Cell monolayers that form a barrier between two structures play an important role for the maintenance of tissue functionality. In the anterior portion of the eye, the corneal endothelium forms a barrier that controls fluid exchange between the aqueous humor of the anterior chamber and the corneal stroma. This monolayer is central in the pathogenesis of Fuchs endothelial corneal dystrophy (FECD). FECD is a common corneal disease, in which corneal endothelial cells deposit extracellular matrix that increases the thickness of its basal membrane (Descemet’s membrane), and forms excrescences (guttae). With time, there is a decrease in endothelial cell density that generates vision loss. Transplantation of a monolayer of healthy corneal endothelial cells on a Descemet membrane substitute could become an interesting alternative for the treatment of this pathology. In the back of the eye, the retinal pigment epithelium (RPE) forms the blood-retinal barrier, controlling fluid exchange between the choriocapillaris and the photoreceptors of the outer retina. In the retinal disease dry age-related macular degeneration (dry AMD), deposits (drusen) form between the RPE and its basal membrane (Bruch’s membrane). These deposits hinder fluid exchange, resulting in progressive RPE cell death, which in turn generates photoreceptor cell death, and vision loss. Transplantation of a RPE monolayer on a Bruch’s membrane/choroidal stromal substitute to replace the RPE before photoreceptor cell death could become a treatment alternative for this eye disease. This review will present the different biomaterials that are proposed for the engineering of a monolayer of corneal endothelium for the treatment of FECD, and a RPE monolayer for the treatment of dry AMD. In the anterior portion of the eye, the corneal endothelium forms a barrier between the aqueous humor of the anterior chamber and the corneal stroma. In the posterior portion of the eye, the retinal pigment epithelium (RPE) forms a barrier between the choroidal blood supply and the photoreceptors. Both are made out of highly metabolically active cells that form a tightly packed cell monolayer. Both are also prone to age-related degenerative diseases, such as Fuchs endothelial corneal dystrophy (FECD) and dry age-related macular degeneration (dry AMD), in which extracellular matrix deposits  form underneath the monolayer, affecting their barrier integrity . In bothOn top of the common properties that biomaterials must have in terms of safety and biocompatibility, biomaterials intended for eye tissue replacement must take into account a curved shape, as both the cornea and the retina are curved structures. To fit perfectly in the eye, the biomaterial must also have the right size and thickness to limit folds, prevent graft displacement, and obtain optimal visual outcome. Abnormal curvature and folds can lead to partial or total graft detachment and loss of visual acuity. For barrier-forming cells, such as the corneal endothelium or the RPE, cells need to mature into a permeable barrier to support their physiological function. Depending on the biomaterial, this can include an additional step of surface modification to incorporate bioactive molecules or specific chemical cues to enhance cell-substrate interactions. The selected biomaterial also needs to consider the controlled permeability and transport properties to mimic the selective barrier function of the native monolayer. Finally, in the case of the corneal endothelium, the biomaterial also needs to be transparent, and should not support neovascularisation as it could lower visual acuity, create inflammation, diminish immune privilege, and lead to graft failure and rejection .Cells can perceive the mechanical proprieties of their substrate and respond to it. Therefore, the biomaterial should have mechanical properties that mimic the native environment, providing appropriate stiffness and elasticity to support cell function. Mimicking the mechanical cues of the native environment can aid in the polarization and functional maturation of both corneal endothelial  and RPE +K+-ATPase pumps and other ion transporters  , Descemet’s membrane, and an endothelium . Descemesporters . Cornealll cycle . Since t density . In oldensity (2 . Followiy (2 (2)  and exceBullous keratopathy is characterized by corneal endothelial decompensation associated with irreversible stromal edema. Conditions or events that give rise to bullous keratopathy include pseudophakic bullous keratopathy (PBK), a sterile or infectious inflammation, or FECD . EndothePBK and FECD are the first common causes of corneal transplantation worldwide . The curin vitro , seed them on a compatible biomaterial, and transplant them as a functional endothelial monolayer.Despite the high success rate of DSAEK/DMEK, important issues remain, such as graft dislocation , immunolOver the years, different types of biomaterials have been proposed for the engineering of the corneal endothelium. They include biomimetic substrates , natural membranes that have been repurposed for the engineering of the corneal endothelium, and synthetic scaffolds that are typically made of polymeric biocompatible materials. Engineering of the corneal endothelium also requires high quality cells that will reform a functional monolayer.As a proof of concept, immortalized CECs  can be uin vitro by disrupting contact inhibition and adding growth factors (2) , and du factors . Maintaitors (2) . Using ttors (2) .+, CD44−/dull, CD24−, and CD105− . Mature differentiated CECs should express the following profile of CD; CD166d CD105− . Some mein vitro .The limited expansion of primary cells can also be circumvented using stem cells. Many types of stem cells can be differentiated into CEC-like cells. Unipotent stem cells can be isolated by sphere-forming assay . HoweverCollagen is an abundant protein in most extracellular matrices , and DesSince collagen is a large protein, that is, hard to manipulate, collagen-like peptides (CLPs) are being studied as short peptides able to self-assemble into triple helices mimicking full-length collagen hydrogels . CLPs coIn vitro, silk membranes can support human  is a polymer that can be added to chitosan without extensive chemical modifications  and alloA mature monolayer of CECs has also been achieved using a self-assembled corneal stromal substitute . The bioIn an effort to be as biocompatible as possible, native thin membranes have also been proposed as biomaterials for the engineering of the corneal endothelium. Unlike biomimetic substrates, they require organ donation but have a more complex composition that can better mimic the Descemet’s membrane composition. However, their allogenic/xenogeneic nature and their mechanical resistance can be issues.Denuded amniotic membranes have been used as a corneal endothelium biomaterial. While the transparency is sub-optimal, endothelialized amniotic membranes have been grafted in rabbits  and catsThe anterior lens capsule is a transparent thick basement membrane with a similar collagen composition (type IV collagen and laminin α5 and β2) as the posterior surface of the Descemet’s membrane  and is cTilapia is a fish that possesses scales composed of type I collagen . Once deDescemet’s membrane itself can be used as a carrier. Indeed, Descemet’s membrane was the first carrier used for the engineering of the corneal endothelium . At the in vitro. However, many synthetic polymers are hydrophobic. This can be an issue since hydrophobic substrates tend to have low permeability to small hydrophilic molecules such as glucose, little to no degradation in aqueous conditions and low biocompatibility  (PMMA), polycaprolactone (PCL), poly (lactic-co-glycolic acid) (PLGA) , poly-ε-tibility . Biomatetibility . Albeit,tibility . To imprtibility . They catibility . A way ttibility . They weAfter demonstrating that cells attach and proliferate onto the biomaterial, the next step is to assess the functionality of the reformed monolayer. For the corneal endothelium, these functionality assessments include the expression of function-related markers, the integrity of the barrier, and the ability of the monolayer to pump fluid out of the stroma.in vitro proliferation phase. Other function-related proteins to study include Na + K + -ATPase, SLC4A11 and NBCe1. They are three membrane proteins that support the transport of ions across CECs cell membranes and help to generate a transendothelial osmotic gradient which facilitates the “pump mechanism” of the corneal endothelium  and return/maintain corneal transparency following transplantation. Rabbits are often used as models because of the size of their cornea (radius of 7.26 mm) . They arin vivo . It is, in vivo .in vivo  can be performed, additional tests might be necessary. When a bioengineered corneal endothelium is grafted into an animal model with known in vivo proliferative capabilities , it is crucial to demonstrate that the reformed endothelium is issued from the graft and not from the animal itself. For this particular purpose, grafted cells can be fluorescently labeled  and different neuronal cells, namely, ganglion, horizontal, bipolar, amacrine, and photoreceptor cells. Photoreceptors are in direct contact with the RPE. The RPE is a monolayer of regularly arranged cuboidal epithelial cells that are tightly packed owing to tight junctions (ZO-1) between cells. RPE cells along with the underlying Bruch’s membrane form the outer blood-retinal barrier (oBRB) that separates the choroid blood supply from the photoreceptors of the outer retina .Bruch’s membrane is a thin (2–4 µm), elastic, acellular, fibrous, and semi-permeable extracellular matrix with a pentalaminar structure that separates the RPE cells monolayer from the choriocapillaris. The five layers of Bruch’s membrane consist of the basement membrane of the RPE, the inner collagenous layer, the elastin layer, the outer collagenous layer and the choriocapillaris basement membrane . The comRPE cells support the adjacent layer of photoreceptors by regulating the diffusion of nutrients, ions, and metabolic wastes through the oBRB, by phagocyting photoreceptor outer segments, and by absorbing scattering light (thanks to their melanin). This oBRB, therefore, helps maintain the structure and function of the photoreceptors and the choroid. In a diseased state, the oBRB becomes disrupted and the interaction between the choroid and RPE cells becomes impaired, which consequently leads to RPE cells degeneration, photoreceptor cells degeneration, and vision loss .Age-related macular degeneration (AMD) is a multifactorial disease that progressively causes irreversible central vision loss in the elderly population (≥65 years old) and accounts for about 10% of blindness worldwide . AMD canDry AMD contributes to 90% of AMD cases, while 10% of patients present wet AMD symptoms. AMD commonly starts with the dry form, then can progress to the wet form . As an iThe current gold standard treatment for wet AMD is intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF). This treatment option has proven to slow exudative AMD progression and improve visual outcomes by decreasing retinal fluid and subretinal neovascularization . For dryTezel and Del Priore described RPE cells as anchorage-dependent cells that should be reattached to a substrate before transplantation to prevent apoptosis . To thatin vitro studies  and induced pluripotent stem cells (iPSC) can be differentiated towards an RPE fate using a rapid and directed method described by Foltz and Clegg . In brieHuman umbilical cord mesenchymal stem cells (hUCMSC) differentiation to PRE cells using CRX, NR2E1, C-MYC, LHX2, and SIX6 transcription factors is outlined recently by in vivo  induced tyrosine kinase activity in RPE cells which in turn enhanced photoreceptor outer segment phagocytosis by RPE cells. This conjugated nano chitosan, synthesized by Jayaraman, et al., could therefore serve as a carrier for retinal drug delivery and AMD treatment , translucid, and elastic tissue that represents the innermost layer of the placenta. Owing to its ECM structural composition , this membrane has exhibited favorable mechanical properties like permeability, cell adhesion, and elasticity . Additioin vitro.Descemet’s membrane is another natural substrate with features resembling Bruch’s membrane characteristics concerning the abundant presence of type IV collagen, laminin and fibronectin. Discussed biomimetic and natural biomaterials have some drawbacks that make them inefficient for clinical usage and need to be overcome in future studies. Poor biomechanical strength, high biodegradability, difficult processing condition, infection probability, and the possibility of constituents and property changes associated with processing procedures are certain disadvantages related to natural biomaterials. Although some methods like cross-linking have been introduced to enhance their mechanical strength, they have the disadvantage of producing a thicker, non-permeable, and non-biodegradable biomaterial .Hydrogels imitate Bruch’s membrane structure and can be physically and chemically cross-linked to natural  and synthetic polymers (poly (ethylene glycol) (PEG), poly-L-lysine (PLL), poly (3-caprolactone) (PCL), poly (methacrylate-co-meth acrylamide) (PMMA), poly  (PVA), and poly (hydroxyethyl methacrylate) (PHEMA)) to encapsulate cells, stem cells, and drugs .+ cells from peripheral blood of three dry AMD patients to produce oncogenic mutation-free clinical-grade iPSC-RPE patches. They seeded iPSC-RPE cells on PLGA substrates and transplanted them into the subretinal area of immunocompromised rats and pigs. These PLGA iRPE patches significantly improved RPE monolayer integration into the host Bruch’s membrane, differentiation, and functionality (Poly (glycolic acid) (PLGA) is an FDA-approved biomaterial with remarkable properties including high biocompatibility, non-toxicity, high cell adhesion, good mechanical properties, and adjustable biodegradation rate. Sharma et al. isolated CD34ionality .Poly (chloro-para-xylylene) (parylene C) is a FDA approved class IV biocompatible polymer, that is, widely adopted for biomedical applications and drug delivery thanks to its mechanical strength, flexibility, transparency, chemical inertness, conformability, and good encapsulation efficiency . In a loin vivo biocompatibility, low melting temperature, hydrophobicity, and high porosity nature  is another FDA approved synthetic polymer for controlled intraocular drug delivery. This polymer is identified by its notable slow degradation rate, great y nature . Belgio ubstrate . Liu et ubstrate , poly  can be used to measure the RPE monolayer barrier’s integrity, which is related to the correct expression of tight junctions . TransmiELISA assay is an approach to assess the concentration of growth factors secreted by RPE cells including pigment epithelium-derived factor (PEDF) and vascular endothelial growth factor (VEGF) . The pha® 568 Hydrazide sodium salt or Allura Red AC (496.42 Da) across the membrane was measured by calculating the permeability coefficients  nor fovea, do not have drusen deposits similar to humans, and have small size eyes . Royal Cin vivo .Macaca mulatta) and cynomolgus macaque (Macaca fascicularis). Limited genetic models, expensive preservation, longer time for AMD induction, and challenging reproduction have restricted their application , in vitro functionality. Finally, another challenge is their surgical compatibility, where the engineered tissue must fit the shape and stay in place once implanted, and the surgery itself must not generate complications for the patient. Further research is required to meet these challenges. Tissue engineering holds great promise in generating functional corneal endothelium or RPE deliverable for transplantation in humans.While many biomaterials have been proposed for the engineering of the corneal endothelium and the RPE using cultured cells, very few have reached the clinical trial phase. Part of the reason resides in the properties of the biomaterial itself. Finding the right combination of thickness, composition, and mechanical properties is a challenge. Part of it is also related to the production of high-quality matured cells that have reformed a functional barrier of high cell density. There is also a need to develop tools to assess tissue quality and


Difficulty kneeling following total knee arthroplasty (TKA) remains highly prevalent, and has cultural, social, and occupational implications. With no clear evidence of superiority, whether or not to resurface the patella remains debatable. This systematic review examined whether resurfacing the patella (PR) or not (NPR) influences kneeling ability following TKA.This systematic review was conducted by following PRISMA guidelines. Three electronic databases were searched utilizing a search strategy developed with the aid of a department librarian. Study quality was assessed using MINROS criteria. Article screening, methodological quality assessment and data extraction were performed by two independent authors, and a third senior author was consulted if consensus was not reached.A total of 459 records were identified, with eight studies included in the final analysis, and all deemed to be level III evidence. The average MINORS score was 16.5 for comparative studies and 10.5 for non-comparative studies. The total number of patients was 24,342, with a mean age of 67.6 years. Kneeling ability was predominantly measured as a patient-reported outcome measure (PROM), with two studies also including an objective assessment. Two studies demonstrated a statistically significant link between PR and kneeling, with one demonstrating improved kneeling ability with PR and the other reporting the opposite. Other potential factors associated with kneeling included gender, postoperative flexion, and body mass index (BMI). Re-operation rates were significantly higher in the NPR cohort whereas PR cohorts had higher Feller scores, patient-reported limp and patellar apprehension.Despite its importance to patients, kneeling remains not only under-reported but also ill-defined in the literature, with no clear consensus regarding the optimum outcome assessment tool. Conflicting evidence remains as to whether PR influences kneeling ability, and to clarify the situation, large prospective randomized studies are required. Despite COVID-19 disruptions, 226,350 primary total knee arthroplasties (TKAs) were carried out within England and Wales between January 2018 to December 2020 as per National Joint Registry (NJR) data and it is estimated that, by the year 2030, about 3.48 million TKAs will be performed annually [Cohort studies revealed that post-TKA satisfaction ranged from 81%–89%, with a large UK cohort study exhibiting that 18.6% of 1217 consecutive patients were either unsure of or dissatisfied with their results one-year post-TKA –6. Many Prost defined kneeling in 1974 as a postural position in which at least one knee is in contact with the ground while body-weight is supported predominantly through the knees . DiffereKneeling ability is consistently the poorest of the patient-reported outcome measures (PROMs) following TKA and remains prevalent in both the short and longer terms, with one study revealing that 67% of patients reported much difficulty or found it impossible to kneel five years after TKA . KneelinAssociations between intraoperative variables and postoperative kneeling ability have been investigated with contradictory results. One such variable is whether or not to resurface the patella during TKA, which remains largely at the discretion of the operating surgeon , 18. ThiThis systematic review was conducted by following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines  and was A systematic search strategy and syntax were developed with the aid of the department librarian. A combination of Medical Subject Heading (MeSH) terms and keywords were incorporated to electronically search EMBASE and Medline libraries using Healthcare Database Advanced Search (HDAS) and the native PubMed database from inception to October 2021 (Table Inclusion criteria were (1) Studies involving patients undergoing a TKA, with PR or NPR, with kneeling outcomes reported, (2) Papers published in English with full text available, (3) Peer reviewed clinical studies. Exclusion criteria included (1) Studies presenting non-original data, case reports, review studies, conference abstracts, editorials, opinion papers and letters to the editor. (2) Mixed cohort of patellar resurfaced (PR)/non-resurfaced (NPR) TKA patients with no direct comparative analysis of kneeling outcomes.Duplicates were removed from the list of papers identified. Titles and abstracts were screened by two independent reviewers , who then screened the full-text papers of relevant studies. The final study selection was completed by two independent reviewers as per pre-defined inclusion/exclusion criteria. Any inconsistencies were discussed with a third, senior reviewer (DHS) available for consultation if consensus was not achieved.The methodological quality of the studies was scored by two independent reviewers  using the Methodological Index for Non-Randomized Studies (MINORS) tool . The levTwo independent authors  extracted data from the included studies, comprising study characteristics, patient demographics, implant characteristics, surgical details, details of kneeling outcomes compared between PR and NPR, details of variables associated with kneeling outcomes other than PR, variables other than kneeling compared between PR and NPR cohorts, study conclusions and limitations.Based on the heterogeneity in study data particularly in the tools utilized to assess kneeling ability, it was decided a quantitative meta-analysis was not feasible.The electronic search of the EMBASE and Medline libraries via HDAS and the native PubMed database identified 459 articles. After removing duplicates and irrelevant records based on titles and abstracts, nine articles were eligible for full-text screening. One additional record was identified by reviewing reference list of a relevant review article. No articles were identified by a search of grey literature. Full texts for a total of ten articles were screened with two records excluded as per inclusion/exclusion criteria, leaving eight records included in the final qualitative analysis of the review Fig. .Fig. 1PRAll eight studies included were of retrospective cohort design with a level of evidence of III –30. AverAll eight studies were published between 2002 and 2020. Four were UK-based, with one each from the USA, Canada, Australia, and Switzerland (Table All eight studies recorded kneeling as a PROM. One study used question SP5 from the Knee Injury and Osteoarthritis Outcome Score (KOOS) . One stuThree studies used a cruciate-retaining (CR) implant preserving the posterior cruciate ligament (PCL) , 29, 30,In two studies, a medial parapatellar approach , 30 was Two studies reported a statistically significant link between PR and kneeling following TKA , 26. HuiSangoi et al. used the summation of OKS questions 5, 7 and 12 to assess self-reported kneeling ability, although only question 7 is specifically about kneeling. They showed that the PR cohort reported greater improvements compared to the NPR group, and the improvement postoperatively was statistically significant for the PR group but not the NPR group . Baker eHuish Jr et al. reported that kneeling ability was significantly higher in female patients , but conOutcomes other than kneeling compared between PR and NPR are presented in Table There remains a sparsity of literature directly comparing kneeling outcomes between PR and NPR cohorts of patients receiving TKA. Of the studies identified in the systematic search process of this review, only two reported statistically significant findings, with one study favoring PR  and anotWilding et al. reported significantly improved kneeling ability after TKA with PR . KneelinConversely, Huish et al. reported that NPR patients had a higher self-reported ability to kneel . ResurfaIt is important to note that Huish Jr et al. reported kneeling ability as a PROM whereas Wilding et al. additionally assessed kneeling ability clinically. Self-reported kneeling ability has been shown to be inferior to observed kneeling ability  and a stHuish Jr et al., however, conducted a follow-up of longer period (both for PR and NPR cohorts) for their study when compared to Wilding et al. This is significant as kneeling PROMs have been shown, in a large prospective study of 5,600 OKS questionnaires, to drastically improve up to a year following surgery and subsequently worsen in the years thereafter, which might be explained by old age of the subjects . In addiWhether or not to resurface the patella remains a contentious topic, with a lack of clear evidence supporting one technique over the other. A meta-analysis of RCTs in 2005 commented on an increased risk of re-operation with NPR  and thesConflicting evidence has also been presented with regards to whether PR influences PROMs. One study found no significant difference in the IKS function score  while anMany studies reported no difference between posterior-stabilized (PS) and cruciate-retaining (CR) designs with regards to clinical, functional and radiological outcomes , 45. HowSkin incision has been shown to impact kneeling ability, with a recent systematic review and meta-analysis reporting that patients had improved odds of kneeling with anterolateral incisions compared to anteromedial incisions; a transverse incision compared to a longitudinal incision and a shorter incision compared to a longer one . Longer One of the non-surgical variables associated with kneeling ability is postoperative ROM. Most kneeling postures are high flexion activities with a minimum of 90 degrees of knee flexion required. Wilding et al. reported that knees that were able to flex to at least 100 degrees had significantly improved chances of kneeling , which iOther non-surgical factors associated with kneeling ability include BMI and gender. An inverse relationship between kneeling ability and BMI has been reported in the literature . This maMorphological differences between male and female knees previously led to the development of gender-specific implants, but studies looking at whether these differences result in variation in clinical and functional outcomes between men and women have produced conflicting findings , 55. RooKneeling and the ability to kneel are poorly defined and infrequently reported in the literature, limiting the number of studies appropriate for inclusion. Variability also remains in how this outcome is assessed, often using Question 7 of the OKS or Question SP5 of the KOOS. There are, however, issues, because Question 7 of the OKS is not designed to be used in isolation to assess kneeling ability and neither question considers kneeling position, kneeling duration, the surface knelt upon, social, cultural or occupational importance. There is also variability with regards to how kneeling is assessed, which makes comparisons difficult. Due to the heterogeneous nature of the data, it was not possible to perform a meta-analysis.Comparing PR and NPR is difficult because there is a lack of standardization in the reporting of the surgical techniques and designs of implants used. There are also various options available to the surgeon with regards to the intraoperative management of the patella, including circumpatellar dennervation, osteophyte removal, patelloplasty and lateral retinacular release, which can be performed in isolation or combination, but once again, but these were not clearly reported.Kneeling is a complex multi-joint movement and hence also is affected by global disease, with arthritis of the spine, hips or contralateral knee affecting kneeling ability regardless of the postoperative outcomes of a TKA.Despite being highly important to patients and known to impact patient satisfaction, kneeling remains ill-defined, under-reported and under-investigated as an outcome measure. The available data regarding intra-operative variables such as PR and its impact on postoperative kneeling ability consists largely of small retrospective studies with no randomized studies identified in the systematic search of this review process. The results were conflicting, with a statistically significant association being identified in only two studies, one favoring PR and the other NPR. Other factors associated significantly with kneeling included BMI, postoperative flexion, and gender, with one study favoring females and the other males. No significant differences were observed between PR and NPR with regards to OKS, KSS and Euroqol scores. However, an increased rate of re-operation was reported in the NPR group. In the absence of large, randomized data sets comparing kneeling ability in PR and NPR patients, it is difficult to reach meaningful conclusions. In order to clarify the situation, large, long-term prospective randomized controlled studies (RCTs) are required with clear definitions of what kneeling entails and how to assess it best, so that standardized reporting can be performed and compared.


GCLSDA is an innovative framework that combines graph convolution networks and self-supervised learning for snoRNA–disease association prediction. Leveraging the repository of MNDR v4.0 and ncRPheno databases, we construct a robust snoRNA–disease association dataset, which serves as the foundation to create bipartite graphs. The computational prowess of the light graph convolutional network (LightGCN) is harnessed to acquire nuanced embedded representations of both snoRNAs and diseases. With careful consideration, GCLSDA intelligently incorporates contrast learning to address the challenging issues of sparsity and over-smoothing inside correlation matrices. This combination not only ensures the precision of predictions but also amplifies the model’s robustness. Moreover, we introduce the augmentation technique of random noise to refine the embedded snoRNA representations, consequently enhancing the precision of predictions. Within the domain of contrast learning, we unite the tasks of contrast and recommendation. This harmonization streamlines the cross-layer contrast process, simplifying the information propagation and concurrently curtailing computational complexity. In the area of snoRNA–disease associations, GCLSDA constantly shows its promising capacity for prediction through extensive research. This success not only contributes valuable insights into the functional roles of snoRNAs in disease etiology, but also plays an instrumental role in identifying potential drug targets and catalyzing innovative treatment modalities.Small nucleolar RNAs (snoRNAs) constitute a prevalent class of noncoding RNAs localized within the nucleoli of eukaryotic cells. Their involvement in diverse diseases underscores the significance of forecasting associations between snoRNAs and diseases. However, conventional experimental techniques for such predictions suffer limitations in scalability, protracted timelines, and suboptimal success rates. Consequently, efficient computational methodologies are imperative to realize the accurate predictions of snoRNA–disease associations. Herein, we introduce GCLSDA— The investigation into small nuclear RNAs (snoRNAs) and their correlation with diseases has gained substantial momentum in recent years. snoRNAs, a class of small noncoding RNAs, are widely distributed within the nucleus of eukaryotic cells . In vert control . Their a control . The per control ,5,6.Deciphering the intricate interplay between snoRNAs and diseases holds immense potential for groundbreaking advancements in diagnostic modalities and therapeutic strategies. For instance, snoRNAs may emerge as promising biomarkers for early disease detection and promising targets for innovative therapeutic interventions. Profound shifts in snoRNA expression within tumor cells, tissues, and bodily fluids could yield novel biomarkers for cancer diagnosis and therapeutic exploration. Furthermore, delving into the interplay between snoRNAs and diseases can furnish invaluable insights into the fundamental mechanisms underpinning disease onset and progression. By discerning the role of snoRNAs in healthy cellular contexts and deciphering their dysregulation’s contributions to disease states, researchers can identify novel avenues and targets for therapeutic intervention, thereby enriching our arsenal against various ailments.Currently, prediction methods for RNA–disease associations can be broadly classified into three categories: machine learning-based, network analysis-based, and deep learning-based approaches. Machine learning-based methods: This category encompasses techniques that utilize known snoRNA–disease association data to construct prediction models through various machine learning algorithms, enabling the prediction of novel associations. For instance, PSnoD  proposesNetwork analysis-based approach: This approach leverages bioinformatics and network analysis tools to investigate the functional interplay between RNA and diseases, often employing co-expression networks and protein interaction networks. For example, Sun et al.  proposedDeep learning-based approach: This class of methods harnesses the power of deep learning algorithms to acquire the embedded representations of RNA and diseases for predicting new associations. For example, GANCDA  proposesThe aforementioned prediction models offer various perspectives and avenues for researching the relationship between snoRNAs and diseases, providing informative references for understanding disease mechanisms and snoRNA functions. However, these methods encounter certain challenges. Machine learning-based approaches may face difficulties in feature selection, overfitting, and adapting to complex datasets. Network analysis-based methods might not adequately account for higher-order associations within intricate networks. Deep learning-based techniques could encounter issues related to overfitting and limited interpretability. Consequently, there is a need to refine these methods to enhance the prediction accuracy and interpretability.In recent years, contrastive learning and graph neural networks have gained significant traction across various research domains. The former entails learning data representations by juxtaposing the similarities and differences between samples, while the latter effectively models interactions between nodes and edges in graphs, enabling both representation learning and prediction tasks. However, certain challenges persist within these methods. Notably, perturbations in the graph structure can lead to the loss of crucial information, thereby causing deviations in the results. To address these issues, we introduce a novel framework named GCLSDA in this study. In our previous study from 2021, we introduced GCNSDA , a pioneGCLSDA adopts a self-supervised approach for predicting snoRNA–disease associations, harnessing the capabilities of the light graph convolutional network (LightGCN) . LightGCIn this section, we outline the outcomes of our experimental endeavors utilizing the GCLSDA method for the prediction of snoRNA–disease associations.To rigorously assess the predictive prowess of our experimental methodology, we employed a systematic and unbiased approach by conducting performance evaluations using both five-fold cross-validation and ten-fold cross-validation techniques . These mThe dataset under consideration contains verified or established associations, which we randomly divided into k distinct subsets. For each iteration of cross-validation, one of these subsets was designated as the test set, while the remaining k-1 subsets were amalgamated to compose the training set. In order to ensure equitable evaluation conditions, we generated an equal number of negative samples at random for the test set. Notably, during the utilization of the training set, the negative sample generation process was omitted, as the algorithm itself encompasses this procedure.Regarding the potential presence of latent associations within the negative samples, their impact is deemed negligible due to their limited proportion within the overall unverified sample pool. Consequently, their influence on the experimental outcomes can be safely disregarded.To assess the predictive ability of our model in a more intuitive and understandable manner, we utilize widely adopted metrics in the industry, including the area under the curve (AUC) and area under the precision–recall curve (AUPR). These metrics provide a comprehensive measure of the model’s performance.The calculation formulas for the evaluation metrics are as follows:TP and FP represent the correct and incorrect classification results on the existing snoRNA–disease adversarial samples, respectively. TN and FN represent the correct and incorrect classification results on unrelated sample sets, respectively. The true positive rate (TPR), representing the proportion of correctly identified positive cases, and the false positive rate (FPR), indicating the proportion of incorrectly identified negative cases, are calculated. By adjusting the decision threshold, we can construct the ROC curve  using the uniform distribution Y and the sign function applied element-wise to the original embedding vector In this equation, Y with the sign of The sign function, denoted as From a geometric standpoint, adding the scaled noise vector to l denotes the layer compared to the final layer. In the training batch, i and j represent the samples of snoRNA and disease, respectively. In the contrastive learning framework, our objective is to minimize the feature representation augmented by the same embedding and maximize the feature representation of the different embedding with its added noise. In this experiment, we adopted the classical contrastive learning approach by utilizing the same perturbed representation for both tasks. Cross-layer contrast is employed to simplify the learning process. To facilitate contrastive learning, we incorporate the InfoNCE loss as an auxiliary task. The InfoNCE loss is defined as follows:Finally, we utilize the embedded representation of snoRNA This equation computes the inner product between the embeddings During training, we employ the pairwise Bayesian personalized ranking (BPR) loss  as the lB represents the training set consisting of triplets s is a snoRNA, Among them, To incorporate the contrastive learning objective, we combine the BPR loss with the contrastive learning loss using a regularization parameter This expression combines the BPR loss and the contrastive learning loss, allowing the model to optimize both the ranking performance and the feature representation learning through self-supervised contrastive learning.In conclusion, our self-supervised framework, GCLSDA, represents a significant advancement in predicting snoRNA–disease associations. By harnessing graph convolutional neural networks and incorporating contrast learning, GCLSDA adeptly addresses challenges related to data sparsity and noise, resulting in enhanced prediction precision and model robustness. The comprehensive evaluation of GCLSDA reaffirms its superiority over existing methodologies, highlighting its potential as a valuable and reliable resource for unraveling the functional underpinnings of snoRNAs in disease contexts.The promising performance of GCLSDA holds profound implications for disease understanding, drug exploration, and therapeutic strategies. Through precise predictions of potential snoRNA–disease associations, GCLSDA opens new avenues for deciphering the intricate pathogenic mechanisms of complex human ailments. This knowledge facilitates the development of refined, individualized diagnostic tools and therapeutic interventions, ultimately improving patient outcomes. As we continue to refine and expand computational tools like GCLSDA, we anticipate transformative impacts on precision medicine. Exploring higher-order associations within the bipartite graph structure and integrating diverse data sources, such as gene expression data, bodes well for future exploration. Further enhancements to snoRNA and disease embeddings through self-supervised learning will continue to amplify GCLSDA’s predictive potency and real-world applicability.However, it is worth noting that our current method has limitations, particularly in terms of database scale. While our approach performs efficiently on relatively small databases, its scalability to larger datasets may present challenges in terms of computational resources and optimization. Addressing these limitations will be a key focus of our future work, as we strive to extend the applicability of GCLSDA to more extensive datasets and further advance the field of computational snoRNA–disease association prediction.


Multiple anatomical variations in the nasal cavity are well-described in the literature. We describe a rare case of pneumatization of the frontal sinus in the nasal septum that we term "Septo-Frontal Cell". To the best of our knowledge, this pattern of nasal septum pneumatization has not been described in the literature before. We have discussed the clinical and radiological findings and management of this patient. Identifying and understanding the complex three-dimensional structures of the nasal cavity and paranasal sinuses (PNS) along with their frequent anatomical variations is crucial for otolaryngologists in the planning of sino-nasal, nasal, and other skull-base surgeries . MultiplA 39-year-old Middle Eastern male patient, not known to have any comorbidities, presented to our ENT clinic with a complaint of long-standing, left-sided nasal obstruction, associated with recurrent episodes of headache. The patient had no history of rhinorrhea, facial pain, reduced smell sensation, recurrent sneezing, nasal itchiness, nasal trauma, or previous nasal surgeries.The general physical appearance revealed a healthy-looking adult with no craniofacial abnormality and the nasal examination showed severe right-sided columellar dislocation and left-sided septal deviation with bilateral moderately enlarged inferior turbinate more on the right side. Internal nasal examination using a zero-degree endoscope showed a left nasal septal spur touching the left inferior turbinate; otherwise, the remaining nasal examination was within normal limits.A CT scan of paranasal sinuses showed a left nasal septal spur contacting the left inferior turbinate with a pneumatized bony nasal septum continuous with the left frontal sinus and a pneumatized crista galli Figure .The patient underwent septoplasty with bilateral submucosal diathermy of the inferior turbinate, intra-operative findings showed an S-shaped nasal septum with columellar dislocation to the right side, severe left-sided septal spur, and deviated maxillary crest to the left. The pneumatized part of the nasal septum was not obstructing the airway and hence was not corrected Figure . The patAnatomical sino-nasal variations, such as the deviated nasal septum, the presence of agger nasi, Haller and Onodi air cells, concha bullosa, and paradoxical middle turbinate, are commonly seen among the population ,3. PneumThe preoperative CT scan sinus in our patient shows in addition to the nasal spur, which is causing the patient’s symptoms, an over-pneumatized frontal sinus along with bilateral agger nasi, a pneumatized crista galli, and a frontal septal cell. These findings are not uncommon, agger nasi cells are seen anterior to or just above the insertion of the middle turbinate in the lateral wall, and their reported prevalence ranges from 10% to 90%  while thThe pneumatized nasal septum, when present, is usually related to the sphenoid sinus  and is nGiven the patient's complaint of nasal obstruction secondary to the deviated nasal septum, the patient opted for nasal septoplasty. A tailored approach for the septoplasty was crucial to avoid a potential anticipated complication, as the inadvertent opening of this cell can lead to either frontal sinus fistula in the septum or recurrent frontal sinusitis. Therefore, intraoperatively, we carefully corrected the nasal septal deviation by removing the left nasal septal spur while avoiding over-resection of the nasal septum; the Septo-Frontal Cell remained intact.To the best of our knowledge, this is the first case that describes a pneumatized anterior nasal septum continuous with the frontal sinus while a rare anatomical variation, shedding light on the possibility that the condition can lead to potential complications in a patient undergoing nasal surgeries. The role of routine preoperative PNS CT scans in patients undergoing septoplasty is controversial given the adverse effect of radiation and the increased cost ,11. HoweThis unique case highlights the previously unreported pneumatized anterior nasal septum continuous with the frontal sinus, which we have termed the "Septo-Frontal Cell", and its potential complications that may arise during nasal surgeries. The routine use of preoperative PNS CT scans remains a topic of debate. Our case underscores the potential value of such scans in assessing nasal anatomy and identifying variations to reduce avoidable surgical failures and complications.


Given the increasing number of people living with obesity and related chronic metabolic disease, precision nutrition approaches are required to increase the effectiveness of prevention strategies. This review addresses these approaches in different metabolic phenotypes (metabotypes) in obesity. Although obesity is typically associated with an increased cardiometabolic disease risk, some people with obesity are relatively protected against the detrimental effects of excess adiposity on cardiometabolic health, also referred to as ‘metabolically healthy obesity’ (MHO). Underlying mechanisms, the extent to which MHO is a transient state as well as lifestyle strategies to counteract the transition from MHO to metabolically unhealthy obesity (MUO) are discussed. Based on the limited resources that are available for dietary lifestyle interventions, it may be reasonable to prioritize interventions for people with MUO, since targeting high-risk patients for specific nutritional, lifestyle or weight-loss strategies may enhance the cost-effectiveness of these interventions. Additionally, the concept of tissue insulin resistant (IR) metabotypes is discussed, representing distinct etiologies towards type 2 diabetes (T2D) as well as cardiovascular disease (CVD). Recent evidence indicates that these tissue IR metabotypes, already present in individuals with obesity with a normal glucose homeostasis, respond differentially to diet. Modulation of dietary macronutrient composition according to these metabotypes may considerably improve cardiometabolic health benefits. Thus, nutritional or lifestyle intervention may improve cardiometabolic health, even with only minor or no weight loss, which stresses the importance of focusing on a healthy lifestyle and not on weight loss only. Targeting different metabotypes towards T2D and cardiometabolic diseases may lead to more effective lifestyle prevention and treatment strategies. Age and sex-related differences in tissue metabotypes and related microbial composition and functionality (fermentation), as important drivers and/or mediators of dietary intervention response, have to be taken into account. For the implementation of these approaches, more prospective trials are required to provide the knowledge base for precision nutrition in the prevention of chronic metabolic diseases. The prevalence of obesity, insulin resistance (IR) and related chronic metabolic diseases such as type 2 diabetes (T2D), cardiovascular diseases (CVD) and mental diseases has grown dramatically over the past decades, with far reaching consequences for individuals, society and economy , 2.A healthy diet may improve cardiometabolic health, even in the presence of minor weight loss . NeverthThis review will discuss the different metabotypes in obesity and their relationship with the risk of developing cardiometabolic disease, and highlight underlying (tissue-specific) metabolic disturbances. Next, our focus lies in assessing the efficacy of a precision-based approach that targets specific (tissue) metabotypes to enhance the success of nutritional or lifestyle interventions in individuals who are living with overweight or obesity. Results from recent dietary intervention studies that used a precision nutrition or lifestyle approach targeting specific metabotypes to further improve intervention effectiveness in individuals living with overweight or obesity will be discussed. Finally, future perspectives and approaches will be addressed.Although obesity is typically related to metabolic dysfunction and an elevated cardiometabolic disease risk, expansion of adipose tissue does not always result in metabolic perturbations. There is a group of individuals with obesity that is relatively protected against the detrimental effects of excess adiposity on cardiometabolic health, also alluded to as ‘metabolically healthy obesity’ (MHO). Several lines of evidence have shown that the absolute amount of body fat is not the main factor determining the metabotype in people with obesity. For example, abdominal liposuction did not improve metabolic health, including IR, in humans . FurtherThe location where lipids are stored is a stronger risk factor for metabolic and cardiovascular diseases than excess adiposity per se. Abdominal obesity (fat accumulation in the upper body) is positively associated with the development of obesity-related comorbidities and all-cause mortality, while lower body obesity  is related to a protective lipid and glucose profile, and a lower prevalence of cardiometabolic diseases after adjustment for total fat mass –21 . Rather, differences in the location where the excessive calories are stored seems to distinguish these obesity phenotypes. Indeed, several studies have shown that individuals with MHO have more subcutaneous adipose tissue , less visceral fat mass, less fat accumulation in the liver and skeletal muscle, and less macrophage infiltration and inflammation in  adipose tissue than people with MUO, matched for age, sex, BMI and fat mass –39. Of nTo date, there is no universally accepted definition of MHO. Most studies that compared characteristics of people with MHO and MUO phenotypes and/or examined the association of MHO with the risk of developing chronic diseases or mortality defined MHO as having ≤ 2 components of the metabolic syndrome, although the homeostasis model assessment of insulin resistance (HOMA-IR) was used to define MHO in other studies . This me2 [In addition to the criteria used to define MHO, the prevalences of MHO and MUO depend on several characteristics of the study populations such as BMI, age, sex, ethnicity and the absence/presence of other chronic diseases. These factors likely explain the large variability in reported MHO prevalence, ranging from ~5%  to ~50% (MHO defined as no metabolic syndrome) . It has 2 , younger2 –47, wome2 –45, and 2 .The risk of developing cardiovascular diseases among individuals in various BMI categories is likely influenced by their metabolic health. An key question is whether and to what extent metabolic health in people with MHO deteriorates over time and how this impacts cardiometabolic disease risk. Several prospective cohort studies and meta-analyses have demonstrated that the majority of people with MHO has an increased risk of T2D and cardiovascular disease compared to healthy people with normal body weight –51. A meA healthy lifestyle can reduce the risk of cardiometabolic complications and many chronic diseases significantly. Several large population studies have investigated habitual dietary intake in people with MHO and MUO. Most of these studies found that total dietary energy intake and macronutrient composition was similar between individuals with MHO and MUO , 68, 69.The first treatment recommended for body weight and cardiometabolic health management is lifestyle intervention . To whatWould it also be possible to improve cardiometabolic health in MUO with nutritional or lifestyle interventions in the absence of marked weight loss? A very recent study investigated whether adherence to healthy diets was related to the incidence of metabolically unhealthy phenotypes in adults in various BMI categories. It was shown that high compliance with the Dietary Approaches to Stop Hypertension (DASH), Mediterranean (MeDi), and Mediterranean-DASH intervention for neurodegenerative delay (MIND) diets was related to a reduced risk of metabolically unhealthy normal weight. Furthermore, adherence to these dietary patterns was negatively associated with the incidence of MUO in those with MHO at baseline . FurtherDifferences in body composition, tissue-specific metabolism and insulin sensitivity between men and women not only underlies sexual dimorphism in cardiometabolic disease risk, but may also affect the response to prevention and treatment strategies in a sex-specific manner . Indeed,Insulin plays a crucial role in regulating nutrient partitioning within the body. Insulin resistance (IR) encompasses impaired insulin action in various tissues, including muscle, liver, adipose tissue, gut, and brain. This dysfunction may occur before the onset of cardiometabolic diseases.Importantly, IR may develop in different organs but the severity may vary between organs. Indeed, in individuals with prediabetes, the state of impaired glucose tolerance (IGT) or the state of impaired fasting glucose (IFG) and are characterized, among other factors by more pronounced peripheral  or more pronounced liver IR . ConsistIndividuals with more pronounced liver insulin resistance (LIR) and individuals with more pronounced muscle insulin resistance (MIR) can already be distinguished in the overweight or obese state . Using aFurthermore, tissue metabotypes may also vary based on tissue fat accumulation and may vary between sexes. Body composition profiles, as assessed by whole body magnetic resonance imaging (MRI), may further our understanding of the complex interplay between muscle and liver metabolism and ectopic fat and adipose tissue fat accumulation. Indeed, distinct etiologies towards cardiometabolic health outcomes have been shown for discordant visceral and liver fat phenotypes  as well Post-hoc analyses in large intervention studies show responders and non-responders that feed back to tissue metabotype –8, 83. PWe recently provided the proof-of-concept that a precision nutrition strategy according to an individual’s tissue metabotype, within the context of healthy dietary guidelines, results in a clinically relevant further improvement in insulin sensitivity and cardiometabolic health (C-reactive protein and plasma triacylglycerol concentrations) in individuals with overweight or obesity, independent of body weight change . IndividDuring recent years, research has shown that a disbalance in gut microbiota communities and functionality is implicated in a large number of chronic metabolic diseases including obesity, IR, T2D and cardiometabolic risk . Early sPrevotella copri and B. vulgatus), which have been linked to adverse metabolic effects [Our gut microbiota produces a large variety of health-modulating products, including short-chain fatty acids (SCFA) and branched-chain fatty acids (BCFA), by fermenting indigestible food components. It is increasingly clear that these products are essential for host health , 103. Th effects . Additio effects –107. Pre effects . Thus, iInterestingly, the tissue IR metabotypes, MIR and LIR are characterized by a differential microbial composition with the LIR metabotype having a higher abundance of SCFA producing genera . In line. Combined, the initial microbial composition and related SCFA production may be important determinants of dietary intervention outcome.Inter-individual differences in gut microbiota composition and functionality may be linked to an altered responsiveness to (dietary) interventions. Initial microbial phenotype has been shown to predict intervention outcome after dietary fiber interventions , after fBy investigating the relationship between metabotypes and intervention outcomes, we can identify which dietary approaches are most suitable for specific individuals or subgroups at risk for chronic cardiometabolic diseases. A better understanding of the biological, psychological and socio-economic factors that may underlie the MHO and MUO phenotypes will generate important knowledge on obesity-related cardiometabolic chronic diseases that may aid in the development of more personalized interventions. Based on the limited resources that are available for lifestyle interventions, it may be reasonable to prioritize interventions to people with MUO to improve the cost-effectiveness of interventions. A study investigating the effect of phentermine/topiramate-induced weight loss on the prevention of T2D in subjects who were stratified by the Cardiometabolic Disease Staging score (very similar to the MHO/MUO concept) in those with a high or a low cardiometabolic risk provided support for this assumption , demonst


Vaccine hesitancy poses a substantial threat to efforts to mitigate the harmful effects of the COVID-19 pandemic. To combat vaccine hesitancy, officials in the United States issued vaccine mandates, which were met with strong antivaccine discourse on social media platforms such as Reddit. The politicized and polarized nature of COVID-19 on social media has fueled uncivil discourse related to vaccine mandates, which is known to decrease confidence in COVID-19 vaccines.This study examines the moral foundations underlying uncivil COVID-19 vaccine discourse. Moral foundations theory poses that individuals make decisions to express approval or disapproval  based on innate moral values. We examine whether moral foundations are associated with dimensions of incivility. Further, we explore whether there are any differences in the presence of incivility between the r/coronaviruscirclejerk and r/lockdownskepticism subreddits.Natural language processing methodologies were leveraged to analyze the moral foundations underlying uncivil discourse in 2 prominent antivaccine subreddits, r/coronaviruscirclejerk and r/lockdownskepticism. All posts and comments from both of the subreddits were collected since their inception in March 2022. This was followed by filtering the data set for key terms associated with the COVID-19 vaccine  and mandates . These key terms were selected based on a review of existing literature and because of their salience in both of the subreddits. A 10% sample of the filtered key terms was used for the final analysis.P<.001).Findings suggested that moral foundations play a role in the psychological processes underlying uncivil vaccine mandate discourse. Specifically, we found substantial associations between all moral foundations  and dimensions of incivility  except for the authority foundation. We also found statistically significant differences between r/coronaviruscirclejerk and r/lockdownskepticism for the presence of the dimensions of incivility. Specifically, the mean of identity attack, insult, toxicity, profanity, and threat in the r/lockdownskepticism subreddit was significantly lower than that in the r/coronaviruscirclejerk subreddit (This study shows that moral foundations may play a substantial role in the presence of incivility in vaccine discourse. On the basis of the findings of the study, public health practitioners should tailor messaging by addressing the moral values underlying the concerns people may have about vaccines, which could manifest as uncivil discourse. Another way to tailor public health messaging could be to direct it to parts of social media platforms with increased uncivil discourse. By integrating moral foundations, public health messaging may increase compliance and promote civil discourse surrounding COVID-19. As of October 2023, more than 6,959,316 deaths and 770,875,433 cases of COVID-19 have been reported worldwide [Public reliance on social media  increased heavily during the COVID-19 pandemic for various reasons, including seeking information to ease pandemic anxiety and due to social distancing—in addition to news consumption . This gaIncivility has been investigated across various social media platforms in political and health contexts -19. AlthMoral foundations help individuals make decisions based on 5 innate moral values . Investigating the moral foundations of uncivil vaccine discourse can provide insight into the drivers of that incivility and offer practical implications for public health interventions against COVID-19. Thus, this work meaningfully contributes to the existing literature focused on eradicating the negative impact of COVID-19 through vaccine uptake.Scholars across different fields have found it difficult to develop one definition of incivility. Some studies have defined incivility as impoliteness, profanity, or specific actions such as derogatory language used by political officials . Coe et The moral foundations theory (MFT) offers one explanation for vaccine discourse incivility on social media platforms. The MFT posits that individuals can adaptively make decisions and express approval or disapproval based on 5 innate moral values: care and harm, fairness and cheating, loyalty and betrayal, authority and subversion, and sanctity and degradation . The carThe MFT reasons that everyone shares the same core moral values. However, individuals prioritize moral values based on external factors such as cultural and environmental influences . Indeed,Although researchers have used surveys to investigate moral foundations and behavior during the COVID-19 pandemic , such asRQ1: What moral foundations are linked to uncivil COVID-19 discourse?The sanctity and degradation moral foundation refers to purity in both the spiritual and physical sense. People who value physical sanctity aim to preserve their bodily well-being. While some research has found the sanctity foundation to predict the usage of masks during the COVID-19 pandemic, other work has found that it can predict vaccine hesitancy ,37. One Research suggests that purity is an area of political disagreement . UnderpiH1: Purity will positively predict COVID-19 vaccine mandate incivility.The existing literature on MFT categorizes distinct moral foundations into two clusters: (1) individualizing foundations , which concern the value of the individual, and (2) binding foundations , which concern group integrity .Individualizing moral foundations  are linked to protective COVID-19 behaviors ,32. ExisH2: Care will positively predict COVID-19 vaccine mandate incivility, andH3: Fairness will positively predict COVID-19 vaccine mandate incivility.Loyalty and betrayal or in-group loyalty refers to a person’s allegiance and devotion to their own group, and it may also have a role in COVID-19 discourse incivility. The pandemic gave rise to 2 different groups, individuals who encouraged protective pandemic behaviors  and individuals who disregarded protective measures  , suggestH4: In-group loyalty will positively predict COVID-19 vaccine mandate incivility.Existing literature suggests that individuals condemn perceived leadership failures in hierarchical organizations . Thus, aH5: Authority will positively predict incivility in discussion about COVID-19 vaccine mandates.Organizational research suggests that incivility results from interactions between community and situational norms, which are shaped by organizational policies . CulturaRQ2: Does discourse incivility vary by cultural norms?Data were scraped from the Reddit website, a social media platform where anonymous users may post and interact with content organized into certain communities termed “subreddits.” We examined subreddits centered around COVID-19–related discussions and were likely to have uncivil discourse. For instance, one subreddit of interest was r/nonewnormal, a place for people to discuss and criticize COVID-19 lifestyle disruptions. R/nonewnormal would have been a worthwhile subreddit to scrape data from, but because it was banned for its strong antivaccine and antimask content, we could not collect the data . BecauseAll posts and comments from r/coronaviruscirclejerk and r/lockdownskepticism were collected since their inception in March 2022. The collected data set was then filtered for key terms related to words related to the COVID-19 vaccine  and key terms related to mandates , a tool that uses machine learning to detect comment incivility, was used to measure 5 dimensions of incivility, namely, toxicity, insults, profanity, threat, and identity attack , insult , toxicity , profanity , and threat . A significant positive correlation was observed between fairness and the dimensions of identity attack , insult , toxicity , and profanity . A significant positive correlation was observed between harm and the dimensions of identity attack , insult , toxicity , and threat . A significant positive correlation was observed only between in-group loyalty and identity attack . There were no significant correlations between authority and any of the dimensions of incivility , indicating that the null hypotheses can be rejected  in the r/lockdownskepticism subreddit were significantly lower than those in the r/coronaviruscirclejerk subreddit, suggesting that incivility does vary by platform norms. Recent studies have argued that platform norms vary within web-based cultures and within the microcultures of these platforms . BecauseThe COVID-19 pandemic has caused disruptions in all facets of life worldwide. Therefore, restoring trust in public health agencies and protocols is paramount. Tailored public health messaging incorporating social values  may help to reach, educate, and persuade individuals in a way that evokes civil responses and improve compliance -76. One This study is novel in that it uses a data set comprising posts from users who are banned from the antivaccine subreddits, which sheds light on unique and otherwise unexplored discourse. Another strength of our research is that it focuses on Reddit, a platform that is often overshadowed by Facebook and Twitter in extant literature. However, our study is also limited in that it focused on 2 specific subreddits, which are not representative of all vaccine-related discourse on Reddit and other social media. Future studies may benefit by focusing on comparing vaccine-related discourse across different social media platforms with a more comprehensive data set. Another limitation of our research is its observational nature that prevents us from implying causation. An extension of this study could focus on establishing a causal relationship between moral foundations and COVID-19 vaccine mandate incivility, if such a relationship exists. Also, our study used only 10% of the sample because of scarce computational resources, which limited us in our analyses. Future researchers should also consider investigating how moral foundations interact with different dimensions of incivility with a larger data set. In addition, future research can also use qualitative approaches and interview users who post uncivil conduct on social media sites such as Reddit. Because incivility is a multifaceted construct, such analyses can aid our understanding of incivility and shed light on the psychological processes that lead to uncivil discourse.This paper examined whether moral foundations were related to incivility surrounding COVID-19 vaccine discourse. We found that purity, fairness, harm, and in-group loyalty were positively related to different dimensions of incivility. This study adds to the growing literature focused on theorizing the mechanisms behind incivility related to COVID-19–related discourse. Our findings highlight the need for health campaigns to design messages appealing to specific moral foundations of specific demographics. For example, organizations such as the CDC have already created messaging that highlights moral foundations such as care and fairness by highlighting the protective nature of vaccines and their availability for all individuals (see


Editorial on the Research TopicCase reports in heart valve disease: 2022Heart valve disease affects tens of millions of people worldwide , greatlyZhou et al. report a successfully managed case of rheumatic right-sided valve disease, a rarely affected tissue that may result in severe rheumatic pulmonary regurgitation, by surgical valvular reconstruction.Understanding emerging causes, effective treatments as well as gaps enables the clinical and research communities to best address heart valve disease originating from bacterial infections. Rheumatic heart disease, an autoimmune inflammatory reaction with streptococci has been almost eradicated in several parts of the world. However, it remains the most common cardiovascular disease in children and young people worldwide, impacting vulnerable communities in sub-Saharan Africa, the Middle East, South-East Asia, and Western Pacific. Despite declining rheumatic heart disease burden, the 2015 Global Burden of Disease study estimated 29.7–43.1 million cases and about 300,000 associated deaths  is a minimally invasive procedure used frequently in high-income countries to treat aortic stenosis patients who are at risk for death from surgery. TAVR has also been suggested to be noninferior to surgery in low-surgical-risk patients . TAVR mais topic . QuadricKnowing the major and emerging causes of heart valve disease, and how to effectively treat them with minimal risk to patients is paramount to achieving declines in patient mortality. While the reports here represent a single or in some instances a small series of cases, they add to that larger goal by providing the heart valve community with greater knowledge on rare conditions as well as best practices to reduce patient treatment risks.


Tissue-resident macrophages (TRMs) are specialized myeloid cells that adapt to the local microenvironment and perform both core macrophage functions, such as phagocytosis and immune surveillance, as well as tissue-specific roles , a master regulator of microglia identity. SALL1 is not expressed in other macrophage populations except for Kolmer's epiplexus cells that populate the choroid plexus and might, in fact, be a subtype of microglia , also known as central nervous system (CNS)-associated macrophages (CAMs), that together maintain homeostasis of the CNS and its surrounding tissues  shares < 60% of amino acid identity between murine and human variants  expression , indicating that such iMGs have not yet attained bona fide microglial identity  are iPSC-derived 3D self-organizing assemblies of brain cell types and are used to model human brain development and disease (Lancaster and Knoblich, APOE4, and tailored to define iMG roles in distinct processes associated with disease progression. For example, how do iMGs respond to vascular amyloid seeding in perivascular neuroimmune organoids, mimicking cerebral amyloid angiopathy characteristic of AD? Importantly, neuroimmune organoids may help clarify how activated microglia shift from playing protective roles at early stages of neurodegenerative diseases to exacerbating tissue damage by sustained pro-inflammatory cytokine secretion and gliosis as the disease progresses (Deczkowska et al., In addition to studying the homeostatic roles of brain macrophages, neuroimmune organoids can be used to reveal macrophage phenotypes in the context of brain diseases . As the Signaling from the tissue microenvironment is indispensable for establishing the TRM identity. Therefore, developing an array of iPSC-derived neuroimmune organoids resembling different brain regions and structures will provide a platform for studying brain macrophage diversity using iMGs. Moreover, neuroimmune organoids will enable modeling of human-specific cell-to-cell interactions between iMGs and other brain-resident cell types, so that novel molecular pathways that establish brain macrophage identity, specialization, and dysfunction in disease may be uncovered. We anticipate that the iPSC-derived iMG and organoid platforms will be widely applied to better define microglia and BAM states, perform high-throughput drug screening, and clarify disease-associated phenotypes. It will be important to compare any findings obtained from neuroimmune organoids to the transcriptomes of primary human brain macrophages to determine whether iMGs in neuroimmune organoids faithfully recapitulate human macrophage biology (Bian et al., JC wrote the manuscript and prepared the figure. JC and YS edited and revised the manuscript. All authors contributed to the article and approved the submitted version.


Frontiers in Endocrinology features a series of studies focused on the paracannabinoids, a family of lipid-derived signalling molecules that include fatty acyl ethanolamides (FAEs) like oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), and fatty acyl esters, like 2-oleoyl-sn-glycerol. In contrast to the endocannabinoids, paracannabinoid substances are independent of CB1 or CB2 receptors; their actions require the activation of nuclear receptors such as peroxisome proliferator-activated receptor-α (PPAR-α), cell-surface transient receptor potential cation channel vanilloid-1 (TRPV1), and G- protein coupled receptor 119 (GPR119). However, most of the documented biological effects of OEA and PEA are exerted through PPAR-α ligation, which may account for their anti- inflammatory action, the control of energy metabolism (11700558), suppression of peripheral nociception , and neuroinflammation (35176443).This Research Topic of The paracannabinoid signalling system contributes to numerous physiological processes in various organs, where it participates in the control of intestinal motility (16143133), lipolysis in white adipose tissue , ketone body formation in the liver, which requires activation of H1 histamine receptors [30318340). Paracannabinoids most often operate in concert with the endocannabinoid system, providing parallel or antagonistic regulatory roles. A classic example is how endocannabinoids and paracannabinoid levels in the gastrointestinal tract change in opposing fashion according to the nutritional status. They also display opposite physiological effects along the gut-brain axis, where anandamide stimulates food intake whereas OEA suppresses it .Igarashi et al. posited that dietary oleic acid is an important satiety-inducing molecule. By feeding mice with a low-content or control oleic acid diet for several weeks, the authors show the impact of dietary oleic acid in the regulation of food intake and satiety via intestinal sensing of dietary fat and OEA, excluding the influence of other FAEs such as PEA and linoleoyl-ethanolamide. Studies in human subjects have shown that levels of dietary oleic acid or intraduodenal oleic acid infusion reduce appetite and energy intake , therefore the study by Igarashi et al. strengthens the notion of nutritional balance as a primary regulator of energy consumption.In the small intestine, dietary oleic acid stimulates OEA production  and in turn, OEA is metabolized into oleic acid and ethanolamine via two enzymatic pathways, the fatty acid amide hydrolase which is expressed in a variety of tissues, and the N- acylethanolamine hydrolysing acid amidase expressed in the intestinal epithelium (17121838). In this Research Topic, Dias-Rocha et al. show that maternal high-fat diet reduced anandamide and 2-arachidonoyl-sn-glycerol in rat breast milk, and increased adiposity in male and female offspring at weaning. Maternal high- fat diet also increased endocannabinoids and dopamine signalling in the nucleus accumbens of male offspring, a response associated with higher preference for fat in adolescence. The authors suggest that changes in the endocannabinoid pathway at weaning may contribute to the earlier metabolic phenotype in males, which present a more severe dysmetabolism in the long-term.Very few studies have investigated the role of endo- and paracannabinoids during lactation, and how these may shape the offspring’s nutrient choice and metabolic profile. For instance, there is a negative correlation between milk contents of OEA, PEA and stearoylethanolamide, and infants’ body weight during lactation (30428553). Maternal hypo- and hypercaloric diets change considerably the profile of both endo-and paracannabinoids in peripheral tissues as well as in the brain . It is assumed that maternal high-fat diet during gestation and lactation, besides changing the endocannabinoid system in a tissue-specific manner, instructs obesity in rodents’ offspring (30776574). In this Research Topic, Romano et al. consider the bloodstream as an alternative way for OEA to affect central homeostatic actions and cognitive responses. The authors report data suggesting that vagal sensory fibres may not be required for the neurochemical effects of exogenous OEA. After intraperitoneal administration, OEA concentrations increased in brain areas associated with the inhibition of food intake within few minutes, confirming that exogenously administered OEA can modulate eating behaviour (11700558), possibly by directly targeting neurons of specific brain nuclei. However, the fact that circulating levels of endogenous OEA do not increase after a meal (11700558) reminds us of the complexity of this problem and suggests that more work is needed to unravel it.OEA is one of the gut-derived satiety factors relaying signals to the hypothalamus to regulate feeding , and to other brain structures to strengthen memory consolidation . In this respect, OEA is one of the key players in the complex communication between the periphery and the central nervous system, linking peripheral functions with cognitive and emotional brain centres. The path by which OEA conveys signals from the periphery to the brain is still a matter of debate. Early studies suggested sensory afferent fibres as the main route (11700558). In this Research Topic, De Filippo et al. summarise in their review recent findings indicating a strict relationship between OEA and the intestinal microbiota in health and disease. The authors suggest that OEA acts as a trait d’union between gut microbiota and dynamic physiological and homeostatic processes. It is, therefore, conceivable that the malfunctioning of the crosstalk between paracannabinoids and intestinal microorganisms contributes to a variety of disorders such as enteropathies, obesity and associated chronic inflammatory status.Dysregulation of the endocannabinoid system has been associated with pathological conditions such as obesity, type 2 diabetes, and intestinal inflammation, and there is convincing evidence that selected intestinal microorganisms and endocannabinoids covary in pathological conditions such as the ones mentioned above (32106469). The active interplay between microbiota and paracannabinoids as well is beginning to be acknowledged as a potent regulatory system of the gastrointestinal homeostasis. This Research Topic of Frontiers in Endocrinology highlighted differences and similarities between the endo- and paracannabinoids, and hopefully it will inspire further research to better understand the complex modes of action of these systems.MBP: Conceptualization, Writing – original draft, Writing – review & editing. DP: Conceptualization, Writing – original draft, Writing – review & editing. GP: Writing – original draft, Writing – review & editing.


Peroxidasin is a heme-containing peroxidase enzyme that plays a vital role in the cross-linking of collagen IV molecules in basement membranes. Collagen IV cross-links are essential for providing structure and mechanical stability throughout tissue development, homeostasis, and wound healing. During cancer progression, the basement membrane is degraded, and proteins typically found in the basement membrane, including peroxidasin and collagen IV, can be found spread throughout the tumour microenvironment where they interact with cancer cells and alter cell behaviour. Whilst peroxidasin is reported to be up-regulated in a number of different cancers, the role that it plays in disease progression and metastasis has only recently begun to be studied. This review highlights the current literature exploring the known roles of peroxidasin in normal tissues and cancer progression, regulators of peroxidasin expression, and the reported relationships between peroxidasin expression and patient outcome in cancer. The basement membrane is a thin layer of highly specialised extracellular matrix that underlies epithelial and endothelial cells. It plays many important roles including providing structural support, determining the polarity of anchored cells, regulating cell growth and differentiation, and acting as a filter to regulate the movement of molecules between the bloodstream and the tissue ,2. Durin− to generate hypochlorous acid (HOCl), LPO oxidises SCN- to generate hypothiocyanous acid (HOSCN), whereas, both PXDN and EPO utilise Br- ions to form hypobromous acid (HOBr) [PXDN is a heme-containing enzyme first identified in the cardiovascular system . Other md (HOBr) . Whilst d (HOBr) , this acd (HOBr) ,10.in vitro studies in which cells were transfected with PXDN, MPO and LPO cDNA and seeded onto uncross-linked basement membrane, only cells transfected with PXDN cDNA were able to generate collagen IV cross-links [Importantly, although both PXDN and EPO produce HOBr and both have been shown to promote angiogenesis ,13, onlyss-links . More ress-links . Thus, tIn this mini-review, we discuss the known and emerging roles of PXDN in cancer progression, the known associations between PXDN expression and patient outcome, and examine the literature surrounding PXDN regulatory pathways and the implications of these in cancer progression.The PXDN enzyme contains four types of domains; the leucine-rich repeat (LLR), immunoglobulin (Ig), peroxidase and von Willebrand factor type C (VWC) domains ,14–17 F. Both peThe active site required for catalysis of HOBr is in the peroxidase domain which requires heme incorporation for correct function . AssociaCompared with matched healthy tissue, PXDN is up-regulated in a number of different cancers  includinInterestingly, no association has been seen between overall survival and PXDN expression levels in oral squamous cell carcinoma and breast cancer, however in both of these cancers there is reported to be an association between high PXDN expression and poorer disease-free or metastasis-free survival ,37. As sThere are limited studies examining the source of expression of PXDN in cancer. PXDN is predominantly expressed by epithelial and endothelial cells in healthy tissue where they are responsible for lens formation in the eye and vascular basement membrane deposition, respectively ,40,41. HPXDN is highly expressed in cancer cells undergoing epithelial to mesenchymal transition (EMT), a process which underpins metastatic dissemination and poor patient outcomes ,48. WhetThe primary known role of PXDN is cross-linking of collagen IV. This is required to provide structural integrity to the basement membrane in normal tissue maintenance and during repair. In cancer, there is commonly a loss of basement membrane integrity. The loss of the basement membrane structure as well as alterations in its biomechanical properties subsequently provides opportunity for increased cell invasion through the basement membrane, a key step associated with metastatic dissemination . CollagePXDN effects on cells are most likely through its collagen IV cross-linking activity, yet there is evidence to suggest that PXDN may have additional functions relevant to the cancer setting. For example, the capacity of the LRR domain in PXDN to interact with laminin  has raisAlternately, some studies have hypothesised that PXDN's use of hydrogen peroxide to catalyse the formation of HOBr, both of which are forms of reactive oxygen species (ROS), may be altering the levels of oxidative stress experienced by cancer cells. In non-cancerous aortic and endothelial cells, knockdown of PXDN with siRNA or shRNA led to a decrease in superoxide and ROS levels during oxidative stress ,56. In pPXDN driven changes in oxidative stress may also be mediated through alterations in cellular energetics and metabolism. Purine metabolism is known to be increased in cells to mitigate oxidative stress . Uric acTreatment of cells with excess exogenous fatty acids, such as palmitate, is known to trigger apoptotic cell death through impairment of autophagic flux. In cardiomyocytes treated with palmitate, increased levels of PXDN were observed, as well as reduced glucose consumption and impairment of autophagic flux, resulting in higher oxidative stress and subsequent cell death . siRNA dO-methylase Fbl has been shown to modify PXDN mRNA when guided by small nucleolar RNAs U32A and U51  as well as experimental setup may yield contrasting results.The exact role that PXDN plays in the progression of different cancers remains unclear and is likely multifaceted. Abnormal expression of PXDN in tumours has been linked to changes in cell viability, proliferation, migration, and invasion. Elevated PXDN was among the main ECM effectors identified in conditioned media from bone marrow derived mesenchymal stromal cells that induced migration of both PC3 prostate and MDA-MB-231 breast cancer cells . Short higration . Increasigration , and higigration . These dPXDN mediated cross-linking of collagen IV has been linked to changes in immune infiltration, which may play an important role in solid tumour progression. Intra-tracheal delivery of PXDN shRNA into the lungs of mice reduced collagen IV cross-linking and subsequently increased cytotoxic T lymphocyte migration into the lungs . These dExpression of PXDN has been linked to vascular tube formation and angiogenesis in endothelial cells ,13. AngiA range of transcriptional regulatory pathways of PXDN expression have been identified in different cancer cells, including methylation, transcription factors and microRNAs . MethylaPXDN typically exhibits a lower mutational burden than many common oncogenes. However, mutations in the PXDN gene appear frequently in uterine cancers , stomachThe nuclear factor Nrf2 has been shown to increase PXDN expression by HeLa cells through binding to the PXDN promoter region . The NrfPXDN regulation in cancer may also be a result of dysregulation of Snai1, a transcriptional repressor. ChiP-PCR analysis and functional assays in HeLa and SiHa cells showed binding of Snai1 to the PXDN promoter region upon TGF-b1 stimulation  led to rThe exact regulatory mechanisms of PXDN during homeostasis are not yet fully understood. For this reason, further research into this area in cancer, particularly in comparison with healthy tissue, is needed. A better understanding of the cancer-specific alterations in PXDN expression and activity, the downstream effects of collagen IV cross-linking, and role this plays in disease progression is needed.in vitro [Kinase signalling plays a pivotal role in cancer progression. Dysregulation of extracellular cues, such as aberrant matrix cross-linking, impact significantly on downstream intracellular signalling networks . Whilst in vitro  mediatedin vitro .PXDN may also play a role in modulating PI3K/Akt signalling in cancer . In U87.Other signalling pathways that have been shown to be modulated in endothelial cells by rPXDN protein include PDGFb, HB-EGF, CXCL, Hey-1, ID-2, SNAI-1 , FAK and50’s of several kinase inhibitors were all reported to be higher in cell lines with high PXDN expression compared with low PXDN. However these results were not separated for different cancer types [There is evidence to suggest that PXDN may influence tumour sensitivity to therapies. The ICer types . Additioer types . Whilst er types . Given tThe increased expression of PXDN in many cancers, as well as its links to increased cell proliferation, migration, invasion, and metastasis, suggest that it may be a viable candidate for therapeutic targeting in cancer. At present, no PXDN specific inhibitors have been developed. There are, however, a number of inhibitors that target peroxidases more broadly which have been shown to inhibit PXDN activity, including 4-aminobenzoic acid hydrazide (4-ABAH) ,7,80, phA key consideration will be the broad inhibition of multiple members of the peroxidase family including MPO and EPO, both of which are known to play important roles in solid tumours, contributing to tumour growth, collagen deposition and metastasis . DeficieGiven that PXDN mediated cross-linking of collagen IV is an essential process in basement membrane generation and repair, inhibition of this process outside of the tumour microenvironment may have negative effects. PXDN does not appear to be essential in development since mice with homozygous deletion of PXDN present with eye defects but no other severe morphological changes . Howeverin vitro with inhibitors such as CMK [An alternative approach would be to target post-translational regulators of PXDN. This approach has been trialled h as CMK , decanoyh as CMK , which th as CMK . Each ofUltimately, more research is needed to understanding the exact role that PXDN plays in different cancer types and how this is regulated before researchers and pharmaceutical companies consider PXDN to be an economically viable target for the development of targeted therapies.Peroxidasin is an enzyme with an emerging role in tumour progression and metastasis that is involved in extracellular matrix (ECM) remodelling and modulating the composition and organisation of the ECM.Peroxidasin promotes cancer cell invasion, angiogenesis, and has been associated with increased metastasis.Further research is required to better understand the molecular mechanisms of peroxidasin in cancer progression, as well as downstream signalling pathways and interacting partners of peroxidasin. This will allow for the development of targeted therapies for cancer treatment.