Heat stress is a major threat to cattle reproduction today. It has been shown that the effect of high temperature not only has a negative effect on the hormonal balance, but also directly affects the quality of oocytes, disrupting the function of mitochondria, fragmenting their DNA and changing their maternal transcription. Studies suggest that the induction of HSP70 may reduce the apoptosis of granular layer cells caused by heat stress. It has been shown that the changes at the transcriptome level caused by heat stress are consistent with 46.4% of blastocyst development disorders. Cows from calves exposed to thermal stress in utero have a lower milk yield in their lifetime, exhibit immunological disorders, have a lower birth weight and display a shorter lifespan related to the expedited aging. In order to protect cow reproduction, the effects of heat stress at the intracellular and molecular levels should be tracked step by step, and the impacts of the dysregulation of thermal homeostasis  should be taken into account. As homeothermic animals, cattle maintain a relatively constant body temperature; however, this can change depending on the temperature and humidity of the environment . Global The place that regulates and integrates the activity of these two systems is the hypothalamus, which, receiving signals from the external or internal environment, generates the appropriate response of the body. As a result of the activation of the SAM system, there is a greater secretion of catecholamines into the bloodstream and an increased concentration of adrenaline (A) and noradrenaline (NA), which—through adrenergic receptors—affect the functions of internal organs. This system is activated in the first moments of exposure to stress, and its purpose is to immediately cope with the stressful situation . The HPAIncreased plasma insulin levels have been observed in dairy cows during heat stress. This hormone is very important in the lipogenesis of adipose tissue. The observed reduced lipolysis under conditions of heat stress is probably a mechanism tending to reduce thermogenesis when exposed to thermal stress. In cows exposed to heat stress, there is also a decrease in blood plasma glucose concentration, as a result of which cows’ milk from cows exposed to heat stress contains less lactose .Inappropriate cooling systems cause an increase in cows’ internal temperature during summer, leading to—among others—reduced fertility . Heat stThermal stress has a particularly negative effect on lactating dairy cows . AnotherTherefore, we aim to provide a better understanding of the mechanisms related to heat stress on bovine oocytes and early embryo development at the level of cellular changes, including transcriptomic and epigenomic changes, which hopefully, will help to develop effective strategies to support cow fertility.Although the period of oocyte maturation is relatively short compared to the entire life span of cows, exposure to HS during this period disrupts oocyte physiology, which has a negative impact on continued fertility . It is wThe production of heat shock proteins (HSPs), as a consequence of exposing oocytes to HS, is a favorable phenomenon for oocytes during the process of cryopreservation . FurtherHeat stress has a negative effect on the oogenesis process, which impairs the reproductive capacity of cows. During the growth of ovarian follicles, the development potential of oocytes is shaped gradually. Disruption of this process caused by heat stress may lead to disorders of oocyte competence. The exposure of cattle to heat stress conditions leads to hormonal changes in their body and directly affects the structure of oocytes, thus, changing their function and reducing their quality. To keep the effects of HS on follicular physiology and subsequent fertility under control, it is important to carefully control cow reproduction, which should be taken into account to evaluate cow estrus and embryo distribution during hot periods .Granulosa cells support the development of oocytes and provide an adequate microenvironment for maturation. Abnormalities in the functioning of granulosa cells may negatively affect the developmental competence of oocytes, and disrupt embryonic development and the establishment of pregnancy . It has It is worth noting that the expansion of cumulus cells appears to be disturbed upon HS . The expMatrix Metalloproteinase-9 (MMP9) transcript levels of CCs. In this regard, it is worth mentioning that appropriate levels of MMP9 are associated with oocyte developmental competence, high pregnancy rates and effective embryonic implantation [Nitric Oxide Synthase 2 (NOS2) transcripts in CCs exposed to high temperatures [Matrix Metallopeptidase-2 (MMP2) [superoxide dismutase 2 (SOD) and catalase (CAT) may regulate forkhead box O3 (FOXO3) and kelch-like ECH-associated protein 1 (KEAP1) in granulosa cells, thereby inhibiting ROS synthesis [Previous research has provided strong evidence that these key genes, which are involved in the response to HS, are activated . It has antation . There weratures . However2 (MMP2) . Heat stynthesis . As a reynthesis . Studiesynthesis . Howeverynthesis . Overallynthesis .Deterioration of the quality of the granular cell layer as a result of heat stress may indirectly affect the development of the ovarian follicle and disrupt the proper course of the fertilization process and further pregnancy.During the first stages of bovine embryo cleavage (before the 8–16 cell stage), the genome is not yet active and the embryo is sensitive to many stressors, including high temperature . Bovine HSP family B member 11 (HSPB11) and HSP family A (Hsp70) member 1A (HSPA1A) was enhanced, in order to protect against the negative effects of high temperature, including the stabilization of ribosomal RNA [HSP genes [As embryonic development progresses, embryos become more resistant to high temperatures. Reduced development was observed when embryos were exposed to a temperature of 41 °C on day 0 and day 2 of development, whereas there were no detectable effects when exposure occurred on days 4 and 6 . When boomal RNA ,52. HS aomal RNA . It has omal RNA . The earomal RNA . Scientiomal RNA . ThermotSP genes .Axis Inhibition Protein 1 (AXIN1) and Lymphoid Enhancer-Binding Factor 1 (LEF1) expression, and a decrease in Cullin-1 (CUL 1) and the gene-encoding PP2A (PPP2A) [methylated paternal H19 and Insulin-Like Growth Factor 2 Receptor (IGF-2R) genes [HSP70, which is considered a candidate heat stress biomarker [Hsp70 Member 1A (HSPA1A), Heat Shock Protein beta-1 (HSPB1), and the synthesis of HSP70, when exposed to HS [The effect of high temperature on early embryos leads to many cytoplasmic changes, including the reorganization of the cytoskeleton, precipitation of chromatin, migration of organelles to the center of blastomeres, and mitochondrial edema, which has a negative impact on the further separation of chromosomes and the proper development of embryos ,53. Mate (PPP2A) . DNA fra (PPP2A) . Previou (PPP2A) . Mouse eR) genes . Heat sted to HS .Heat stress has negative effects on pregnant cows and may in utero affect fetal development . EspeciaNewborn calves from heat-stressed cows have a higher rectal temperature compared to calves from mothers that were kept in a cooler environment in the last stages of pregnancy . UnderstThe proper functioning of the mammary gland during the dry period and lactation is crucial for maintaining high milk yield and milk quality . In lactHigh air temperature leads to an increase in udder temperature, which results in a reduced expression of genes involved in the construction or biosynthesis of epithelial cells and an increased expression of genes responsible for protein repair . ExposurHSP70 mRNA expression is induced in the epithelial cells of the mammary gland to protect against protein aggregation and degradation [It has been shown that, as a result of heat stress, radation ,66. A chradation . Heat stradation . During radation . ExposurAs mentioned earlier, heat stress leads to a decrease in milk yield. Reduced milk yield can result from various mechanisms such as reduced feed intake and a disturbing number and secretory activity of mammary cells ,65. In aTrying to prevent heat stress in dairy cows has become one of the most important paths to improving the quality of oocytes, embryos, and thus, the quality of female reproduction . A few iAbbreviations: ACTH—adrenocorticotropic hormone; CRH—corticotropin-releasing hormone; GnRH–gonadotropin-releasing hormone; HSP–heat shock protein; IGF—insulin-like growth factor; IL-interleukin.Heat stress has a negative effect on most reproductive functions of cows. The exposure of cattle to high temperatures leads to overheating of the reproductive organs, disrupting the process of oogenesis and embryogenesis. In addition, heat stress leads to hormonal changes, reducing estrus symptoms. The effects of heat stress on the body of cows are probably the result of the animals’ attempts to adapt to heat conditions by trying to minimize endogenous heat production. Such a situation leads to disturbances in the energy metabolism in oocytes and embryos, which fundamentally impacts their developmental competence. Finally, precisely recognizing the biological factors responsible for the heat stress-mediated induction of impairments in reproductive physiology and endocrinology in cattle and other mammalian species might enable the multifaceted estimation of genomic, epigenomic, transcriptomic and proteomic profiles in the embryos, fetuses and offspring created and multiplied by such novel assisted reproductive technologies and in vitro embryo production strategies as the ex vivo fertilization of oocytes, with the aid of either classic penetration by capacitated spermatozoa ,92 or in


Within the central nervous system, ependymal cells form critical components of the blood-cerebrospinal fluid barrier and the cerebrospinal fluid-brain barrier. These barriers provide biochemical, immunological and physical protection against the entry of molecules and foreign substances into the cerebrospinal fluid while also regulating cerebrospinal fluid dynamics, such as the composition, flow and removal of waste from the cerebrospinal fluid. Previous research has demonstrated that several neurodegenerative diseases, such as Alzheimer’s disease and multiple sclerosis, display irregularities in ependymal cell function, morphology, gene expression and metabolism. Despite playing key roles in maintaining overall brain health, ependymal barriers are largely overlooked and understudied in the context of disease, thus limiting the development of novel diagnostic and treatment options. Therefore, this review explores the anatomical properties, functions and structures that define ependymal cells in the healthy brain, as well as the ways in which ependymal cell dysregulation manifests across several neurodegenerative diseases. Specifically, we will address potential mechanisms, causes and consequences of ependymal cell dysfunction and describe how compromising the integrity of ependymal barriers may initiate, contribute to, or drive widespread neurodegeneration in the brain. et al. report that compromised ependymal barriers in the central nervous system, namely the cerebrospinal fluid-brain barrier and the blood-cerebrospinal fluid barrier, may contribute to the initiation and progression of several neurodegenerative diseases. Evidence suggests that disrupted ependymal barriers dysregulates cerebrospinal fluid homeostasis, alters gene expression, impairs cilia function and modifies ependymal metabolic functions.Nelles   In the same way that disruption to the blood–brain barrier may cause neurodegeneration, disruption to ependymal barriers may also contribute to aspects of neurodegeneration.19 In this review, we examine potential mechanisms of ependymal cell dysfunction, causes of impaired barrier function and the relationship between ependymal cell dysregulation and the pathogenesis of neurodegenerative diseases. Consequently, these findings will help to establish the role of ependymal cells in neurodegeneration and may encourage the development of targeted treatments and novel diagnostic methods that utilize important biomarkers of ependymal cell dysfunction.The localization and function of ependymal cells within the CNS ventricular system makes them important cellular barriers that regulate the transport and exchange of molecules between the brain and the body.20 The polarized structure and organization of the ependymal cell lining enables the uptake, exchange and removal of biomolecules, signalling factors, ions, metabolites and immune cells between the parenchymal interstitial fluid and the CSF.21 Despite only being a partial barrier due to the lack of tight junctions between individual ependymal cells, the CSF-brain barrier maintains and regulates the composition of the CSF.22 Ependymal cells also form components of the blood-CSF barrier, where specialized subtypes of ciliated ependymal cells make up the epithelial layer of the choroid plexus and form an interface between the CSF-filled ventricles and the blood.23 Since the endothelium of the choroid plexus is fenestrated, the ependymal cells are linked together by tight junctions in order to precisely control the influx and efflux of molecules between the CSF and circulating blood.12 As a complete barrier, the ependymal cells of the blood-CSF barrier provide physical, biochemical and immunological protection to the brain in order to maintain the integrity of CSF dynamics.24 Disruption to the blood-CSF barrier may compromise the flow and composition of the CSF, as has been observed in several neuropathologies, such as Alzheimer’s disease and hydrocephalus.25 The proper function of both the CSF-brain barrier and the blood-CSF barrier is essential in preserving homeostasis in the brain,25 such that damage or disruption to the ependymal cells that form these barriers may initiate, contribute to, or drive neurodegenerative disease.Ependymal cells form the CSF-brain barrier, which is a cellular barrier mediating the bidirectional flow of substances at the interface between the CSF and cerebral or spinal tissue.26 There are three main factors that contribute to CSF equilibrium: the amount of CSF that is produced, that is in circulation, and that can be absorbed at any given time.27 The CSF is composed of nutrients, biomolecules, ions, neurotransmitters and endocrine factors, where harmful metabolites, toxins and waste are continually removed from the CSF.27 The multiciliated E1 ependymal cells play an important role in regulating the unidirectional flow of CSF via a synchronized cilia beating pattern found on the apical surface facing the ventricular cavities.28 The beating pattern of cilia also assists in the distribution of neuroactive hormones and neurotransmitters throughout the CNS.29 Not only does ependymal cilium prevent the pooling and accumulation of CSF within the ventricular system, but it provides a large surface area where the CSF can sufficiently interact with the apical surface of the ependymal cell lining in order to facilitate the transport of molecules at the CSF-brain interface.30 The steady and continuous flow of CSF enables nutrients, essential biomolecules and signalling factors to be delivered throughout the CNS and for ion homeostasis to be maintained.31 In addition, a constant flow of CSF facilitates the turnover, detoxification and removal of metabolic waste and toxins that are normally produced by the brain, such as amyloid-beta monomers.31 The glymphatic system further contributes to waste removal in the brain, such that metabolic waste and excess fluid is actively removed from the interstitial fluid.33 The glymphatic system also propels the flow of CSF within the periarterial spaces, thus enabling the contents of the CSF and parenchymal interstitial fluid to be continually exchanged and for waste to be eliminated prior to perivenous drainage.33 Since the glymphatic system and the ependymal-mediated CSF circuit are closely intertwined,33 ependymal cells may play a multifaceted role in cleansing the CSF, though this has not yet been examined. Consequently, the dysfunction of ependymal cilia may impair CSF flow and alter CSF composition, both of which have been linked to several neurodegenerative diseases, such as Alzheimer’s disease and Huntington’s disease.34 Since ependymal cells play a major role in maintaining CSF homeostasis, it is likely that ependymal cell dysfunction may underlie aspects of neurodegeneration.The CSF is produced from specialized populations of ependymal cells within the choroid plexus that form the blood-CSF barrier.36 Ependymal cells are typically formed between embryonic Day 16 and 18, with the ependymal cell lining fully complete between 26 and 28 weeks gestation and fully differentiated by the first postnatal week.4 The immature embryonic ependymal cells synthesize and secrete a plethora of neurodevelopmental factors and morphogens to support neurogenesis, differentiation, axonal pathfinding and guidance, and NSC self-renewal.38 Specifically, these secretions include epidermal growth factor, fibroblast growth factor 2, noggin, Notch-1, bone morphogenic protein, ephrins and pigment epithelium-derived factor.39–41 During development, ependymal cells and NSCs reorganize themselves along the ventricular walls into pinwheel structures called rosettes, such that the ependymal cells form an outer shell around the NSCs.6 During maturation, ependymal cells develop defining structures, such as cilia and adhesion molecules, which enables ependymal cells to function as independent units as well as collectively with neighbouring ependymal cells to form the ependymal cell barrier.6 The cilia of embryonic ependymal cells are particularly important in propelling embryonic CSF throughout the developing ventricular system and generating a morphogen gradient that drives neuroblast migration.37 Expression of the genes FOXJ1 and SIX3 is essential in promoting ependymal ciliogenesis and postnatal maturation.43Radial glial stem cells, which are derived from the neuroepithelium, give rise to several types of glial cells and neurons, including ependymal cells and a population of neural stem cells (NSCs), both of which form the neurogenic niche within the ventricular-subventricular zone (V-SVZ).38 Other components of the V-SVZ include neuroblasts, astrocyte-like NSCs and blood vessels.44 Although ependymal cells are associated with the stem cell niche, it remains unclear if ependymal cells possess stem cell-like properties.45 While some evidence supports the idea that ependymal cells behave as NSCs,46 other studies suggest that ependymal cells lose their stem cell-like features upon maturation1 and are not involved in adult neurogenesis.47 Recent single-cell RNA-sequencing data further supports the claim that ependymal cells do not possess the same stem cell-like properties that are unique to NSCs.48 However, it is important to note that ependymal cells regulate NSC activity through paracrine signalling pathways, such as through the expression of noggin.40 The same mechanism that enables ependymal cilia to direct CSF flow likely also drives neurogenesis within the adult,49 where the synchronized cilia beating pattern promotes neuroblast migration towards the olfactory bulb.37 In contrast to the V-SVZ, the spinal ependymal layer within the central canal has been identified as an endogenous NSC layer due to its regenerative ability in response to mechanical injury of the spinal cord.50 Consequently, the role of ependymal cells in adult neurogenesis is vague and requires further research in order to determine if ependymal cell recovery or replenishment can be achieved in the brain following injury or dysfunction.In the adult, a subset of ependymal cells is found within the V-SVZ, which is a pluripotent stem cell niche within the lateral ventricles that is responsible for neurogenesis and self-renewal of NSCs in the fully developed brain.51 Cilia can be further classified based on their structure and function as either primary or motile cilia.52 Primary cilia are immotile projections from the cell surface and function in sensory perception of the extracellular environment and signal transduction.52 Rather, motile cilia coordinate a synchronized beating pattern in order to regulate CSF circulation, consisting of a complex cytoskeleton made up of axonemes and a ciliary membrane.27 Primary cilia is typically organized in the ‘9 + 0’ axoneme configuration, whereas motile cilia are generally found in the ‘9 + 2’ axoneme configuration.9 Thus, cilia morphology and function are used to categorize ependymal cells into different subtypes. As previously described, E1 ependymal cells contain multiple motile cilia, E2 ependymal cells contain one motile cilium and one primary cilium, and E3 ependymal cells contain one primary cilium.6 Since the motile cilia of E1 ependymal cells regulates CSF flow, the dysfunction of E1 ependymal cells would likely impair the unidirectional flow of CSF within the ventricular system. With the cilia of E2 and E3 ependymal cells primarily functioning to sense the CSF composition and transmit extracellular signals, dysfunction of these subtypes would likely alter CSF homeostasis and hinder signalling pathways. Consequently, damage to ependymal cilia or mutations in the genes that control cilia functionality would likely impair the production, circulation and reabsorption of CSF.20 However, it remains unclear as to how each specific subtype of ependymal cell contributes to the development of neurodegenerative disease and if additional factors aside from compromised cilia might also impair CSF dynamics and homeostasis to the same extent.Cilia are hair-like structures located on the apical surface of ependymal cells that function in several physiological and developmental processes.2 Several glucose transporters (GLUT), such as GLUT1, GLUT2, GLUT3 and GLUT4 are expressed on the apical surface of ependymal cells and facilitate the transport of glucose across the CSF-brain interface.53–55 The urate transporter 1 is also localized to the apical surface and is involved in the transport of uric acid between the interstitial fluid and the CSF.56 It has been proposed that uric acid contributes to the synchronized beating pattern of cilia and helps to maintain the flow of CSF.56 In general, ependymal cells express a variety of anion and cation transporters and channels, such as the sodium-glucose cotransporter 2 and the Na + -K+ ATPase (sodium-potassium ATPase pump), which are essential in controlling CSF ion homeostasis.58 Additionally, ependymal cells express connexin proteins which aggregate to form gap junctions, functioning to couple electrical and metabolic signals among individual ependymal cells and to coordinate a synchronized cilia beating pattern required for the bulk flow of CSF.59 Aquaporin channels are highly concentrated on the basolateral aspect of ependymal cells, reaffirming the critical role of water influx and efflux to maintain an osmotic gradient.60 Specifically, aquaporin 4 mediates the flow of water between cerebral interstitial fluid and the CSF, such that its dysregulation has been implicated in edema and hydrocephalus.61 Altogether, these protein transporters and channels work together to regulate metabolic processes and sustain the composition of CSF.The inherent polarity of ependymal cells drives the specific localization of protein channels and transporters that function to regulate ependymal metabolic processes and maintain CSF composition.62 At the apical-lateral interface between adjacent ependymal cells, prominent adherens junctions are formed by extracellular homotypic cadherin interactions and intracellular interactions between cadherins and catenins.63 The F-actin cytoskeleton provides an anchoring point for adherens junctions and enables the distribution of mechanical and tensile forces so that the ependymal cells can withstand the forces generated from the beating pattern of the cilia.64 Additionally, the F-actin network is involved in coordinating cilia movement at the apical surface.64 At the CSF-brain interface, the ependymal cell layer forms a partial barrier due to the presence of incomplete tight junctions which enables paracellular diffusion of solutes.65 However, specialized ependymal cells of the choroid plexus that form the blood-CSF barrier do contain tight junctions.65 Disruption to the tight junctions at this interface likely impairs molecular homeostasis and increases the permeability of this barrier for larger biomolecules and immune cells, as is seen in several neurodegenerative diseases.20The integrity of the ependymal cell monolayer that forms the CSF-brain barrier is maintained by adherens junctions.66 Although the ependymal lining of the choroid plexus secretes the majority of the CSF, the ependymal lining of the circumventricular organs, such as the subcommissural organ (SCO), secretes additional factors involved in CSF homeostasis.66 These ependymal cells secrete the glycoprotein SCO-spondin into the CSF, such that the aggregation of SCO-spondin molecules form a Reissner’s Fiber.67 While Reissner’s Fiber and SCO-spondin play an important early developmental role in commissural axonal pathfinding and guidance,68 Reissner’s Fiber is speculated to be involved in osmoregulation and detoxification. This is likely a result of its ability to bind to and remove neurotoxins and neurotransmitters from the CSF while strongly propelling the CSF through the cerebral aqueducts.69 Since SCO-ependymal cells that lack the ability to secrete SCO-spondin have been associated with hydrocephalus, the secretory role of these ependymal cells remains essential in maintaining CSF homeostasis.69Specialized ependymal cells that comprise the choroid plexus and line the circumventricular organs possess high secretory abilities.70 Researchers have recently proposed a link between ependymal cell dysfunction and the pathogenesis of multiple sclerosis.71 Indeed, ependymal cells are particularly sensitive to inflammation72 and develop morphological abnormalities, referred to as the ‘Dot-Dash’ sign, which is believed to be induced by inflammation.73 The ‘Dot-Dash’ sign correlates with ependymal perivenular inflammation—an early histopathological event in multiple sclerosis—which is a more sensitive biomarker for the early diagnosis of multiple sclerosis via MRI technology.73 Thus, inflammation-induced damage to the ependymal cell lining may reflect a potential origin of the pathogenesis of multiple sclerosis. The altered CSF composition that is observed in multiple sclerosis patients also supports the idea that ependymal cells become dysfunctional.72 This is likely attributed to the fact that ependymal cells regulate CSF homeostasis and are the only cell type in constant direct contact with the CSF,71 such that their dysregulation may alter CSF flow and composition. The CSF of multiple sclerosis patients becomes laden with pro-inflammatory factors, such as the chemokine CXCL12, interleukins IL-22 and IL-2, tumour necrosis factor and IFNγ (interferon-γ),74 although it remains unclear if dysfunctional ependymal cells secrete these factors into the CSF or if these factors accumulate in the CSF as a result of impaired waste clearance. While the mechanism by which ependymal cells become dysfunctional is unknown, the dysfunction of ependymal cells may be reflected through upregulation of the cytokine receptors CXCL12 and IFNγ, both of which are involved in inflammatory response cascades.71 Similarly, inducible nitric oxide synthase, which is a downstream mediator of inflammation, is upregulated within the ependymal cell lining and has been associated with plaque formation, tissue damage and demyelination.75 Additionally, ependymal cell loss or death may be mediated by Fas binding interactions that occur at the ependymal cell surface with infiltrated helper T-cells.48Multiple sclerosis is a neurodegenerative and autoimmune disease characterized by the demyelination of nerve fibres in the CNS, chronic inflammation, cerebral atrophy and axonal loss.76 One hypothesis of Alzheimer’s disease pathogenesis is the amyloid cascade hypothesis, which states that the accumulation and deposition of amyloid plaques initiates neurodegeneration and drives the downstream formation of neurofibrillary tangles.77 Since ependymal cells are essential for the removal of metabolic waste and protein aggregates from the CSF, particularly amyloid-beta monomers, ependymal cell dysfunction may impair the normal CSF detoxification process and cause amyloid neurotoxicity.78 Indeed, ependymal cell dysfunction may promote an environment that favours the oligomerization of amyloid-beta monomers into amyloid plaques, which is a molecular event thought to precede and propel the formation of neurofibrillary tangles.80 Deposits of amyloid plaques and neurofibrillary tangles have been observed within the periventricular regions in Alzheimer’s disease patients, thus reflecting an imbalance between the production and clearance of amyloid plaques at the ependymal cell lining.82 One receptor type that becomes dysregulated in ependymal cells is the receptor for advanced glycation endproducts, where its upregulation is believed to sustain the influx of glycated amyloid-beta monomers into the brain and promote the formation of amyloid plaques.83 In addition, researchers have proposed a link between impaired lipid metabolism and Alzheimer’s disease pathogenesis, where this has been observed within the ependymal cell lining.84 Triglyceride lipid droplets rich in oleic acid were found to accumulate within ependymal cells in both a triple-transgenic Alzheimer’s disease mouse model and post-mortem brains of Alzheimer’s disease patients, where subsequent inhibition of NSC regeneration was observed within the mouse model.85 Even though lipid droplets are abundantly present in ependymal cells under non-pathological conditions, this amount is significantly increased in Alzheimer’s disease.86 The mechanism by which excess lipid droplets accumulate in ependymal cells and the implications of retaining excess lipids with respect to the neuropathology of Alzheimer’s disease in humans is yet to be elucidated.87 Similar to multiple sclerosis, widespread neuroinflammation and oxidative stress are also key factors in the pathogenesis of Alzheimer’s disease and may cause ependymal cells to become pathogenic as a result of their sensitivity to inflammation,88 though this has been more broadly studied in glial cells.Alzheimer’s disease is a progressive neurodegenerative disease characterized by the deposition of extracellular amyloid plaques, intracellular neurofibrillary tangles, atrophy of neurons and synaptic loss.89 Although the role of ependymal cells in the pathogenesis of Parkinson’s disease has not been a focal point in Parkinson’s disease research, some studies suggest a link between ependymal cell dysfunction and Parkinson’s disease.90 Deposits of aggregated alpha-synuclein within subependymal tissues and ependymal cells have been observed in Parkinson’s disease patients and correspond with the Braak stages 5 and 6,90 which is a well-established staging system of the progression of Parkinson’s disease.91 Loss of function mutations in the parkin co-regulated gene (PACRG) have also been linked to the pathogenesis of Parkinson’s disease, where PACRG is a gene involved in the formation of the axoneme microtubule structure in motile and non-motile cilia.93 Since PACRG is highly expressed and localized to the ependymal cilia lining the ventricular system,93 loss of function mutations in PACRG may reflect impaired ependymal cilia function, which may contribute to the pathogenesis of Parkinson’s disease. However, it remains unclear if damage to ependymal cells causes dysregulation of PACRG or if mutations in PACRG driven by genetic or environmental factors are able to trigger ependymal cell dysfunction. Dysregulation of lipid metabolism has also been identified as a driving factor in the deposition of alpha-synuclein and pathogenesis of Parkinson’s disease,94 although this has not been specifically examined in ependymal cells.Parkinson’s disease is defined by neurodegeneration of dopaminergic neurons within the substantia nigra and is associated with both motor symptoms  and non-motor symptoms .HTT gene.95 Recently, the role of ependymal ciliary function and ciliogenesis has been identified as a potential pathogenic mechanism of Huntington’s disease.96 In both HTT knockout mice and patients with Huntington’s disease, ependymal cells displayed delocalized pericentriolar material 1 (PCM1), disorganized cilia, altered CSF flow and hydrocephalus.98 Indeed, the HTT-PCM1-HAP1 (Huntington-associated protein 1) pathway is thought to regulate ciliogenesis and CSF homeostasis, where mutant mice lacking HTT exhibited an uncoordinated cilia beating pattern, abnormal CSF production and circulation, and altered ciliogenesis.98 These observations suggest a role of the HTT gene in regulating ependymal ciliary function,99 although it is not fully understood if dysfunctional cilia is an early molecular event in the pathology of Huntington’s disease.Huntington’s disease is a progressive and inheritable neurodegenerative disorder caused by excessive repeats of the cytosine-adenine-guanine codon within the 100 Some studies have found that damage to the ependymal cell lining may contribute to the pathology of TBI.101 Ependymal ciliary loss has been observed in TBI mouse models and was found to decrease ventricular CSF flow and alter nutrient-waste exchange.102 Mild TBI (mTBI) or concussion may also induce DNA damage in ependymal cells, among other types of glial cells.103 In cases of mTBI, expression of γH2AX, a marker of double-stranded DNA breaks, was observed in the ependymal cell lining of the ventricles.104 Interestingly, the presence of γH2AX within the ependyma was observed in cases of mTBI displaying clinical symptoms but lacking a neuropathological diagnosis.104 These findings suggest that DNA damage in the ependymal cell lining may be an early molecular event post-mTBI and may precede neuropathological diagnosis.104 Commonly observed clinical symptoms of TBI include psychiatric and mood disorders, where altered gene expression of p11 in ependymal cells has been recently linked to reduced CSF flow and stress-induced depression.105 Thus, ependymal cells may be implicated in both the pathogenesis and clinical presentations of TBI. In addition, TBI has been associated with an increased susceptibility of developing neurodegenerative diseases later in life, particularly Alzheimer’s disease.106–108 However, limited research has specifically explored how mTBI-induced DNA damage in the ependymal cell lining may contribute to neurodegeneration.108 Nonetheless, these findings suggest that ependymal cells are sensitive to TBI and their dysfunction may initiate the pathogenesis of long-term brain dysfunction associated with TBI.Traumatic brain injury (TBI) occurs with an external physical assault to the head that disrupts normal brain functions.109 Hydrocephalus can be classified as primary , secondary  or idiopathic, however, the genetic factors underlying primary hydrocephalus suggest a role of ependymal cilia in its pathogenesis.27 As previously described, ependymal cilia generate forceful synchronized beats that direct CSF circulation within the ventricular system. Indeed, loss of function mutations in MDNAH5, a gene that regulates axonemal dynein, has been linked to primary ciliary dyskinesia and hydrocephalus in mice.110 Similarly, mutant mice strains for the HYDIN gene, which regulates ciliary motility and fluid transport in the brain, resulted in ciliary immobility and hydrocephalus.111 Overall, the biogenesis and maturation of cilia is regulated by FOXJ1, MCIDAS and RFX3, three master transcription regulators that are highly expressed and tightly regulated in ependymal cells.112 These studies suggest that functional ependymal cilia is critical for maintaining CSF homeostasis within the ventricular system, such that dysfunction may lead to phenotypes of hydrocephalus.Hydrocephalus is a condition characterized by the buildup of CSF within the ventricles leading to ventriculomegaly, where enlarged ventricular spaces hinder the flow of CSF.113 In a recent single-cell RNA-sequencing study looking at different molecular pathways observed in superoxide dismutase 1 mouse models of ALS, genes involved in the transport of toxins in ependymal cells were differentially expressed.114 In cases of sporadic ALS, the CSF of ALS patients contained neurotoxic compounds and inflammatory cytokines, which is thought to be a result of ependymal cell dysfunction.115 Isolated and cultured motor and spinal cord neurons displayed signs of ALS-specific neurodegeneration when exposed to the CSF extracted from ALS patients,117 thus reflecting altered CSF dynamics in ALS patients. Since ependymal cells facilitate toxin removal from the CSF, ependymal cell dysfunction may underlie this phenotype. To further support the implication of ependymal cells in ALS pathogenesis, a novel regimen designed to target and reverse the outcomes of dysfunctional ependymal cells slowed ALS progression in four individuals.115 However, the sheer number of studies regarding the role of ependymal cells in ALS progression is limited, and this potential relationship merits further research.Amyotrophic lateral sclerosis (ALS) is a neurodegenerative motor neuron disease resulting in the loss of motor control.118 Among these changes are the loss of ependymal cells within the V-SVZ, morphological abnormalities, altered protein expression and dysregulated lipid metabolism, which is thought to impair lipid-raft and lipid-trafficking interactions.120 The progressive loss and thinning of ependymal cells in aging is met with an increase in migratory astrocytes that interpose themselves within the ependymal cell layer and form junctions with the remaining ependymal cells.121 In a model of aging mice, ependymal cells accumulated lipid droplets within the cytoplasm, which reflects either metabolic dysregulation or increased uptake of lipids from either the CSF or interstitial fluid of the brain.119 Specifically, a reduction in myristoylated alanine-rich C-kinase substrate expression resulted in a decline in ependymal lipid metabolism, accumulation of lipid droplets, oxidative stress, inflammation, and infiltration of reactive microglia, macrophages and astrocytes.122 In addition, both astrocytes and ependymal cells develop dense bodies, accumulate intermediate filaments and upregulate inflammatory markers.123 The morphological abnormalities include tangled or absent ciliary tufts on the apical surface of ependymal cells within several ventricular regions in aging mice,123 therefore negatively impacting the flow of CSF. Interestingly, a recent study found that the reduced flow of CSF is linked to the onset of cognitive deficit in healthy elderly individuals,124 thus suggesting that natural alterations in CSF homeostasis occur with aging. The reduced production of CSF and the buildup of waste products in the CSF were also found to initiate age-related dementia in adults.125 Additionally, neurocognitive decline has been associated with the loss of ependymal cells and periventricular and ventricular abnormalities.126 The relationship between CSF dynamics and cognitive deficits indicates the importance of ependymal cell function in preserving overall cognition. Consequently, it is believed that natural dysfunction of ependymal cells occurs during the normal aging process, where this dysfunction may be pre-mature or exacerbated in neurodegenerative diseases.As demonstrated across several neurodegenerative diseases, the dysfunction of ependymal cells is multifaceted and has several molecular presentations, as shown in 127 Senescence is a process that occurs naturally with age or it can be triggered with continuous activation of the DNA-damage response pathway in response to unresolved DNA damage.128 Senescent cells typically develop a senescence-associated secretory phenotype (SASP), in which cells secrete pro-inflammatory interleukins, chemokines and cytokines into the environment, with prominent markers of senescence being IL-6, IL-1, IL-8, insulin-like growth factor and soluble matrix metalloproteinase.129 Senescence has been described as a contributing factor in several neuropathologies.130 In the case of mTBI-induced DNA damage within ependymal and other glial cells, the high expression of inflammatory SASP-related factors and morphological markers of senescence suggests that senescence occurs post-mTBI.104 Since senescence is believed to initiate a positive feedback loop where the SASP drives a cycle of chronic DNA damage and inflammation,131 senescent ependymal cells may secrete SASP factors into the CSF, thus altering CSF composition and flow while potentially spreading senescent signals to nearby brain regions.104 Senescence has also been found to alter the CSF composition in age-related dementias,125 such that the CSF becomes enriched with tau and ferritin.133 Since the dysfunction of ependymal cells is known to alter CSF composition and waste removal, ependymal cells that become senescent likely become dysfunctional. In addition, several hallmark phenotypes of multiple sclerosis, such as chronic inflammation and oxidative stress, are well-established triggers of senescence, even though senescence within the ependymal cell lining has not been specifically examined in multiple sclerosis.134 The relationship between senescence and ependymal cell dysfunction merits further research in order to better understand the precise mechanisms by which ependymal cell dysfunction occurs and the repercussions that it may incur in other brain regions.Cellular senescence is characterized by cell-cycle arrest, the inability to further proliferate and persistent inflammation.Ependymal cells form important cellular barriers that are critical in maintaining overall brain health. While disruption to the blood–brain barrier has been extensively studied in disease, compromised function of the CSF-brain and blood-CSF ependymal barriers have been critically overlooked, though they likely contribute to neurodegeneration as well. Damage or injury to ependymal cells have been shown to impair cilia function, dysregulate CSF dynamics and circulation, promote the secretion of pro-inflammatory factors, and potentially trigger pre-mature senescence. Due to the importance of CSF homeostasis in regulating normal brain activities, ependymal cell dysfunction has even been suggested as an early manifestation of certain neurodegenerative diseases. Consequently, this raises the question if ependymal cells may be a potential origin of disease and if dysfunction of the ependymal cell lining may lead to widespread dysfunction and neurodegeneration of the brain. Further research into this area may lead to the development of diagnostic methods and treatments that utilize biomarkers of ependymal cell dysfunction to detect and target earlier stages of specific neurodegenerative diseases.


In particular, cardiotoxicity (hERG liability), probably the worst early adverse reaction studied during clinical studies focused on acute toxicity, was predicted, and some of the most used and robust metrics available were considered to select which of the analyzed compounds could be repositioned as possible oral antipsychotics.The endocannabinoid system (ECS) plays a very important role in numerous physiological and pharmacological processes, such as those related to the central nervous system (CNS), including learning, memory, emotional processing, as well pain control, inflammatory and immune response, and as a biomarker in certain psychiatric disorders. Unfortunately, the half-life of the natural ligands responsible for these effects is very short. This perspective describes the potential role of the inhibitors of the enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MGL), which are mainly responsible for the degradation of endogenous ligands in psychic disorders and related pathologies. The examination was carried out considering both the impact that the classical exogenous ligands such as Δ Clinical and social psychologists seldom use an ancient Hindu parable to illustrate the seductive potential of our perspective on a complex problem—the well-known story of the blind men and the elephant  . When a 2 receptor  att att93] a1R-dependent stress-induced analgesia employing the covalent and partial reversible carbamate inhibitor URB602  and BRF , to provide the requested predictions. Importantly, all the compounds under investigation fall within the applicability domain of the model  predicted as responsible for a high CNS activity (CNS = 2). Finally, interesting data were also provided by MJN110 (15), predicted to be responsible for significant CNS activity (CNS = 1) and high oral availability  cytochrome P450 isoforms . The prediction was performed using as software program CypReact, recently published by Tian et al.  and avai19 and 20 were predicted as poor substrates of all cytochrome P450 isoforms, thus performing as the best candidate for repositioning when metabolic liability is concerned.All FAAH and MGL selective inhibitors should be substrates of several cytochrome P450 isoforms and thus possibly act as metabolic auto-/heteroinducers. Possible adverse events due to drug-drug metabolic interactions should be considered. Interestingly, both FAAH/MGL inhibitors A complementary analysis may be obtained using three of the most used and robust metrics to classify the selected inhibitors.(1) As an indicator of promiscuity liability , the property forecast index has been proposed . This in(2) CNS penetration may be forecasted from the CNS multiparameter optimization descriptor obtained by a linear combination of six parameters, each weighted one if in the desirable range, 0 when in the undesirable range, and scaled when falling between the targeted values  .(3) As a ligand efficiency evaluator, the lipophilic efficient index is generally considered the most robust descriptor and represents a measure that correlates potency and lipophilicity. It is obtained from the difference between a measure of the potency of the ligand and its clogP and, therefore, can be considered as a measure of the gain in potency net of the (non-specific) entropic contribution due to the mere increase in lipophilicity . An effi21). Thus, compounds ASP8477 (10), V158866 (11), and SA-57 (20), while displaying high efficiency and good CNS penetration, should be considered carefully for possible toxicity issues stemming from their profiles that seem close to the one of BIA10-2474 (21). Interestingly, compounds JNJ-42165279 (7) and MJN110 (15) are located near the high efficiency/selectivity/CNS permeation volume and may be considered a good compromise between efficiency and safety requirements. It is worth noting that CBD (2) is the less efficient inhibitor, highly promiscuous, and presents acceptable CNS permeation properties. This outcome agrees with what has been reported so far on CBD pharmacology.In A relatively lower incidence of psychosis is found in Spain and Italy than in Northern Europe . This ev7, 15, 10), V158866 (11), ABX-1431 (17), and SA-57 (20)] may be considered as starting points for structural simplification/optimization endeavors to reduce possible hERG liability (17) and selectively favoring FAAH/MGL over other targets. None of the stated compounds is chiral, while chirality has been related to clinical success [20), lactamide (R = Me, Based on the performed predictions focused on CNS activity, oral adsorption, and ligand efficiency, the FAAH inhibitor JNJ-42165279 7,  seems to success  and toxi success . Chiral  R = Me,  and mand R = Me,  pyridyl


EWSR1) by fluorescence in situ hybridisation and he underwent neoadjuvant chemotherapy and surgical excision with grafting before he presented to our institute, where the pathologists reviewed the biopsy slides, which were positive for HMB45 and negative for Melan-A suggestive of clear cell sarcoma. The next-generation sequencing suggested EWSR1-ATF1 fusion, which again reinforced the diagnosis. This case throws light on the importance of expert pathology and interpreting molecular results in the right context.Sarcoma pathology discrepancy is well known owing to the extremely heterogenous and rare nature of this tumour. Through this case, we want to highlight the difficulty that a patient has to undergo in a case of misdiagnosis. A 20-year-old male presented with swelling in the right foot for 4 months, which was initially diagnosed as alveolar rhabdomyosarcoma, subsequently as synovial sarcoma and finally as Ewing’s sarcoma (based upon positive Ewing Sarcoma Breakpoint Region 1 ( Soft tissue sarcomas (STSs) are a group of remarkably diverse neoplasms that frequently pose significant diagnostic challenges to surgical pathologists . PatholoClear cell sarcoma (CCS) is a rare tumour first described in 1968 and also referred to as malignant melanoma of soft parts [8]. It has characteristics of both STS and malignant melanoma with a predilection for the deep soft tissues of lower extremity and typically affects young adults [9]. This tumour is characterised by the translocation tq13;q12) and consequent fusion of the Ewing Sarcoma Breakpoint Region 1 (EWSR1) and ATF1 genes which is not documented in malignant melanoma [9] and its detection using advanced molecular techniques helps in the confirmation of a diagnosis of CCS. The literature is rife with studies in which CCS has been misdiagnosed as melanoma, metastatic carcinoma, fibrosarcoma, etc. –13.;q12 and A thorough understanding about the molecular abnormalities of STSs is necessary to avoid misdiagnosis of a tumour, as there are multiple tumours which behave differently with similar morphology and immunopositivity. This case where the diagnosis was altered thrice before coming to the final diagnosis emphasises the need for timely referral to a sarcoma specialist to avoid misdiagnosis and mismanagement.A 20-year-old male from Kathmandu, Nepal, developed pain on the undersurface of his right foot since January 2021, which was exaggerated by walking. He also noticed a swelling which was better felt than seen  at the sAn MRI was done  on the 2The patient underwent a trucut biopsy of the tumour and on histopathological examination, sheets of malignant, round to polygonal cells with intervening fibrous septa were seen with foci of necrosis. The overall impression in the initial report was alveolar rhabdomyosarcoma. Immunostains were not used at this point of time. The patient was administered neo-adjuvant chemotherapy with two cycles of vincristine, cyclophosphamide and dactinomycin on the 12th of May and the 3rd of June 2021 following which, a repeat MRI of foot was done on the 21st of June, which showed no interval changes compared to the previous MRI. Histopathology was again reviewed in another Centre and immunohistochemistry (IHC) markers were done, and the cells were positive for CD99 and TLE-1 and negative for CK, Desmin, S100, CD45, Myo-D1, TdT, NKX2.2 and synaptophysin. The report was subsequently reviewed and a diagnosis of monophasic synovial sarcoma was made. He further underwent wide local excision of the tumour and Ray’s amputation of the 4th and 5th toes of right foot was done with skin and soft tissue grafting on the 27th of June.EWSR1 and SS18 rearrangement was done which detected EWSR1 rearrangement  for angement  and 4 anEWSR1 rearrangement detected earlier was related to CCS rather than Ewing’s sarcoma/PNET.At our institute, the Pathologists reviewed the slides of the resected specimen. The morphology of the tumour showed oval to spindle shaped cells arranged in nests as well as syncytial pattern. The tumour cells showed moderate pleomorphism with vesicular chromatin and prominent nucleoli with moderate to abundant cytoplasm with epithelioid morphology at places . The tumEWSR1::ATF gene fusion, which confirmed the diagnosis of CCS. Tumour tissue was analysed using semiconductor-based next-generation sequencing technology . High-quality tumour tissue RNA extracted from the submitted specimen was subjected to target enrichment by multiplex polymerase chain reaction (PCR) amplification by Sarcoma Fusion panel. Sequenced data was analysed using a customised in-house pipeline DCGL NGS Bioinformatics v4.2. An FDG PET performed on the 17th of July showed no other focus of disease. Hence, the patient was advised to undergo radiotherapy as there is no role for chemotherapy in CCS in the adjuvant setting. In view of delay in flap healing, radiation therapy was delayed and repeat PET scan after 3 months showed metastatic disease to pelvic lymph nodes and lung metastasis. After which he was started on tab pazopanib but died after 2 months.We further sent the specimen for next-generation sequencing analysis, which detected The above case demonstrates the importance of correctly diagnosing soft tissue tumours in the early phase of presentation itself. CCS has slight female preponderance and is found in 15–35 years age group , 14, medThis case also highlights the pitfalls associated with a delay in referral to a sarcoma speciality clinic in the event of a diagnostic dilemma associated with a STS. Delay in correct diagnosis leads to mistreatment, larger tumour burden, functionally debilitating surgeries and significant distress in the patient which might last longer than treatment duration –20. Thiset al [A study by Thway et al  showed tet al . This juEWSR1 gene, located at chromosome22q12, encodes a 656-amino acid nuclear protein that is thought to have roles in meiotic cell division, mitotic spindle formation and stabilisation of microtubules, as well as DNA repair mechanisms and cellular ageing. EWSR1 is a member of TET family of genes which has an RNA binding domain at the carboxy terminus of the gene product which is important in protein-RNA binding, transcription and RNA metabolism [EWSR1 has been identified as a translocation partner in a wide range of clinically and pathologically diverse tumours which include the Ewing family of tumours, desmoplastic small round cell tumour, myxoid liposarcomas, extra-skeletal myxoid chondrosarcoma, angiomatoid fibrous histiocytoma, CCS of soft tissue and clear cell sarcoma-like tumours of the gastrointestinal tract, primary pulmonary myxoid sarcoma, myoepithelial tumours of skin, soft tissue and bone and rare examples of low-grade fibro-myxoid sarcoma, sclerosing epithelioid fibrosarcoma and mesothelioma [tabolism –25. EWSRThe errors that accompanied this patient were inappropriate chemotherapy, as CCS is chemo resistant , 27 and The sensitivity to chemotherapy and immunotherapy in this subset has rarely been demonstrated , 30. HowOur case depicts that the molecular markers should be interpreted in the context of meticulous histopathological examination. Also, in Low-middle income countries (LMICs), a well-structured framework is direly needed to improve sarcoma care in the absence of expert pathology, radiology, dedicated sarcoma surgeons and sarcoma medical oncology. The development of pathology services in LMICs faces a number of challenges, including insufficient funds, lack of skilled personnel at all levels (technicians to pathologists), unavailable equipment and unreliable supply chains for consumables . PatientThis case shows how a misdiagnosis can change the entire course of the disease rather appallingly. Discrepancy of pathological diagnosis is a well-established entity as far as STSs are concerned. This case adds to the existing knowledge and given the dire need of expertise in pathology in sarcoma, this needs to be re-emphasised with more cases.This case reveals that expert pathology and appropriate molecular tests for rare sarcomas are essential for appropriate management, along with a second pathology opinion for sarcomas at an expert centre, which should be the norm rather than exception.No conflicts of interest.We did not receive any funding for this manuscript and have no financial interests.


Drosophila melanogaster) have emerged as a powerful model in Sensory Biology studies. This tiny organism is quite sensitive to changes in their environment and immediately react with simple and robust behaviors, relying on their simple neural circuits. In addition to fruit flies, the importance of insect studies has been growing particularly in insect pests exemplified by mosquitoes and brown planthoppers, a threat for public health and crops, respectively. Unraveling these complex sensory processes in insect models, therefore, is beneficial for basic neuroscientific research and in the development of new strategies of pest management.Sensory functions are an initial step in communicating with our environment. All biological systems need to monitor fluctuation of the surrounding physical/chemical parameters to respond to adjust their inner states and adapt to new circumstances. Recent advances in Sensory Biology have identified a diverse set of molecules involved in the sensory functions. There exists, however, a number of uncertainties regarding how the environmental signals are received, converted, and transmitted by those sensory molecules, which consequently affect behavioral outputs. In the last two decades, fruit flies  channel family is involved in almost every sensory modality. There are about 30 members of TRP channels in insect genomes, and most of them are expressed in sensory neurons thereby controlling behaviors related to vision, smell, taste, hearing, thermosensation, nociception, proprioception and others. However, it is less understood whether TRP channels are involved in reproduction processes such as an egg laying behavior. Drosophila melanogaster, and intracellular Ca2+ level plays key roles in modality-specific neural and behavioral responses. Patel et al. identified that metabotropic GABAB-R2 receptor and Ca2+ induced Ca2+ release (CICR) via inositol trisphosphate receptor (IP3R) were specifically responsible for noxious cold responses. In contrast, in the same neurons, CICR via the ryanodine receptor (RyR) was generally required for cold nociception and innocuous touch response. Both the GABAB-R2 and RyR contributed to cooling-induced activity of CIII neurons and firing patterns. The authors also confirmed that Pkd2, one of the TRP channels in CIII neurons, was involved both in cold nociception and touch sensation, whereas IP3R was responsible only for cold nociception. These results reveal the multiple yet partially overlapping sets of molecules that could be important for modality specific intracellular Ca2+ levels and behavioral outputs.Class III (CIII) neurons function as a multimodal sensor in Aedes aegypti (Aa), an infamous disease vector for yellow fever, utilizes auditory function to discriminate wing beat frequency and it is particularly important for males to target conspecific females for courtship, which is called phonotaxis. Xu et al. showed that serotonin receptors 5-HT7A and 5-HT7B were abundantly expressed in the Johnston's organ (JO), an auditory unit in the head, and their pharmacological manipulation altered the properties of JOs in Aa males: stimulating with serotonin injection induced shifts in male ear tuning to higher frequencies, while inhibition of serotonin synthesis led to a reduction in tuning frequencies. The authors also demonstrated an interference of Aa male phonotactic behaviors by inhibiting serotonin synthesis, which resulted in reduction of responsiveness to sounds and the range of frequencies that the males responded. The serotonergic system in Aa mosquitoes could be a new target for vector control.Kohatsu et al. dissected the roles of Gr5a-positive and Gr61a-positive gustatory receptor neurons  and found that the former predominantly controlled the preference of trehalose over other sugars and meal size, while the latter affected only sugar preference. They labeled the neurons with Gr5a- and Gr61a-Gal4 drivers in tarsal segments and found two distinct populations: Gr5a-/Gr61a+ and Gr5a+/Gr61a+ GRNs. These GRNs projected separately to the CNS to form alternative neural circuits, and the authors propose that the two types of GRNs/sensory pathways may function in different gustatory responses.Taste sensation is critical for final decision making upon nutrient uptake and diverse sets of Gustatory receptors (Grs) play major roles in various regions of the insect body. Schoberleitner et al. proposed a model fly which may be associated with age-related decline processes in animals. The ATP-dependent chromatin remodeling factor chromodomain-helicase-DNA binding protein 1 (CHD1) had a crucial role in the incorporation of the histone variant H3.3 in the fly brain. The Chd1 mutant flies resulted in widespread upregulation of transcription including the control of hunger and satiety-related genes. The mutants had impairments in nutrient metabolism and food intake. Furthermore, Chd1 mutant flies showed impairments in olfactory and gustatory perception, but not visual perception. The mutants also had defects in climbing and exploratory walking. Most phenotypes were rescued by expression of the Chd1 cDNA using pan-neuronal GAL4. However, the olfactory defects were suggested by indirect non-neuronal regulation.Among the interesting contributions, All the articles above advance our understandings and provide insight into the molecular machineries of sensory functions. This trend has been expanding in the last two decades, and the Sensory Biology field is indeed widely acknowledged in the scientific communities now, as the Nobel Prize in Physiology or Medicine in 2021 was awarded for “the discoveries of receptors for temperature and touch”. Future work will further prove the advantages of insect models in Sensory Biology that benefits basic research as well as applications for insect pest management.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.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.


Helminth infection currently affect over 2 billion people worldwide, with those with the most pathologies and morbidities, living in regions with unequal and disproportionate access to effective healthcare solutions. Host genetics and environmental factors play critical roles in modulating and regulating immune responses following exposure to various pathogens and insults. However, the interplay of environment and genetic factors in influencing who gets infected and the establishment, persistence, and clearance of helminth parasites remains unclear. Inbred strains of mice have long been used to investigate the role of host genetic factors on pathogenesis and resistance to helminth infection in a laboratory setting. This review will discuss the use of ecological and environmental mouse models to study helminth infections and how this could be used in combination with host genetic variation to explore the relative contribution of these factors in influencing immune response to helminth infections. Improved understanding of interactions between genetics and the environment to helminth immune responses would be important for efforts to identify and develop new prophylactic and therapeutic options for the management of helminth infections and their pathogenesis. Research into factors that influence host response during helminth infection are usually focused on use of inbred mice raised in a specific pathogen free environment as found in most research institutes and academic institutions across the world. However, in the real-world setting, helminth infections are characterized by infections of individuals living in various communities with different lifestyles as well as with wide genetic variations. Also, the intensity of helminth infection among individuals varies markedly and can be influenced by various genetic and environmental factors , 2. TherStudies with genetically modified mice on the C57BL/6 background has transformed our understanding of Type 2 responses to helminths in the last few decades. Immune responses during helminth infection are characterized by recruitment and accumulation of innate immune cells such as eosinophils, basophils, innate lymphoid cells (ILC2), neutrophils, alternatively activated macrophages as well as cell of the adaptive immune system such as B cells, Th2 and T regulatory CD4 T cells . These cOur ability to genetically manipulate mice has been fundamental for increased understanding of mammalian physiology. As this technology evolved over time, the C57BL/6 strain of mice has emerged as the inbred strain of choice for most immunological studies. As a result, our understanding of the basic mechanisms that surround immune response during helminth infection has also improved significantly with the use of genetically modified mouse models for dissecting various mediators and immune cell populations in the regulation of helminth induced immune responses. Increasing complexity of mouse models include cell specific knockouts, genetic inducible fate mapping models, in addition to the global knock-out and/or transgenic mice models have been critical in identifying new pathways that regulate Type 2 and immunoregulatory responses to helminths. To reduce variation in these reductionist experiments to characterize detailed mechanisms, genetically identical mice strains of similar age groups and sometime sex are used to isolate and study the role of specific cell types and immune mediators.Litomosoides sigmodontis, a filarial nematode, compared to the C57BL/6 mice or the C57BL/10 mice  together with release of alarmins like IL-33, IL-25 and TSLP at epithelial barriers , 84. ThiS. mansoni infection, when challenged with a similar number of cercariae. This may be due to differences in the switch from a pro-inflammatory T helper 1 (Th1)/T helper 17 (Th17) response to a tissue protective Type 2 response. The CBA mice show higher levels of proinflammatory Th1/Th17 cytokines which does not diminish but instead persists alongside the rising T helper 2 (Th2) responses, while C57BL/6 mice can regulate the Th17 response during the expansion of Th2 cells resulting in milder pathology , a stromal factor, has also been implicated in the pathophysiology of these disease  on BALB/c background, but the serum from vaccinated wild-type BALB/c mice confers protection to IL-4Rα-/- mice, suggesting the Th2 antibodies is crucial for parasite elimination and resistance in BALB/c mice (S. mansoni-infected high morbidity CBA mice display increased expression of CD209a (C-type lectin receptor – CLRs) which is necessary for the production of IL-1β and IL-23 that drives pathogenic Th17 cells, as opposed to the low morbidity C57BL/6 mice , the E strain (isolated in Edinburgh) and the E-J strain  can induce different immune response following infection of mice. The E and E-J strains of T. muris generally induce a Th2 skewed response whereas the S-strain induces a Th1 skewed response characterized by production of IFN-gamma and IL-12 , which all induce a Type 1 immune response, can limit the host response during subsequent infection with helminth parasites like Fasciola hepatica, Nippostrongylus brasiliensis and Strongyloides stercoralis  and embryo transfer from wild and pet store mice , 154. ThIn conclusion, there is considerable interest in developing these new tools , 152 to H. polygyrus infection or S. mansoni infection can influence the worm burden following helminth infection  to alter susceptibility to helminth infection . How theOther host variables such as age, sex, nutritional status could interact with genetics and environmental factors to influence immunity and affect the outcome of helminth infection. A combination of controlled re-wilding experiments –144, 147Environmental exposure and host genetic background are important drivers of inter-individual variation in susceptibility and outcome of helminth parasite infections. Both play a role in driving heterogeneity of responses either as independent variables or through specific interactions that remain poorly understood. Since disease morbidity and parasite burden is observed primarily in small subsets of infected individuals, it is important that necessary resources and research efforts are allocated into studies deciphering how genetic and environmental interactions influences susceptibility to the world’s most neglected disease in human and veterinary medicine. This will require bringing together skillsets and technologies from diverse fields including ecology, quantitative genetics, genomics, immunology, biostatistics, and parasitology. Together, such studies can improve our understanding of key translational factors that regulate immune responses during parasitic helminth infection. Findings from a diverse range of inbred and outbred strains of mice in different environments might provide a more accurate reflection of factors important in diverse human and animal population under free living conditions. There are also opportunities for the identification of new pathways and alleles or regulatory elements that regulate responses in other Type 2 immune mediated diseases such as allergic, metabolic and fibrotic diseases , 88. AddThe content of this manuscript is solely the responsibility of the authors and does not necessarily represent the views of the National Institute of Health.OO wrote the first draft of the manuscript. CS and P’NL made significant direct and intellectual contribution to the manuscript. CS made the figure. P’NL edited the manuscript. All authors contributed to the article, read, and approved the submitted version.This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH Order #NLR2110677 and funded the open access publication fees.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.The handling editor declared a shared affiliation with the authors at time of review.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.


Currently, microRNAs have been established as central players in tumorigenesis, but above all, they have opened an important door for our understanding of immune and tumor cell communication. This dialog is largely due to onco-miR transfer from tumor cells to cells of the tumor microenvironment by exosome. This review outlines recent advances regarding the role of oncomiRs in enhancing cancer and how they modulate the cancer-related immune response in the tumor immune microenvironment.MicroRNAs (miRNAs) are a type of noncoding RNA that are important posttranscriptional regulators of messenger RNA (mRNA) translation into proteins. By regulating gene expression, miRNAs enhance or inhibit cancer development and participate in several cancer biological processes, including proliferation, invasion metastasis, angiogenesis, chemoresistance and immune escape. Consistent with their widespread effects, miRNAs have been categorized as oncogenes (oncomiRs) or tumor suppressor (TS) miRNAs. MiRNAs that promote tumor growth, called oncomiRs, inhibit messenger RNAs of TS genes and are therefore overexpressed in cancer. In contrast, TS miRNAs inhibit oncogene messenger RNAs and are therefore underexpressed in cancer. Endogenous miRNAs regulate different cellular pathways in all cell types. Therefore, they are not only key modulators in cancer cells but also in the cells constituting their microenvironments. Recently, it was shown that miRNAs are also involved in intercellular communication. Indeed, miRNAs can be transferred from one cell type to another where they regulate targeted gene expression. The primary carriers for the transfer of miRNAs from one cell to another are exosomes. Exosomes are currently considered the primary carriers for communication between the tumor and its surrounding stromal cells to support cancer progression and drive immune suppression. Exosome and miRNAs are seen by many as a hope for developing a new class of targeted therapy. This review outlines recent advances in understanding the role of oncomiRs in enhancing cancer and how they promote its aggressive characteristics and deeply discusses the role of oncomiRs in suppressing the anticancer immune response in its microenvironment. Additionally, further understanding the mechanism of oncomiR-related immune suppression will facilitate the use of miRNAs as biomarkers for impaired antitumor immune function, making them ideal immunotherapy targets. Altered regulation of signaling pathways primarily linked to dysregulation of their epigenetic machinery and genetic alterations are major hallmarks of cancer. Tumor behaviors should, however, not be analyzed apart from their microenvironment interactions, which support tumor growth and immune evasion . The proSmall noncoding RNAs known as miRNAs are posttranscriptional regulators of gene expression. MiRNAs inhibit expression of their target genes by silencing messenger RNA (mRNA) translation and degrading mRNA transcripts. Consistent with their wide-ranging effects in cancer, miRNAs have been divided into two categories: oncomiRs, which are oncogenic, and TS miRNAs. OncomiRs can undergo gain-of-function in cancer, and TS miRNAs can undergo loss-of-function in tumors. Moreover, several miRNAs exert dual effects, acting as either TSs or as oncomiRs depending on the tumor cell type. This has been demonstrated in various miRNA family including as known tumoral activator miR-30 and miR-21. MiR-30 in pancreatic cancer acts as an oncomiR. The high expression of miR-30 in pancreatic cancer modulated by CD133 promotes migration and invasion of pancreatic cancer cell . In glioThe most fascinating aspect of miRNAs is that they not only regulate gene expression in the cancer cells themselves but are also used by the tumor to modify its microenvironment. MiRNAs can be released outside the cell and picked up by nearby cells in which they will also regulate gene expression. MiRNAs are at the center of an intercellular communication network, controlling dynamic multidirectional crosstalk not only between cancer cells and their microenvironment but also inducing cascading effects between the different components of the tumor microenvironment. Immunity-related miRNAs have received much attention, and among other effects, the regulation of immune checkpoint expression by miRNAs in various cancer types has been extensively reported .To communicate with their surrounding microenvironment and to reprogram the functions of various cells, including immune cells, tumors produce exosome . exosomeThis review systematically summarizes the role of miRNAs with oncogenic functions that not only contribute to the promotion of tumorigenesis but are also key players in immune cell function regulation of the tumoral surroundings and stresses the significant role of oncomiRs as potential clinical biomarkers and targets for immunotherapies.via inhibition of argonaute 1 (AGO1)  axis involved in cell metabolism regulation. HIPK3 inhibition by miR-101-3p strengthens oncogenicity by improving aerobic glycolysis  . Several1 (AGO1) . Aberran1 (AGO1) , 30. MiR1 (AGO1) , 31. A r1 (AGO1) . Moreove1 (AGO1) . Further1 (AGO1) . The onc1 (AGO1) . Recentl1 (AGO1) . Abrogat1 (AGO1) , associaycolysis . LactateMiRNA expression is controlled at multiple levels, including transcriptional and posttranscriptional regulation . Total mThe tumor microenvironment is a complex set of cellular and extracellular elements that is in constant interaction with tumor cells. The cellular elements consist of tumor stroma cells (cancer associated fibroblasts (CAFs), mesenchymal stromal cells, endothelial cells) innate and adaptive immune cells, such as T cells, NK cells, and macrophages. The extracellular environment is composed of the extracellular matrix and is rich in active molecules such as growth factors, proteolytic enzymes and cytokines . During To communicate with their surrounding microenvironment and to reprogram the functions of various cells, tumors produce small exosome called tumor-derived exosomes (TEXs) to build a communication network . The conExosomal miRNAs constitute one of the most dynamic facets of the TME collaborative network . A majorThe reprogramming of macrophages by tumor-educated macrophages through exosome carrying oncomiRs leads to the creation of a microenvironment for tumor growth. M2 macrophages in turn take responsibility for cancer cells by releasing exosomes that promote tumor growth and metastasis. M2 macrophage-derived exosomes can promote the progression of colon cancer  and gastCancer cells develop multiple mechanisms to counteract the immune system antitumoral attack. A major one is the alteration of miRNA expression both in tumor cells and their microenvironment. Tumor cells aberrantly express several miRNAs, and this deregulation of the expression is characterized by high expression levels of oncomiRs and downregulation of TS miRNAs. In cancer cells, miRNAs can downregulate antigen presentation to impair recognition by T cells. To suppress an effective immune response, cancer cells can downregulate TS miRNAs that inhibit immunosuppressive factors and inhibitory costimulatory molecule expression to directly suppress T-cell and NK-cell activation. MiRNAs also regulate different stromal cells and indirectly impact the recruitment and differentiation of suppressive immune cells, such as Tregs, TAMs and others that are present in the TME . A previTumor infiltration by leukocytes is usually considered a good prognostic marker and is necessary for successful immune elimination. Impaired antitumor activities of T cells are a major goal of cancer cells. The growth and development of tumors is often associated with deregulation of antigen expression, which impairs the recognition of tumor cells by immune effector cells . This alFrequently, cancer cells escape lysis by cytotoxic T lymphocytes (CTLs) and NK cells by downregulating human leukocyte antigen (HLA) class I expression on their surface . T cellsvia the miR-21-5p/YOD1/YAP/β-catenin pathway , macrophages or a reduction in key players of the antigen presentation machinery in these cells could lead to ineffective T-cell stimulation and consequently drive a T-cell activation reduction that directly affects T-cell function and polarization . Given t pathway , 60 . This deregulation of ICP expression is associated with the emergence of T-cell exhaustion in many cancers . Cancer via immune checkpoint inhibitors. Additionally, miR-23a was discovered to be a target of cancer cells in CD8 T cytotoxicity, and miR-23a expression in CD8+ T cytotoxicity inhibited the expression of B lymphocyte-induced maturation protein-1 (BLIMP-1), which is an important regulator required for the development and activation of T cells as well as their recruitment to the site of infection  and MHC class I-related chain A and B (MICA/B) expressed in cancer cells. All of these molecules are recognized by an NKG2D receptor that is expressed on the cell surface of various cells in the innate and adaptive immune systems , monocyte chemoattractant protein 1 (MCP1), CD80) and the production of TNF-α, and IL-1β decreases the secretion of TGF-β and IL-10 by these cells. Consequently, this leads to attenuated cancer growth by shifting M1 macrophages to M2 polarization  and PXN, two genes involved in the migration and infiltration of macrophages  by directly targeting its sequence  mice model, treatment by anti-miR-21 encased in nanoparticles showed specific uptake to breast cancer stem cells (BCSCs) and TNBC cells and high efficacy for tumor growth inhibition . SimilarCurrently, it has become obvious that miRNAs are widely involved in the interactions between cancer and immune cells in the TME. MiRNAs with oncogenic characteristics regulate cancer progression through several mechanisms, including inhibition of TS genes, suppression of immune cell antitumoral function, and especially modulation of suppressive immune cell function, such as TAMs and Tregs, in favor of cancer growth. Exosomal oncomiRs, which are actively produced by cancer cells, play a crucial role in the TME to support tumor progression and invasion. Several studies have provided mechanistic evidence that exosomal miRNAs absorbed by target cells can modulate gene expression patterns and thereby indirectly promote the development and invasion of cancer cells. The immune system is an important component of the TME. Several studies have shown that immune cells recognize cancer cells and could potentially eliminate them. Nevertheless, cancer cells develop numerous escape and resistance mechanisms; they can alter the expression of tumor antigens on their surface and increase the level of immune checkpoint proteins to modulate immune gene expression to disrupt the recognition of cancer cells by the immune system, contributing to immune evasion. Although our current understanding of the impact of miRNA expression on cancer progression is still in its early stage, the major role of oncomiR mediated interactions between immune and cancer cells opens the door to the development of therapeutic strategies targeting oncomiRs. In this review, we summarized the most common roles of oncomiRs in the development of cancer, focusing on recent advances in their role in regulating critical signaling pathways of cancer cells, and we discussed the potential application of exosomal oncomiRs as novel cancer-related biomarkers as well as their application in the treatment of cancer.The first author wrote the first draft. All authors contribute to editing and improving the manuscript and checked the literature for accuracy of references. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.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.


Endometriosis (EMS) is a chronic gynecological disease that affects women of childbearing age. However, the exact cause remains unclear. The uterus is a highly vascularized organ that continuously exposes endometrial cells to high oxygen concentrations. According to the “planting theory” of EMS pathogenesis, when endometrial cells fall from the uterine cavity and retrograde to the peritoneal cavity, they will face severe hypoxic stress. Hypoxic stress remains a key issue even if successfully implanted into the ovaries or peritoneum. In recent years, increasing evidence has confirmed that hypoxia is closely related to the occurrence and development of EMS. Hypoxia-inducible factor-1α (HIF-1α) can play an essential role in the pathological process of EMS by regulating carbohydrate metabolism, angiogenesis, and energy conversion of ectopic endometrial cells. However, HIF-1α alone is insufficient to achieve the complete program of adaptive changes required for cell survival under hypoxic stress, while the unfolded protein response (UPR) responding to endoplasmic reticulum stress plays an essential supplementary role in promoting cell survival. The formation of a complex signal regulation network by hypoxia-driven UPR may be the cytoprotective adaptation mechanism of ectopic endometrial cells in unfavorable microenvironments. Endometriosis is a common benign gynecological disorder characterized by the presence and growth of functional endometrial glands and stroma outside the uterine cavity, usually accompanied by reactive fibrosis and muscular metaplasia of affected organs , 2. UnfoEMS is closely related to dysmenorrhea, painful intercourse, painful defecation, and infertility in women of reproductive age and may seriously affect their quality of life , 6. In aThe exact pathogenesis of EMS is still unclear. However, the implant theory is still widely accepted as the mainstream theory . The hypAlthough menstrual reflux theory cannot explain all forms of EMS, it remains the most accepted hypothesis of EMS. Some scientists found that 76~90% of women have the phenomenon of menstrual blood regurgitation of fallopian tubes , and lapThe anatomical characteristics of the uterine vessels are that the body branches of the uterine arteries vertically discharge the arch artery along with the muscle layer of the lateral wall of the uterus. The uterine spiral artery then extends vertically into the endometrium, finally forming a blood-rich capillary network in the endometrium  family. HIFs, first discovered by Semenza et al.  in 1992,in vivo and in vitro  under endoplasmic reticulum stress (ERS) plays an essential complementary role in this process , 47. UPRThe endoplasmic reticulum (ER) is an extensive intracellular membranous network extending to the entire cytoplasm. The key site for lipid and glucose metabolism, calcium homeostasis, detoxifying drugs, and metabolisms is the central processing unit responsible for protein translation, folding, and modification . In protUPR is mediated by a partner molecule specific for the endoplasmic reticulum, namely glucose-regulated protein78(GRP78), and three transmembrane protein stress sensors , namely via TRAF2. It also promotes the expression of proteins related to disulfide bond formation and molecular chaperones and proteins involved in ER degradation and vesicle transport , a transcription factor containing zinc finger structure, is critical for UPR signaling network and acts on the folding of multiple proteins regulated by downstream target molecules. Under normal conditions, XBP1 exists in XBP1 unspliced (XBP1u). In the hypoxia state, XBP1u is activated into XBP1 spliced (XBP1s) by IRE1, enabling effective transcription of multiple target genes in the nucleus. Meanwhile, hypoxia can also induce XBP1 expression and activate its mRNA splicing in a HIF-1α dependent pathway, leading to increased XBP1s . When XBvia IL-8 related pathways. The protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway plays an essential role in enhancing the invasiveness of cells, and inhibition of this pathway can effectively reduce the invasiveness of various cancer cells , Department of Education of Zhejiang Province (Y202045691), and Zhejiang Province Key R&D Program (2021C03095).We gratefully acknowledge the assistance of Home for Researchers for language modification.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.