to study the spatial and temporal dynamics of the ROS response at individual feeding sites, and could open new avenues of research in host-plant resistance to aphids.2O2 accumulation was observed in resistant but not in tolerant or susceptible genotypes , but a virulent biotype did not, and could reverse prior ROS induction by avirulent aphids  or that colonized it only weakly (Myzus cerasi) induced stronger H2O2 accumulation at 24 h than M. persicae, which is well-adapted to Arabidopsis  on susceptible winter wheat (T. aestivum) revealed earlier, stronger, and more persistent ROS accumulation in response to the phytotoxic species, suggesting a correlation between ROS generation and symptom development  plays a role in plant–aphid interactions . Pea aphradicals . This suradicals . For exa drought . Whereas drought ; for exasylation . In thisIn summary, there is evidence from pea and wheat that NO contributes to plant defenses against aphids, and may interact with ROS to modulate the oxidative response.N. benthamiana  to suppress expression of the ROS elicitor cathepsin B3 increases feeding by a non-host adapted green peach aphid lineage on thamiana . Similarphorbiae . In plance tests . RNAi ofce tests . It is iR. padi, a species that cannot reproduce on Arabidopsis, and these mutations also enhance the population growth of the green peach aphid and a related species (M. cerasi) that normally has limited ability to colonize this plant (B. brassicae)  . In potaassicae) .2O2 accumulation in the host plant and reduces aphid feeding; the effects of CMV on aphid feeding can be eliminated by deleting the viral protein that triggers ROS induction or by suppressing NADPH oxidase activity in the plant  that limits ROS induction; silencing this protein increases ROS induction and decreases aphid feeding  that decreased the sensitivity of Arabidopsis to O2– also decreased plant symptom development after prolonged (14 days), heavy infestations of the green peach aphid  to tobacco, the virus induces Hhe plant . Therefo feeding . Treatin feeding ; this fi feeding , and by ignaling . Loss ofactivity . A mutatch aphid .Together, these reports suggest that while ROS contribute to defense in many plant–aphid interactions, aspects of the oxidative response can also facilitate aphid infestation and/or promote feeding damage in certain compatible interactions.in vivo ROS accumulation, is important to remember that pro- and antioxidants in plants are intertwined in a complex redox signaling system  investigate the adaptive significance of ROS production in the chloroplast and other intracellular sites compared with apoplastic ROS; (2) explore the role of NO in modulating the ROS response; (3) identify the downstream effects of ROS that may mediate resistance or susceptibility, such as the potential impacts of ROS on cell walls, membrane lipids, post-translational protein modification, and global gene expression; and (4) integrate our knowledge of individual pro- and antioxidants in the plant into a more comprehensive systems-view of redox responses to aphid challenge. Research in this area is opening new horizons in agroecology; for example, it is helping to explain how and why components of the microbial community such as aphid symbionts, viruses, and plant rhizobacteria can influence plant susceptibility to aphids . This reFG and HF conceived and wrote this review article. Both authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Acute kidney injury after cardiac surgery is characterized by specific patterns of damage and recovery that are important to consider for management and outcome. The Kidney Disease: Improving Global Outcomes (KDIGO) classification covers only part of the conceptual framework and is thus insufficient for a comprehensive diagnosis. This review highlights the strengths and limitations of the recent criteria and provides an overview of biomarkers of cardiac surgery-associated acute kidney injury (CSA-AKI). The evolving understanding of CSA-AKI as a time-sensitive condition has increased the demand to enhance the diagnostic criteria and translate biomarkers into clinical practice. Acute kidney injury (AKI) is a common but still underrecognized complication, occurring in 10 to 15% of all hospitalized patients and in almost 60% of patients admitted to the intensive care unit . CardiovWhile the term “AKI” summarizes a syndrome of acute organ damage and dysfunction with various pathophysiologies, the subset occurring after cardiac surgery is specifically referred to as cardiac surgery-associated acute kidney injury (CS-AKI). Characterizing the different entities of AKI has become increasingly important, since emerging evidence suggests that each type has unique molecular and diagnostic features and requires differentiation in treatment .The majority of patients undergoing cardiac surgical procedures present with a range of predisposing factors and comorbidities, such as advanced age, insulin-dependent diabetes mellitus, heart failure, and chronic kidney disease. It is widely recognized that these conditions are strongly associated with an unfavorable renal outcome and should therefore be addressed by risk assessments . ClinicaExposure of this at-risk population to the noxious stimuli of cardiopulmonary bypass and ischemia-reperfusion injury following aortic cross-clamp might contribute to the development of CSA-AKI. Hypoxemia and the accumulation of metabolic products cause acidosis and cellular damage. Extracorporeal circulation is associated with significant hemodynamic alterations, renal hypoperfusion, and hemolysis . The infSeveral definitions of the condition formerly known as acute renal failure have limited the comparability of clinical outcome measures and the general provision of consensus recommendations. The first standardized definition of changes in kidney function, the RIFLE  classification, was introduced in 2004 and later advanced by the Acute Kidney Injury Network, resulting in the AKIN criteria in 2007 ,17. FinaNew insights have furthered our understanding of AKI as part of a continuum, ranging from a healthy state to chronic kidney disease. The spectrum of this conceptual framework covers subclinical damage preceding KDIGO stage 1 and embeds AKI persisting beyond 7 days within the category of Acute Kidney Disease and Disorders (AKD). While renal recovery in whole or in part may begin at any point within this timeline, the persistence or progression of disease may occur as well, eventually resulting in chronic kidney disease (CKD) after a duration of 3 months  19,20].,20.19,20This conceptual change increasingly challenges the biomarkers that are used to define AKI, since serum creatinine and urine output are of limited value in predicting recovery or the progression of disease and even less fit for detecting subclinical damage.Traditional renal biomarkers still continue to be the standard of care and remain indispensable for the assessment and monitoring of kidney function. Serum creatinine is ubiquitously accessible and changes are easily recognized and can even be integrated into electronic alerts for automated detection ,22. The P = 0.004). Moreover, 8.1% of patients who presented initially with decreased urine output alone developed chronic kidney disease at day 180, compared to 5.2% of patients without AKI. The authors concluded that a decreased urine output after cardiac surgery is associated with a worse long-term outcome  × [IGFBP7] that is commercially available in several European countries and was approved in 2014 by the Food and Drug Administration in the United States  × [IGFBP7] was also challenged for its variable diagnostic performances. Recently, Grieshaber et al. reported the results from a risk-score-guided observational trial with [TIMP-2] × [IGFBP7] measurements in high-risk patients among a cohort of 613 patients undergoing cardiac surgery. [TIMP-2] × [IGFBP7] was merely predictive of early AKI 24 h after surgery  .p < 0.0001). Additionally, high preoperative levels were associated with significantly reduced long-term kidney function and were reflective of AKI-to-CKD transition  × [IGFBP7]-guided implementation of a simple care bundle consisting of the optimization of volume status and hemodynamics, functional hemodynamic monitoring, the avoidance of nephrotoxic drugs, and the prevention of hyperglycemia effectively reduced the incidence of stage 2 and 3 AKI in comparison to the control group ; = 0.034) . This tr= 0.034) ,61,62. CA consensus statement by the Acute Disease Quality Initiative Consensus Conference on the implementation of biomarkers in clinical routine to prevent, diagnose, and manage AKI proposed an advanced staging system based on biomarkers of function and damage . In thisCardiac surgery-associated AKI features specific patterns of damage and recovery that go unrecognized by recent diagnostic criteria. The role of timing as a crucial factor in the management of CS-AKI demands enhanced criteria reflective of subclinical damage. Biomarkers of CS-AKI provide additional discriminative features and are on the threshold of finding their way into clinical practice.


Autophagy related protein 5 (ATG5) is an important autophagosome formation related protein, and its involvement in the biological process of autophagy has been shown to correlate with tumor metabolic patterns and the formation of tumor heterogeneity. However, the role of ATG5 in tumor metabolism and tumor immunity remains unclear.In order to explore this problem, this study was designed to reveal the role of ATG5 in tumor metabolism and tumor immunity through pan-cancer analysis of multi-database. GTEx database, CCLE database, and TCGA database were used to describe the expression, prognosis, immune microenvironment, immune new antigen, immune checkpoint, TMB, and microsatellite instability of ATG5 in 33 types of tumors. A series of bioinformatics tools and methods were used for quantitative analysis and panoramic description, such as to Estimate, Scanneo and GSEA.The differential analysis results of multiple databases showed that ATG5 was ubiquitously highly expressed in pan-cancer, especially in solid tumors. Survival analysis revealed that ATG5 was universally associated with the prognosis of pan-cancer, and high ATG5 expression was significantly associated with poor patient prognosis in most cases. Further, the expression level of ATG5 was confirmed to be associated with tumor immune infiltration and tumor microenvironment, especially in BRCA, KIRC, and LIHC. In addition to this, ATG5 expression was confirmed to correlate with these clinically significant phenotypes, in conjunction with immune neoantigens and immune checkpoint gene expression profiles in pan-cancer. In addition to TMB and microsatellite instability in pan-cancer, we confirmed that ATG5 expression affects the expression of DNA repair genes and methyltransferases in pan-cancer, and found through gene set enrichment analysis that ATG5 is involved in the regulation of numerous signaling pathways involved in cancer metabolism and cancer immunity.ATG5 participated in the formation of autophagosomal membrane important molecule LC3-II outside, and played an important role in tumor metabolism and tumor immunity. The comprehensive pan-cancer analysis not only revealed the potential of ATG5 in tumor-targeted therapy but also suggested ATG5 as a promising tumor predictive biomarker in most solid tumors. Autophagy related protein 5 (ATG5) is an important autophagosome formation related protein that functions as an E1-like activating enzyme in eukaryotic cells . In addiIn recent years, autophagy has been shown to correlate with tumor metabolic patterns and the formation of tumor heterogeneity . On the Unfortunately, the role of ATG5, as an important autophagy-related molecule, in tumor metabolism versus tumor immunity remains obscure. Therefore, this study plans to reveal it by pan-cancer analysis of the combined multi-database. In recent years, the rise of high-throughput sequencing based cancer atlas initiatives with omics technologies has provided a new perspective in cancer research. The use of transcriptome technology to reveal the role of gene expression in tumor cells has long been appreciated, and emerging deconvolution network algorithms allow tumor investigators to extract the expression profiles of immune cells from transcriptome data and describe their distribution patterns. In addition to this, the vast amount of data generated by the unprecedented bioinformatics revolution can be used to delineate the panoramic landscape covering all known genes and cancer types . This biIn this study, we utilized a pan-cancer analysis to analyze the association of ATG5 expression, prognosis, immune microenvironment, immune neoantigens, immune checkpoints genes, TMB, and microsatellite instability in 33 tumors. Confirmed that ATG5 expression affects the expression of DNA repair genes and methyltransferases in Pan-cancer, and found that ATG5 is involved in the regulation of signaling pathways involved in cancer metabolism and tumor immunity by gene set enrichment analysis.https://gtexportal.org/) and TCGA database . Among them, 31 cancers were included in gene expression analysis with GTEx and 27 cancers were included in TCGA integrated analysis with GTEx. The expression data of each tumor cell line were downloaded from the CCLE database . The pan-cancer immune infiltrating cell score data were downloaded from the timer database (https://cistrome.shinyapps.io/timer/). Tumor name abbreviations and corresponding meanings are given below: ACC; BLCA; BRCA(Breast invasive carcinoma); CESC; CHOL(Cholangiocarcinoma); COAD(Colon adenocarcinoma); COAD (Colon adenocarcinoma); READ ; DLBC(Lymphoid Neoplasm Diffuse Large B-cell Lymphoma); ESCA; GBM(Glioblastoma multiforme); HNSC(Head and Neck squamous cell carcinoma); KICH(Kidney Chromophobe); KIRC; KIRP; LAML(Acute Myeloid Leukemia); LGG(Brain Lower Grade Glioma); LIHC(Liver hepatocellular carcinoma); LUAD(Lung adenocarcinoma); LUSC(Lung squamous cell carcinoma); MESO(Mesothelioma); OV(Ovarian serous cystadenocarcinoma); PAAD(Pancreatic adenocarcinoma); PCPG(Pheochromocytoma and Paraganglioma); PRAD(Prostate adenocarcinoma); READ(Rectum adenocarcinoma); SARC(Sarcoma); SKCM(Skin Cutaneous Melanoma); STAD(Stomach adenocarcinoma); STES; TGCT(Testicular Germ Cell Tumors); THCA(Thyroid carcinoma); THYM(Thymoma); UCEC; UVM.The gene expression matrix and clinical information data in each tumor and normal were obtained from the GTEx database , as a quantifiable biomarker, can be used to reflect the number of mutations contained in a tumor cell. The TMB of each tumor sample was counted separately using Spearman’s rank correlation coefficient. Microsatellite instability (MSI) refers to the occurrence of a new microsatellite allele phenomenon when compared with normal tissue, in a tumor, any alteration in the length of a microsatellite caused by an insertion or deletion of a repeat unit. Correlation of ATG5 expression with MSI was analyzed using Spearman’s rank correlation coefficient.Mismatch repair is an intracellular mismatch repair mechanism, and loss of function of key genes of this mechanism results in DNA replication errors that cannot be repaired, which in turn leads to the generation of higher levels of somatic mutations. The correlation of five MMRs genes  with ATG5 expression was assessed using the expression profile data from TCGA. DNA methylation is a form of chemical modification of DNA capable of altering epigenetic inheritance and controlling gene expression without altering the DNA sequence. Here we analyzed the correlation between ATG5 expression and the expression of four methyltransferases. Visualization analysis was done by ggplot. Correlations were considered significant and positive when p<0.05 and R>0.20.Gene set enrichment analysis (GSEA) is an analytical method that compares genes with predefined gene sets to explore their expression status within a specific functional gene set and whether such expression status is associated with a biological process, molecular function, or cellular component in some way statistically significant . Kyoto EAs shown in The association of ATG5 expression with overall survival was first calculated for 33 tumors in TCGA using univariate survival analysis. As shown in + T cells  and neutrophils  in BRCA, and B cells , CD8+ T cells , neutrophils  and dendritic cells  in KIRC. As shown in + T cells , CD8+ T cells , neutrophils , macrophages , and dendritic cells . In addition, to explore the roles that the ATG5 influenced tumor immune microenvironment has during tumor development, we analyzed the immune score and stromal score of individual tumor samples using the R package Estimate, as shown in Tumor infiltrating lymphocytes are independent predictors of sentinel lymph node status and survival in cancer, and immune infiltration analysis confirmed that ATG5 expression correlates with the level of immune infiltration in different types of cancer, especially in BRCA, KIRC, and LIHC. As shown in As shown in TMB, usually measured as the number of somatic mutations occurring at an average of 1M bases in the coding regions of the tumor cell genome, is sometimes directly represented by the total number of nonsynonymous mutations, and the mutation types mainly include various forms of mutations such as single nucleotide variations (SNVs) and small insertions/deletions (Indels). TMB was used to reflect the number of mutations contained in tumor cells, is a quantifiable biomarker. As shown in As shown in To observe the effect of gene expression on tumors, we divided the human pan-cancer samples into two groups with high and low expression according to the expression levels of ATG5 and analyzed the enrichment of signaling pathways in KEGG and hallmark in high and low expression groups by GSEA, as shown in As a fundamental biological process of energy metabolism and material recycling, the role, process, and function of autophagy in the heterogeneous metabolic pattern of tumors have long been widely concerned. Cellular autophagy itself can be hijacked by tumor cells for the synthesis of biomacromolecules required for tumor cell proliferation . The metIn addition, our single gene set enrichment analysis performed in the pan-cancer analysis of ATG5 using high and low ATG5 expression as a signature of sample subgroups showed that ATG5 can participate in a wide range of metabolic pathways and biosynthesis, including glycolysis, PI3K-Akt-mTOR signaling, mTORC1 signaling, p53 signaling, pyrimidine metabolism, TGF-β signaling, IL2-STAT5 signaling, and oxidative phosphorylation. And the highest enrichment scores of these signaling pathways all fell in the high expression area of ATG5. This suggests that high ATG5 expression is involved in the positive regulation of these signaling pathways, and ATG5 may play a pathological role in promoting aerobic glycolysis, maintaining tumor cell viability, and promoting tumor cell proliferation by driving the upregulation of these metabolic pathways and signal transduction pathways.+ T cells, this work observed changes in other immune cells such as MDSCs, CD4+ T cells, and CD103+ DCS upon autophagy inhibition, which also explains the results exhibited by our correlation analysis between ATG5 and tumor immune infiltration, suggesting that autophagy-mediated immune escape from tumors may be ubiquitously through signaling pathways in different tumor immune cells.If the results presented above justify the idea that autophagy determines the metabolism of tumor heterogeneity, then the latest report by Yamamoto et al. , showed Naturally, blocking the autophagy pathway can be considered as a core strategy in tumor-targeted therapy. Indeed, a series of clinical studies based on the therapeutic application of the autophagy inhibitor chloroquine in tumors have been initiated and it was demonstrated that in some kinds of tumors, inhibition of autophagy contributes to the survival of tumor patients , 25. HowATG5, as an autophagy gene, played an important role in the process of autophagosome formation and autophagic flux and regulated multiple biological behaviors of tumors –8. The AThe original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding authors.CXX and YSZ have contributed equally to this work. MX, YCZ, and YXZ conceptualized and designed the study. YXZ, WQC, and HZ performed the bioinformatics analysis. CXX and YXZ wrote the first draft of the manuscript. All authors wrote sections of the manuscript. All authors contributed to the article and approved the submitted version.YXZ was employed by Biotrans Technology Co., LTD.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The sequencing identified multiple biological processes, such as cilium morphogenesis and cell signaling, that were significantly changed between IPF and healthy ciliated cells. Ferritin light chain (FTL) was downregulated in IPF, which suggests that iron metabolism may be affected in the IPF ciliated cells. The RNA expression was confirmed at the protein level with histological localization in lung tissue, prompting future functional assays to reveal the potential role of FTL. Taken together, our data demonstrate the importance of careful analyses in pure cell populations to better understand the IPF disease mechanism.Cell-based therapies hold great promise in re-establishing organ function for many diseases, including untreatable lung diseases such as idiopathic pulmonary fibrosis (IPF). However, many hurdles still remain, in part due to our lack of knowledge about the disease-driving mechanisms that may affect the cellular niche and thereby possibly hinder the function of any transplanted cells by imposing the disease phenotype onto the newly generated progeny. Recent findings have demonstrated increased ciliation of lung cells from IPF patients, but how this affects ciliated cell function and the airway milieu is not well-known. Here, we performed single-cell RNA sequencing on primary ciliated (FOXJ1 Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease with severe symptoms and a low survival rate with a median survival after diagnosis of 2–3 years . IPF is IPF has previously been reported to primarily affect lung tissue between alveoli, with changes in the extracellular matrix and fibrosis . HoweverThe majority of the nonalveolar airway epithelium consists of ciliated cells, which function as the first line of defense against inhaled pathogens . In addiThus, this study aims to investigate the potential role of ciliated epithelial cells in IPF in order to understand disease-related changes and potentially illuminate new cell-based approaches to treat IPF.Human lung tissue  was obtained from Lund University Hospital and Sahlgrenska University Hospital. All donors gave informed consent, and ethical approval for the study was obtained from the Swedish Ethical Review Authority . For patient information, see Single-cell suspensions were prepared from distal lung tissue pieces and were dissociated according to previously established protocol . Single-Cells were thawed and resuspended in staining buffer (PBS with 2%FBS) and incubated with fluorescent antibodies see  and analSingle-cell RNA sequencing was performed using the 10x genomics system, and the data were processed as reported previously . All dat+) and FTL+cells in a number of randomly chosen nonbronchial airways from healthy and IPF patient tissue sections . The FTL expression was calculated as the percentage of FOXJ1+ cells that expressed FTL.Immunohistochemistry was performed on formalin-fixed, paraffin-embedded distal lung tissue sections (4 µm thick). After rehydration with xylene and ethanol according to standard procedure, HIER with pH 6.1 was used with DAKO PT link . Immunofluorescent staining was performed as reported previously . For ant+ cells and basally with KRT5+ cells from healthy and IPF samples can be seen in +, red) and ciliated cells  in a pseudostratified layer. Similar epithelial layers were identified in the IPF samples, together with typical pathological features of IPF such as honeycomb cysts. These were lined with epithelial cells positively stained for FOXJ1 and KRT5  as well as FOXJ1 (ciliated cells). Representative images of the airway epithelium lined apically with FOXJ1and KRT5 G–I. Thisand KRT5 K–N. The In order to investigate the potential role of ciliated airway cells in IPF pathogenesis, we obtained lung tissue from two IPF patients as well as four healthy controls. To enrich ciliated cells, we sorted all 7AAD-CD45-CD31-cells using flow cytometry after tissue dissociation A. Figure+); however, sample identity indicates that the ciliated cells in cluster 2 were all from IPF patients, while clusters 1 and 5 contained healthy ciliated cells, demonstrating that ciliated cells in IPF differed in gene expression from their healthy counterparts. This can also be seen in The initial cluster analysis revealed that the majority of the primary IPF cells clustered separately from the primary healthy epithelial cells, demonstrating a difference in gene expression between the healthy and diseased samples C. Overalp-value followed by the highest fold change in gene expression. Next, we identified the top differentially expressed genes in the IPF ciliated cell cluster in comparison to the clusters of healthy ciliated cells. The most differentially expressed genes of interest were selected by sorting the genes expressed in clusters 1 and 5  and cluster 2 (IPF ciliated cells) by the lowest Next, we performed gene ontology analysis of all the differentially expressed genes in IPF ciliated cells versus healthy control ciliated cells. + ciliated cells  was 20.54 ± 2.980% .In order to assess the level of FTL protein expression in ciliated cells specifically, we next used Qupath to quantify FTL in multiple ciliated airways and patients U, demonsPreviously, single-cell RNA sequencing studies have been performed on IPF tissue, where disease-specific changes in gene expression were observed in alveolar and basal cells ,24. HoweThe gene ontology analysis suggested pathways connected to cilium formation and movement were upregulated in IPF ciliated cells, indicating an active role of ciliated cells in the diseased tissue, which was of interest for further study. This is in line with previous findings demonstrating an upregulation of cilia in all IPF airway cells .In examining the genes with the highest fold change in expression between ciliated cells from healthy and IPF tissue, IPF ciliated cells were found to highly express FTO and NEAT1, both markers implicated in lung cancer development. In addition, SYT8 was highly expressed in IPF ciliated cells, suggesting an active formation of extracellular vesicles that may propagate the disease by influencing the cellular microenvironment.FTL was among the top upregulated genes by healthy cells (and therefore comparatively downregulated in IPF). In line with this finding, FTL protein expression was found in a lower percentage of airway ciliated cells in IPF tissue sections compared to healthy airways, verifying the sequencing data. Iron is stored intracellularly and metabolized by ferritin, a protein consisting of the ferritin light chain (FTL) and the ferritin heavy chain (FTH1) . FTL is Thus, further elucidating the role of iron in chronic and interstitial lung diseases such as IPF is important and of interest in this study. A possible effect of the lower levels of FTL expressed by the IPF ciliated cells may be that free iron is not stored and protected from oxidation inside the cells and instead accumulates in the airways, which can influence the environment and be damaging to the epithelium. Furthermore, the lack of FTL-mediated storage of iron in the cells may inhibit regular metabolic processes. Therefore, future studies should investigate the importance of ferritin levels in IPF in order to address the possibility of targeting this as a treatment or amelioration of the disease symptoms. For this, it would be advantageous to include more cases to strengthen the results, and especially to include more functional assays. Additionally, it would be of interest to examine other chronic fibrotic lung diseases, e.g., fibrotic hypersensitivity pneumonitis, in which honeycombing may exist and bronchiolization is more common than in IPF.Still, these findings may have implications on future cell-based therapies attempting to regenerate damaged lung tissue in an otherwise unchanged disease microenvironment. Even though new airway stem cells  could be transplanted, the differentiated progeny may still become affected by factors such as extracellular iron levels and ciliated cell-mediated signaling, possibly reversing any therapeutic effects and maintaining the disease phenotype. For example, if the reduced levels of FTL still persist after successful transplantation of healthy stem cells, ciliated cells lacking FTL could potentially go through an epithelial–mesenchymal transition  and add In conclusion, this study showed a differential gene expression between ciliated cells from healthy and IPF distal lung tissue, which is also reflected at the protein level. Ciliated cells make up a large portion of airways and have important tasks in normal lung function, such as protection from pathogens and mediation of cell signaling. Therefore, it is important to further examine these findings in order to understand the possible effects of these aberrant ciliated cells and what genes or pathways may contribute to IPF pathogenesis. FTL was shown to be under-expressed in ciliated cells from IPF tissue, which suggests that a disease-related association with iron storage may contribute to a decline in lung function and possibly constitutes a target for development of future IPF therapies.


Muscle is one of the main targets for the biological effects of vitamin D. This hormone modulates several functions of skeletal muscles, from development to tissue repair after injury, through genomic and non-genomic mechanisms. Vitamin D deficiency and supplementation seem to significantly affect muscle strength in different populations, including athletes, although optimal serum 25(OH)D3 level for sport performance has not been defined so far. Additionally, vitamin D deficiency results in myopathy characterized by fast-twitch fiber atrophy, fatty infiltration, and fibrosis. However, less is known about regenerative effects of vitamin D supplementation after sport-related muscle injuries. Vitamin D receptor (VDR) is particularly expressed in the embryonic mesoderm during intrauterine life and in satellite cells at all stages of life for recovery of the skeletal muscle after injury. Vitamin D supplementation enhances muscle differentiation, growth, and regeneration by increasing the expression of myogenic factors in satellite cells. The objective of this narrative review is to describe the role of vitamin D in sport-related muscle injury and tissue regeneration. Since its identification as an effective cure for nutritional rickets, much of the scientific research on the biology of vitamin D is directed at its role in controlling the homeostatic mechanisms of calcium. The discovery that the vitamin D receptor (VDR) is widely expressed in many tissues has prompted a series of studies aimed at understanding its roles in physiological responses unrelated to calcium homeostasis. In the last few decades, huge attention was paid to the biological functions of this secosteroid on skeletal muscle physiopathology, from contraction to tissue regeneration after immobilization or injury ,2. The pVitamin D deficiency was also observed among athletes, not only in those practicing indoor activities  , but alsIn this context, a key issue is the definition of both vitamin D status D3.) and optimal levels, particularly among the athletes.In the general population, concentrations of >30 ng/mL are considered acceptable in terms of benefits on bone health. On the other hand, the specific threshold for reaching optimal sport performance is not established in athletes ; althougHistorically, it was well known that vitamin D deficiency is characterized by myopathy  with muscle fiber atrophy accompanied by fatty infiltration and fibrosis, particularly affecting fast-twitch muscle fibers , with consequent slow peak muscle contraction . MoreoveAlthough evidence suggests multiple benefits of vitamin D supplementation for skeletal muscle to improve athletic performance , less isThe striated muscle represents about 40% of the total body mass and is critical for the posture and global and selective body movements . Muscle Vitamin D receptor is localized both in the cytoplasm and in the nucleus of muscle fibers, to mediate non-genomic and genomic actions ,36. MoreIn addition to modulating calcium absorption, vitamin D participates in the metabolism of phosphate for cellular energy needs . ThroughThe role of vitamin D in muscle development is clearly suggested by the early presence of VDR in the embryonic mesoderm and in muscle precursor cells  at all stages of life . It is eEven negligible muscle injuries, such as acute microinjury during resistance training, increase VDR and CYP27B1 suggesting the enhanced sensitivity of injured and healing muscle to vitamin D . MorpholVitamin D modulates muscle repair by regulating satellite cell proliferation and differentiation as well as mitochondrial density and function . VDR andTraditionally, the role of vitamin D in calcium metabolism was widely investigated, whereas the effect of this hormone on phosphorus metabolism was not addressed so extensively and dates back mainly to the 1970s and 1980s, although the effects of vitamin D on skeletal muscle were attributed to the modulation of phosphate metabolism ,65. PhosVitamin D supplementation also mitigates the effects of muscle damage secondary to high intensity exercise as demonstrated in both animal and human studies  ,70. DuriIn Even in humans, vitamin D status significantly affects muscle repair after injury. It was documented that the serum levels of 25(OH)D3 before exercise are inversely related to post-exercise muscle weakness in a healthy adult male population . InterveAnother issue to be clarified is the effect of initiation timing of vitamin D treatment after injury, as suggested by experimental data. Subcutaneous administration of cholecalciferol to male Wistar rats soon after crush injury resulted in enhanced proliferation of immune cells, such as macrophages, as well as satellite cells, along with a reduction of cell apoptosis that preserved muscle structure . HoweverThe serum 25(OH)D3 is a key issue to be considered in the context of vitamin D treatment. Young males with vitamin D deficiency undergoing exercise-induced muscle injury received cholecalciferol (4000 IU daily for 6 weeks) showed significant recovery of peak torque at 2- and 7-days post exercise . MoreoveVitamin D has documented effects on muscle regeneration through mechanisms and biological pathways that mainly depend on the interaction with the pool of satellite cells within muscle and that are particularly active during recovery from a traumatic event to enhance the structural and functional restoration of the muscle. However, the number of studies addressing the role of vitamin D on muscle repair in athletes is relatively small and well-designed randomized controlled trials are lacking. Therefore, future research should be directed to improve knowledge about the clinical benefits of vitamin D supplementation in sport-related muscle injury.