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Erythropoietin-producing hepatocellular (Eph) receptors comprise the largest group of surface receptors and are responsible for cellular signals. Eph/ephrin signaling has been identified to play a role in key cancer development and progression processes, especially in the upper gastrointestinal tract. The Eph/ephrin system has been described as a tumor suppressor in duodenal cancer, while in esophageal, gastric, hepatic, and pancreatic cancer, the system has been related to tumor progression. For their significant role in developing a wide range of malignancies, Eph receptors and their ligands have proven to be an important target for new anticancer therapies. In this review, we present an overview of the literature and highlight evidence supporting the role of the Eph/ephrin system in upper digestive tract cancers. In addition, we discuss molecular findings that represent promising therapeutic targets for these cancers. Eph receptors and ephrin in upper digestive system cancers [ABSTRACT FROM AUTHOR]

Background: Wound healing has a vital importance for the organism and various agents are used to accelerate wound healing. Although the effect of boron on wound healing is known, its mechanisms are not completely clear yet. In this study, the effect of boron in the Ephrin /Eph pathway will be evaluated. Methods: Forty adult female rats were used in the study. A full-thickness excisional wound model was created in all groups divided as Control, Fito, Boron and Plu groups. After the applications performed twice a day and lasting 7 days, skin tissues obtained and evaluated histopathological (inflammatory cell infiltration, oedema, and fibroblast proliferation density) and immunohistochemical (TNF-α, EphrinA1, EphrinB1, EphrinB2 and EphB4). Results: Inflammatory cell infiltration score was found to be higher in the Fito group compared to Boron group (p =.018). Fibroblast proliferation density was higher in Plu group than Boron group (p =.012). While TNF-α was lower in boron group than Plu (p =.027) and Fito (p =.016) groups, EphrinA1 was higher in Boron group than Plu group (p =.005). EphrinB1 expression was higher in Boron group compared to Plu (p =.015) and Fito (p =.015) groups, and the same difference was also observed in EphrinB2 (p values.000). Similarly, EphB4 immunoreactivity was higher in the Boron group compared to Plu (p =.000) and Fito (p =.002). Conclusion: One of the mechanisms of action of boron in wound healing is to increase EphrinB1, EphrinB2 and EphB4. Low TNF-α and histopathological findings indicate that boron limits extensive wound healing. [ABSTRACT FROM AUTHOR]

Erythropoietin-producing hepatocellular (Eph) receptors comprise the largest group of surface receptors and are responsible for cellular signals. Eph/ephrin signaling has been identified to play a role in key cancer development and progression processes, especially in the upper gastrointestinal tract. The Eph/ephrin system has been described as a tumor suppressor in duodenal cancer, while in esophageal, gastric, hepatic, and pancreatic cancer, the system has been related to tumor progression. For their significant role in developing a wide range of malignancies, Eph receptors and their ligands have proven to be an important target for new anticancer therapies. In this review, we present an overview of the literature and highlight evidence supporting the role of the Eph/ephrin system in upper digestive tract cancers. In addition, we discuss molecular findings that represent promising therapeutic targets for these cancers.

Bone homeostasis is a complex process in which some Eph kinase receptors and their ephrin ligands appear to be involved. In the present study, we address this issue by examining, both in vitro and in vivo, the role of EphB2 and EphB3 in mesenchymal stromal/stem cell (MSC) differentiation into bone tissue. This was first evaluated by quantitative reverse transcription PCR (RT-qPCR) and histological staining in MSCs cultured in specific mediums revealing that although EphB2−/− MSCs mainly expressed pro-adipogenic transcription factors, EphB3−/− MSCs showed abundant osteogenic transcripts, such as Runx2, Msx2, and Sp7. To clarify the underlying molecular mechanisms, we found that the lack of EphB3 signaling alters the genetic profile of differentiating MSCs, reducing the expression of many inhibitory molecules and antagonists of the BMP signaling pathway, and increasing Bmp7 expression, a robust bone inductor. Then, to confirm the osteogenic role of EphB3 in vivo, we studied the condition of 2 mouse models of induced bone loss (ovariectomy or long-term glucocorticoid treatment). Interestingly, in both models, both WT and EphB2−/− mice equally developed the disease but EphB3−/− mice did not exhibit the typical bone loss, nor an increase in urine Ca2+ or blood serum CTX-1. This phenotype in EphB3-KO mice could be due to their significantly higher proportions of osteoprogenitor cells and preosteoblasts, and their lower number of osteoclasts, as compared with WT and EphB2-KO mice. Thus, we conclude that EphB3 acts as a negative regulator of the osteogenic differentiation, and its absence prevents bone loss in mice subjected to ovariectomy or dexamethasone treatment. Lay Summary: Osteoporosis affects more than 200 million people, mostly women. Our work shows that the EphB3 receptor restricts bone formation, and its absence prevents bone loss in osteoporotic mice. The bone protection observed in EphB3-deficient mice is due to the presence of more bone-forming cells and fewer bone-degrading cells. Molecularly, we found that when there's no EphB3 in mesenchymal stem cells, some bone-promoting genes are increased while many inhibitors are reduced. Therefore, this receptor could become a key target for new therapies that would help to improve the quality of life for those suffering from bone diseases. We're really excited to share our findings with a broad audience, including patients, healthcare professionals, researchers, and the life sciences industry. Graphical Abstract [ABSTRACT FROM AUTHOR]

Aim: Previous reports have suggested successful infection by Epstein–Barr virus (EBV) in various brain cells; however, the entry mechanism is still elusive. In the present study, we investigated the entry pathway of EBV into astrocytes. Materials & methods: For virus entry, receptors are considered as a instrumental moieties for infection. Upon EBV infection, the expression of receptors such as Ephrin, neuropilin and nonmuscle myosin heavy chain-II were assessed in a time-dependent manner. Then, by using inhibitors, we investigated the role of membrane cholesterol, the dynamin protein and, eventually, EBV colocalization in endosomal vesicles. Results: EBV induced changes in the expression of numerous receptors, especially EphA4, EphA10 and NMHC-IIB. Upon binding to its receptor, the virus translocates into the lipid raft region of the plasma membrane, and its depletion results in decreased EBV internalization. The inhibition of dynamin also mitigated EBV entry. Subsequently, EBV colocalized in the endosomal compartment with markers such as EEA1, Rab5, Rab7 and LAMP1. Conclusion: The current work implicitly indicates that EBV follows the endocytic pathway to enter brain cells, although further validation by knocking down these proteins is needed. These findings will further enable us to pinpoint therapeutic targets. Plain Language Summary Epstein–Barr virus (EBV) is linked to neurodegenerative diseases like multiple sclerosis (MS). Immune cells responding to EBV infection have been found in the brain of these patients. The exact way in which the virus enters cells in the brain is unknown. Our study looks at how EBV enters a type of brain cells called astrocytes. Article highlights Epstein–Barr virus enters astrocytes via different receptors, such as EphA4 and NMHC-IIB. EBV internalization decreased upon depletion of the lipid rafts. The dynamin protein plays a crucial role in EBV entry into astrocytes, and its depletion indicates a decrease in EBV entry. The colocalization of EBV with endosomal vesicles was detected via markers such as EEA1, Rab5, Rab7 and LAMP1. [ABSTRACT FROM AUTHOR]

Pediatric neoplasms represent a complex group of malignancies that pose unique challenges in terms of diagnosis, treatment, and understanding of the underlying molecular pathogenetic mechanisms. Erythropoietin-producing hepatocellular receptors (EPHs), the largest family of receptor tyrosine kinases and their membrane-tethered ligands, ephrins, orchestrate short-distance cell–cell signaling and are intricately involved in cell-pattern morphogenesis and various developmental processes. Unraveling the role of the EPH/ephrin signaling pathway in the pathophysiology of pediatric neoplasms and its clinical implications can contribute to deciphering the intricate landscape of these malignancies. The bidirectional nature of the EPH/ephrin axis is underscored by emerging evidence revealing its capacity to drive tumorigenesis, fostering cell–cell communication within the tumor microenvironment. In the context of carcinogenesis, the EPH/ephrin signaling pathway prompts a reevaluation of treatment strategies, particularly in pediatric oncology, where the modest progress in survival rates and enduring treatment toxicity necessitate novel approaches. Molecularly targeted agents have emerged as promising alternatives, prompting a shift in focus. Through a nuanced understanding of the pathway's intricacies, we aim to lay the groundwork for personalized diagnostic and therapeutic strategies, ultimately contributing to improved outcomes for young patients grappling with neoplastic challenges. [ABSTRACT FROM AUTHOR]

From the moment a cell is on the path to malignant transformation, its interaction with other cells from the microenvironment becomes altered. The flow of molecular information is at the heart of the cellular and systemic fate in tumors, and various processes participate in conveying key molecular information from or to certain cancer cells. For instance, the loss of tight junction molecules is part of the signal sent to cancer cells so that they are no longer bound to the primary tumors and are thus free to travel and metastasize. Upon the targeting of a single cell by a therapeutic drug, gap junctions are able to communicate death information to by-standing cells. The discovery of the importance of novel modes of cell–cell communication such as different types of extracellular vesicles or tunneling nanotubes is changing the way scientists look at these processes. However, are they all actively involved in different contexts at the same time or are they recruited to fulfill specific tasks? What does the multiplicity of modes mean for the overall progression of the disease? Here, we extend an open invitation to think about the overall significance of these questions, rather than engage in an elusive attempt at a systematic repertory of the mechanisms at play. [ABSTRACT FROM AUTHOR]

The eye lens is a transparent, ellipsoid tissue in the anterior chamber that is required for the fine focusing of light onto the retina to transmit a clear image. The focusing function of the lens is tied to tissue transparency, refractive index, and biomechanical properties. The stiffness and elasticity or resilience of the human lens allows for shape changes during accommodation to focus light from objects near and far. It has long been hypothesized that changes in lens biomechanical properties with age lead to the loss of accommodative ability and the need for reading glasses with age. However, the cellular and molecular mechanisms that influence lens biomechanical properties and/or change with age remain unclear. Studies of lens stiffness and resilience in mouse models with genetic defects or at advanced age inform us of the cytoskeletal, structural, and morphometric parameters that are important for biomechanical stability. In this review, we will explore whether: 1) tissue level changes, including the capsule, lens volume, and nucleus volume, 2) cellular level alterations, including cell packing, suture organization, and complex membrane interdigitations, and 3) molecular scale modifications, including the F-actin and intermediate filament networks, protein modifications, lipids in the cell membrane, and hydrostatic pressure, influence overall lens biomechanical properties.

Morphogenesis is a physical process that requires the generation of mechanical forces to achieve dynamic changes in cell position, tissue shape, and size as well as biochemical signals to coordinate these events. Mechanical forces are also used by the embryo to transmit detailed information across space and detected by target cells, leading to downstream changes in cellular properties and behaviors. Indeed, forces provide signaling information of complementary quality that can both synergize and diversify the functional outputs of biochemical signaling. Here, we discuss recent findings that reveal how mechanical signaling and biochemical signaling are integrated during morphogenesis and the possible context-specific advantages conferred by the interactions between these signaling mechanisms.

Abstract Purpose Emergency surgical procedures involve considerable risks. Among these, early postoperative hypoxemia (EPH) is a frequent anesthetic complication in the post-anesthetic care unit (PACU). There is a great concern for EPH among health professionals, specifically, those providing emergency surgery during the nighttime. This raised anesthesia-ended time-related risk of EPH question. Thus, this study aimed to determine the magnitude of EPH and its associated factors among adult patients who undergo emergency surgery under general anesthesia. Methods A prospective observational study through a consecutive sampling technique was conducted. Binary logistic regression analysis was used to identify associated risk factors. All variables that were found statistically significant on bivariable analysis were entered into a multivariable logistic regression analysis. Result Of 352 patients who had undergone emergency surgery, 149 (42.3%) patients developed EPH. Factors significantly associated with EPH were anesthesia ended during nighttime (AOR = 1.76, 95%CI [1.01, 3.05], p = 0.045), ASA III (AOR = 12.35, 95%CI: [4.5, 34.02], p ≤ 0.001), age greater than 55 (AOR = 3.2, 95%CI: [1.7, 5.91], p ≤ 0.001), surgery duration greater than 2 h (AOR = 2.012, 95%CI: [1.2, 3.51], p = 0.014), hypotension (AOR = 10.3, 95%CI: [2.4, 44.16], p = 0.002), muscular strength score zero (AOR = 2.944, 95%CI: [1.8, 4.82], p ≤ 0.001), and preoperative oxygen saturation less than 95% (AOR = 2.371, 95%CI: [1.35,4.16], p = 0.003). Conclusion The magnitude of EPH among patients who have undergone emergency surgery was high and thus recommended that oxygen should be provided timely to decrease it. Identified risk factors were night-time ended anesthesia, ASA III, age greater than 55, surgery duration greater than 2 h, hypotension, muscular strength score zero, and preoperative oxygen saturation less than 95%. This study found anesthesia ended during early morning favors early morning early postoperative hypoxemia (EMEPH). To avert EMEPH, the anesthetist should avoid factors that favor the circadian rhythm of the lung-based early morning anesthesia augmented EPH.

Craniofacial morphogenesis is a highly dynamic process that requires changes in the behaviors and physical properties of cells in order to achieve the proper organization of different craniofacial structures. Boundary formation is a critical process in cellular organization, patterning, and ultimately tissue separation. There are several recurring cellular mechanisms through which boundary formation and cellular organization occur including, transcriptional patterning, cell segregation, cell adhesion and migratory guidance. Disruption of normal boundary formation has dramatic morphological consequences, and can result in human craniofacial congenital anomalies. In this review we discuss boundary formation during craniofacial development, specifically focusing on the cellular behaviors and mechanisms underlying the self-organizing properties that are critical for craniofacial morphogenesis.

Purpose: Emergency surgical procedures involve considerable risks. Among these, early postoperative hypoxemia (EPH) is a frequent anesthetic complication in the post-anesthetic care unit (PACU). There is a great concern for EPH among health professionals, specifically, those providing emergency surgery during the nighttime. This raised anesthesia-ended time-related risk of EPH question. Thus, this study aimed to determine the magnitude of EPH and its associated factors among adult patients who undergo emergency surgery under general anesthesia. Methods: A prospective observational study through a consecutive sampling technique was conducted. Binary logistic regression analysis was used to identify associated risk factors. All variables that were found statistically significant on bivariable analysis were entered into a multivariable logistic regression analysis. Result: Of 352 patients who had undergone emergency surgery, 149 (42.3%) patients developed EPH. Factors significantly associated with EPH were anesthesia ended during nighttime (AOR = 1.76, 95%CI [1.01, 3.05], p = 0.045), ASA III (AOR = 12.35, 95%CI: [4.5, 34.02], p ≤ 0.001), age greater than 55 (AOR = 3.2, 95%CI: [1.7, 5.91], p ≤ 0.001), surgery duration greater than 2 h (AOR = 2.012, 95%CI: [1.2, 3.51], p = 0.014), hypotension (AOR = 10.3, 95%CI: [2.4, 44.16], p = 0.002), muscular strength score zero (AOR = 2.944, 95%CI: [1.8, 4.82], p ≤ 0.001), and preoperative oxygen saturation less than 95% (AOR = 2.371, 95%CI: [1.35,4.16], p = 0.003). Conclusion: The magnitude of EPH among patients who have undergone emergency surgery was high and thus recommended that oxygen should be provided timely to decrease it. Identified risk factors were night-time ended anesthesia, ASA III, age greater than 55, surgery duration greater than 2 h, hypotension, muscular strength score zero, and preoperative oxygen saturation less than 95%. This study found anesthesia ended during early morning favors early morning early postoperative hypoxemia (EMEPH). To avert EMEPH, the anesthetist should avoid factors that favor the circadian rhythm of the lung-based early morning anesthesia augmented EPH. [ABSTRACT FROM AUTHOR]

Breast cancer (BC) is the most common malignant tumor in women. Erythropoietin-producing hepatocellular receptors (EPHs), receptor tyrosine kinases binding the membrane-bound proteins ephrins, are differentially expressed in BC, and correlate with carcinogenesis and tumor progression. With a view to examining available therapeutics targeting the EPH/ephrin system in BC, a literature review was conducted, using the MEDLINE, LIVIVO, and Google Scholar databases. EPHA2 is the most studied EPH/ephrin target in BC treatment. The targeting of EPHA2, EPHA10, EPHB4, ephrin-A2, ephrin-A4, as well as ephrin-B2 in BC cells or xenograft models is associated with apoptosis induction, tumor regression, anticancer immune response activation, and impaired cell motility. In conclusion, EPHs/ephrins seem to represent promising future treatment targets in BC. [ABSTRACT FROM AUTHOR]

Kupffer cells are maintained via self-renewal in specific microenvironmental niches, primarily the liver sinusoidal endothelial cells (LSECs). In this study, we propagated tissue-resident macrophages (Mø) from mouse liver using mixed culture with hepatic fibroblastic cells. Propagated liver Mø express Id3, Lxra and Spic transcription factors, which are required for Kupffer cell characterization. Thus, Kupffer cell properties are likely to be maintained in liver Mø propagated using mixed culture with fibroblastic cells. We revealed (i) gene expression of certain Eph receptors and ephrin ligands including EphA2, ephrin-A1, EphB4, and ephrin-B1 in propagated liver Mø and primary LSECs, (ii) immunohistochemical localization of these Eph/ephrin member molecules indicating common expression in Kupffer cells and LSECs, and (iii) surface expression of several integrin α and β subunits, including α4β1, αLβ2, αMβ2, and αXβ2 integrin in propagated liver Mø and that of the corresponding ligands ICAM-1 and VCAM-1 in primary LSECs. Moreover, EphA/ephrin-A and EphB/ephrin-B interactions promoted liver Mø adhesion to the ICAM-1-adsorbed surface, which mimicked that of LSECs and may be implicated in the residence of Kupffer cells in the liver sinusoid. Further studies on regulating the residence and regeneration of Kupffer cells in related hepatic disorders are required to validate our findings. [ABSTRACT FROM AUTHOR]

Este trabajo estudia las características observables que determinan la duración de un individuo dentro del desempleo en Argentina para el período comprendido entre 2003 y 2019. El principal objetivo es presentar de una forma sistemática y ordenada las estadísticas sobre desempleo para caracterizar dicho período. Utilizando modelos de duración (Exponencial, Weibull y proporcionales de Cox) se obtiene que la edad de la persona es una de las variables que más inciden en dicho lapso, donde a mayor edad más aumenta la probabilidad de quedarse dentro del desempleo. Además de existir una diferencia significativa por región y por sexo, aquellos individuos que son jefe/a de hogar reducen la probabilidad de seguir en el estado de desocupación. Finalmente, no se halla evidencia empírica de que el sector donde se trabajó anteriormente influya en la duración de la búsqueda de empleo.

Neural tube defects (NTDs) are common birth defects with a complex genetic etiology. Mouse genetic models have indicated a number of candidate genes, of which functional mutations in some have been found in human NTDs, usually in a heterozygous state. This study focuses on Ephs-ephrins as candidate genes of interest owing to growing evidence of the role of this gene family during neural tube closure in mouse models. Eph-ephrin genes were analyzed in 31 Malaysian individuals comprising seven individuals with sporadic spina bifida, 13 parents, one twin-sibling and 10 unrelated controls. Whole exome sequencing analysis and bioinformatic analysis were performed to identify variants in 22 known Eph-ephrin genes. We reported that three out of seven spina bifida probands and three out of thirteen family members carried a variant in either EPHA2 (rs147977279), EPHB6 (rs780569137) or EFNB1 (rs772228172). Analysis of public databases shows that these variants are rare. In exome datasets of the probands and parents of the probands with Eph-ephrin variants, the genotypes of spina bifida-related genes were compared to investigate the probability of the gene–gene interaction in relation to environmental risk factors. We report the presence of Eph-ephrin gene variants that are prevalent in a small cohort of spina bifida patients in Malaysian families. [ABSTRACT FROM AUTHOR]

Although intracellular signal transduction is generally represented as a linear process that transmits stimuli from the exterior of a cell to the interior via a transmembrane receptor, interactions with additional membrane-associated proteins are often critical to its success. These molecules play a pivotal role in mediating signaling via the formation of complexes in cis (within the same membrane) with primary effectors, particularly in the context of tumorigenesis. Such secondary effectors may act to promote successful signaling by mediating receptor-ligand binding, recruitment of molecular partners for the formation of multiprotein complexes, or differential signaling outcomes. One signaling family whose contact-mediated activity is frequently modulated by lateral interactions at the cell surface is Eph/ephrin (EphA and EphB receptor tyrosine kinases and their ligands ephrin-As and ephrin-Bs). Through heterotypic interactions in cis, these molecules can promote a diverse range of cellular activities, including some that are mutually exclusive (cell proliferation and cell differentiation, or adhesion and migration). Due to their broad expression in most tissues and their promiscuous binding within and across classes, the cellular response to Eph:ephrin interaction is highly variable between cell types and is dependent on the cellular context in which binding occurs. In this review, we will discuss interactions between molecules in cis at the cell membrane, with emphasis on their role in modulating Eph/ephrin signaling.

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tDCS, a new, safe, non-invasive physical therapy method, is often used in motor dysfunction rehabilitation. However, the effects and underlying mechanisms of tDCS on hippocampal neurogenesis after cerebral ischemia (CI) are still unclear. This study aimed to investigate the promotive effect and mechanism of repetitive anodal-tDCS on hippocampal neurogenesis after CI in mice. The CI model in mice was established using bilateral common carotid artery occlusion (BCCAO). The pathological changes in the hippocampal CA1 region and cognitive function were assessed by hematoxylin and eosin staining and Morris water maze test, respectively. Hippocampal neurogenesis was observed by immunofluorescence staining. The levels of expression of ephrinb1, EPHB2, MAP-2, and NMDAR in the hippocampi were analyzed by qRT-PCR and Western blotting. Compared with the sham mice, the model mice showed significant neuronal damage in the hippocampal CA1 region (P < 0.01), cognitive dysfunction (P < 0.01), and endogenous hippocampal neurogenesis (P < 0.01). These results suggested that the CI model was successfully established, and that CI could promote endogenous hippocampal neurogenesis, but this hippocampal neurogenesis was unable to recover cognitive dysfunction. Compared with the model mice, the tDCS mice had ameliorated pathological damage in the CA1 region (P < 0.01), improved cognitive function (P < 0.01), increased hippocampal neurogenesis (P < 0.01), and increased mRNA and protein expression of ephrinb1, EPHB2, MAP-2, and NMDAR (P < 0.05). Repetitive anodal-tDCS can promote hippocampal neurogenesis and improve cognitive function in CI mice. The effect may be related to the activation of the ephrinb1/EPHB2/MAP-2/NMDAR signaling pathway. [ABSTRACT FROM AUTHOR]

Ephrin-B2, a member of the Eph/ephrin family of cell signaling molecules, has been implicated in the guidance of cranial and trunk neural crest cells (NCC) and development of the branchial arches(BA), but detailed examination in mice has been hindered by embryonic lethality of Efnb2 null loss of function due to a requirement in angiogenic remodeling. To elucidate the developmental roles for Efnb2, we generated a conditional rescue knock-in allele that allows rescue of ephrin-B2 specifically in the vascular endothelium (VE), but is otherwise ephrin-B2 deficient. Restoration of ephrin-B2 expression specifically to the VE completely circumvents angiogenic phenotypes, indicating that the requirement of ephrin-B2 in angiogenesis is limited to the VE. Surprisingly, we find that expression of ephrin-B2 specifically in the VE is also sufficient for normal NCC migration and that conversely, embryos in which ephrin-B2 is absent specifically from the VE exhibit NCC migration and survival defects. Disruption of vascular development independent of loss of ephrin-B2 function also leads to defects in NCC and BA development. Together, these data indicate that direct ephrin-B2 signaling to NCCs is not required for NCC guidance, which instead depends on proper organization of the embryonic vasculature.

The expression of members of the Eph family of receptor tyrosine kinases and their ephrin ligands is frequently dysregulated in medulloblastomas. We assessed the expression and functional role of EphB1 in medulloblastoma cell lines and engineered mouse models. mRNA and protein expression profiling showed expression of EphB1 receptor in the human medulloblastoma cell lines DAOY and UW228. EphB1 downregulation reduced cell growth and viability, decreased the expression of important cell cycle regulators, and increased the percentage of cells in G1 phase of the cell cycle. It also modulated the expression of proliferation, and cell survival markers. In addition, EphB1 knockdown in DAOY cells resulted in significant decrease in migration, which correlated with decreased β1-integrin expression and levels of phosphorylated Src. Furthermore, EphB1 knockdown enhanced cellular radiosensitization of medulloblastoma cells in culture and in a genetically engineered mouse medulloblastoma model. Using genetically engineered mouse models, we established that genetic loss of EphB1 resulted in a significant delay in tumor recurrence following irradiation compared to EphB1-expressing control tumors. Taken together, our findings establish that EphB1 plays a key role in medulloblastoma cell growth, viability, migration, and radiation sensitivity, making EphB1 a promising therapeutic target.

Herpesviruses are ubiquitous viruses, specifically the Epstein Barr virus (EBV). EBV and Kaposi's sarcoma-associated herpesvirus (KSHV) establish their latency for a long period in B-cells and their reactivation instigates dreadful diseases from cancer to neurological modalities. The envelope glycoprotein of these viruses makes an attachment with several host receptors. For instance; glycoprotein 350/220, gp42, gHgL and gB of EBV establish an attachment with CD21, HLA-DR, Ephs, and other receptor molecules to hijack the B- and epithelial cell machinery. Ephs are reported recently as potent receptors for EBV entry into epithelial cells. Eph receptors play a role in the maintenance and control of various cellular processes including morphology, adhesion, proliferation, survival and differentiation. Alterations in the structure and expression of Eph and ephrin (Eph ligands) molecules is entangled with various pathologies including tumours and neurological complications. Along with Eph, integrins, NRP, NMHC are also key players in viral infections as they are possibly involved in viral transmission, replication and persistence. Contrarily, KSHV gH is known to interact with EphA2 and -A4 molecules, whereas in the case of EBV only EphA2 receptors are being reported to date. The ELEFN region of KSHV gH was involved in the interaction with EphA2, however, the interacting region of EBV gH is elusive. Further, the gHgL of KSHV and EBV form a complex with the EphA2 ligand-binding domain (LBD). Primarily by using gL both KSHV and EBV gHgL bind to the peripheral regions of LBD. In addition to γ-herpesviruses, several other viruses like Nipah virus, Cedar virus, Hepatitis C virus and Rhesus macaque rhadinovirus (RRV) also access the host cells via Eph receptors. Therefore, we summarise the possible roles of Eph and ephrins in virus-mediated infection and these molecules could serve as potential therapeutic targets.

Kupffer cells are maintained via self-renewal in specific microenvironmental niches, primarily the liver sinusoidal endothelial cells (LSECs). In this study, we propagated tissue-resident macrophages (Mø) from mouse liver using mixed culture with hepatic fibroblastic cells. Propagated liver Mø express Id3, Lxra and Spic transcription factors, which are required for Kupffer cell characterization. Thus, Kupffer cell properties are likely to be maintained in liver Mø propagated using mixed culture with fibroblastic cells. We revealed (i) gene expression of certain Eph receptors and ephrin ligands including EphA2, ephrin-A1, EphB4, and ephrin-B1 in propagated liver Mø and primary LSECs, (ii) immunohistochemical localization of these Eph/ephrin member molecules indicating common expression in Kupffer cells and LSECs, and (iii) surface expression of several integrin α and β subunits, including α4β1, αLβ2, αMβ2, and αXβ2 integrin in propagated liver Mø and that of the corresponding ligands ICAM-1 and VCAM-1 in primary LSECs. Moreover, EphA/ephrin-A and EphB/ephrin-B interactions promoted liver Mø adhesion to the ICAM-1-adsorbed surface, which mimicked that of LSECs and may be implicated in the residence of Kupffer cells in the liver sinusoid. Further studies on regulating the residence and regeneration of Kupffer cells in related hepatic disorders are required to validate our findings.

BackgroundEph receptors, comprising the A- and B-subfamilies, are the largest family of receptor tyrosine kinases in the mammalian genome, and their function is critical for morphogenesis in a variety of contexts. Whereas signaling through B-type Ephs has been demonstrated to play a role in cleft lip and palate (CL/P), the involvement of A-type Ephs has not been examined in this context notwithstanding a recent genome-wide association study that identified the EPHA3 locus as a candidate for non-syndromic CL/P.ResultsHere, we present a systematic analysis of the gene expression patterns for the nine EphA receptors at progressive stages of mouse development and find that EphA3, EphA4, and EphA7 exhibit restricted overlapping patterns of expression during palate development. We find that homozygous mutation of EphA3 or compound homozygous mutation of EphA3 and EphA4 in mice does not result in defective midfacial development, supporting the possibility of redundant function with EphA7. We also document previously undescribed expression patterns in other tissues of the craniofacial complex including the lacrimal duct and salivary glands.ConclusionsTogether, these results are consistent with the hypothesis that mutations in EPHA family genes may cause CL/P and also suggest that functional redundancy between family members may be at play.

Ongoing research continues to elucidate the complex role of ephrin receptors (EPHs) and their ligands (ephrins) in breast cancer pathogenesis, with their varying expression patterns implied to have an important impact on patients’ outcome. The current study aims to investigate the clinical significance of EPHA2, EPHA4, and EPHA7 expression in triple-negative breast cancer (TNBC) cases. EPHA2, EPHA4, and EPHA7 protein expression was assessed immunohistochemically on formalin-fixed and paraffin-embedded (FFPE) TNBC tissue sections from 52 TNBC patients and correlated with key clinicopathologic parameters and patients’ survival data (overall survival (OS); disease-free survival (DFS)). EPHA2, EPHA4, and EPHA7 expression was further examined in TNBC cell lines. EPHA2 overexpression was observed in 26 (50%) of the TNBC cases, who exhibited a shorter OS and DFS than their low-expression counterparts, with EPHA2 representing an independent prognostic factor for OS and DFS (p = 0.0041 and p = 0.0232, respectively). EPHA4 overexpression was associated with lymph node metastasis in TNBC patients (p = 0.0546). Alterations in EPHA2, EPHA4, and EPHA7 expression levels were also noted in the examined TNBC cell lines. Our study stresses that EPHA2 expression constitutes a potential prognostic factor for TNBC patients. Given the limited treatment options and poorer outcome that accompany the TNBC subtype, EPHA2 could also pose as a target for novel, more personalized, and effective therapeutic approaches for those patients.

Eph receptors are the largest family of receptor tyrosine kinases and mediate a myriad of essential processes in humans from embryonic development to adult tissue homeostasis through interactions with membrane-bound ephrin ligands. The ubiquitous expression of Eph receptors and ephrin ligands among the cellular players of the immune system underscores the importance of these molecules in orchestrating an optimal immune response. This review provides an overview of the various roles of Eph receptors and ephrin ligands in immune cell development, activation, and migration. We also discuss the role of Eph receptors in disease pathogenesis as well as the implications of Eph receptors as future immunotherapy targets. Given the diverse and critical roles of Eph receptors and ephrin ligands throughout the immune system during both resting and activated states, this review aims to highlight the critical yet underappreciated roles of this family of signaling molecules in the immune system.

Eph receptors are the largest family of receptor tyrosine kinases and mediate a myriad of essential processes in humans from embryonic development to adult tissue homeostasis through interactions with membrane-bound ephrin ligands. The ubiquitous expression of Eph receptors and ephrin ligands among the cellular players of the immune system underscores the importance of these molecules in orchestrating an optimal immune response. This review provides an overview of the various roles of Eph receptors and ephrin ligands in immune cell development, activation, and migration. We also discuss the role of Eph receptors in disease pathogenesis as well as the implications of Eph receptors as future immunotherapy targets. Given the diverse and critical roles of Eph receptors and ephrin ligands throughout the immune system during both resting and activated states, this review aims to highlight the critical yet underappreciated roles of this family of signaling molecules in the immune system. [ABSTRACT FROM AUTHOR]

The biological functions of the Eph/ephrin system have been intensively investigated and well documented so far since its discovery in 1987. Although the Eph/ephrin system has been implicated in pathological settings such as Alzheimer's disease and cancer, the molecular mechanism of the Eph/ephrin system in those diseases is not well understood. Especially in cancer, recent studies have demonstrated that most of Eph and ephrin are up‐ or down‐regulated in various types of cancer, and have been implicated in tumor progression, tumor malignancy, and prognosis. However, they lack consistency and are in controversy. The localization patterns of EphA1 and EphA2 in mouse lungs are very similar, and both knockout mice showed similar phenotypes in the lungs. Ephrin‐A1 that is a membrane‐anchored ligand for EphAs was co‐localized with EphA1 and EphA2 in lung vascular endothelial cells. We recently uncovered the molecular mechanism of ephrin‐A1‐induced lung metastasis by understanding the physiological function of ephrin‐A1 in lungs. This review focuses on the function of EphA1, EphA2, and ephrin‐A1 in tumors and an establishment of pre‐metastatic microenvironment in the lungs. ADAM12‐cleaved ephrin‐A1 induces receptor endocytosis and RhoA activation leading to cell retraction. Cleaved ephrin‐A1 competes for pre‐existing Eph/ephrin interactions. Ephrin‐A1‐stimulated vascular endothelial cells are shrunk, and thereby enhances lung vascular permeability. [ABSTRACT FROM AUTHOR]

Among the ever-growing number of self-replicating proteins involved in neurodegenerative diseases, the prion protein PrP remains the most infamous for its central role in transmissible spongiform encephalopathies (TSEs). In these diseases, pathogenic prions propagate through a seeding mechanism, where normal PrPC molecules are converted into abnormally folded scrapie isoforms termed PrPSc. Since its discovery over 30 years ago, much advance has contributed to define the host-encoded cellular prion protein PrPC as a critical relay of prion-induced neuronal cell demise. A current consensual view is that the conversion of PrPC into PrPSc in neuronal cells diverts the former from its normal function with subsequent molecular alterations affecting synaptic plasticity. Here, we report that prion infection is associated with reduced expression of key effectors of the Notch pathway in vitro and in vivo, recapitulating changes fostered by the absence of PrPC. We further show that both prion infection and PrPC depletion promote drastic alterations in the expression of a defined set of Eph receptors and their ephrin ligands, which represent important players in synaptic function. Our data indicate that defects in the Notch and Eph axes can be mitigated in response to histone deacetylase inhibition in PrPC-depleted as well as prion-infected cells. We thus conclude that infectious prions cause a loss-of-function phenotype with respect to Notch and Eph signaling and that these alterations are sustained by epigenetic mechanisms. [ABSTRACT FROM AUTHOR]

Keywords: thymic epithelial cells; thymocyte education; Eph; ephrin; regulatory T-cells EN thymic epithelial cells thymocyte education Eph ephrin regulatory T-cells N.PAG N.PAG 3 03/12/21 20210308 NES 210308 Introduction The central tolerance to self-antigens is achieved in the thymus through a complex process in which developing thymocytes (T) sequentially interact with thymic epithelial cells (TECs) in a 3D network histologically organized in a cortex and a medulla ([1]). On the other hand, the presence of small groups of TECs properly organized from a histological view and expressing key molecules involved in the functional crosstalk between TECs and thymocytes would be sufficient to allow the thymocyte differentiation in mutant thymuses ([3], [7]). [Extracted from the article]

Uveal melanoma is the most common primary intraocular malignancy in adults. The development of distant metastases is associated with a poor prognosis. Ephrine receptors (Eph) are the largest subpopulation of tyrosine kinase receptors. They play an important role in processes related to the formation and progression of cancer. The aim of the study was to evaluate the expression of ephrin receptors EphA1, EphA5, and EphA7 in uveal melanoma and its associations with clinicopathological parameters, overall survival, and disease-free survival. The study included 94 previously untreated patients who underwent enucleation due to uveal melanoma. High expression of EphA1 was positively correlated with a smaller tumor size, less frequent extra-scleral extension, lower mitotic activity, and more frequent vitreous hemorrhage. High expression of EphA5 was associated with less frequent chromosome 3 loss, absence of distant metastases, and more frequent vitreous hemorrhage. High expression of EphA7 was associated with a more frequent primary tumor location in the posterior pole. High EphA5 expression was associated with longer overall survival time. The above findings indicate that high expression of EphA1 and EphA5 can be considered a beneficial prognostic factor in uveal melanoma.

Erythropoietin-producing hepatocellular carcinoma A (EphA) receptors and their ephrin-A ligands are key players of developmental events shaping the mature organism. Their expression is mostly restricted to stem cell niches in adults but is reactivated in pathological conditions including lesions in the heart, lung, or nervous system. They are also often misregulated in tumors. A wide range of molecular tools enabling the manipulation of the ephrin-A:EphA system are available, ranging from small molecules to peptides and genetically-encoded strategies. Their mechanism is either direct, targeting EphA receptors, or indirect through the modification of intracellular downstream pathways. Approaches enabling manipulation of ephrin-A:EphA forward signaling for the dissection of its signaling cascade, the investigation of its physiological roles or the development of therapeutic strategies are summarized here.

For a long time, the effects of distinct Eph tyrosine kinase receptors and their ligands, ephrins on the structure, immunophenotype, and development of thymus and their main cell components, thymocytes (T) and thymic epithelial cells (TECs), have been studied. In recent years, the thymic phenotype of mutant mice deficient in several Ephs and ephrins B has been determined. Remarkably, thymic stroma in these animals exhibits important defects that appear early in ontogeny but little alterations in the proportions of distinct lymphoid cell populations. In the present manuscript, we summarize and extend these results discussing possible mechanisms governing phenotypical and functional thymocyte maturation in an absence of the critical T–TEC interactions, concluding that some signaling mediated by key molecules, such as MHCII, CD80, β5t, Aire, etc. could be sufficient to enable a proper maturation of thymocytes, independently of morphological alterations affecting thymic epithelium.

One important thing in supporting Reliability Building to meet safety, is building capabilities in tackling a fire hazard, set out the Fire Emergency Action Plan. Reliability Action Plan Emergency Fire is an important part of the safety aspects of a building, and it can beevaluated on the readiness of the hardware and software as well as a means of supporting the Action Plan Emergency Fire which managed the building. This research is motivated curiosity of how far the readiness of Fire Emergency Action Plan in Rusunawa UNNES and how the response, feedback or ratings by students as inhabitants of the performance systems fire prevention at this Rusunawa UNNES. Based on the results of 96 students, students' perceptions of readiness in Fire Emergency Action Plan are as follows.There are 6% found APEF Rusunawa was in the excellent category; 72% found Rusunawa APEF UNNES Semarang was in good categories; 16% found Rusunawa APEF UNNES was in quite-good category and 6% found Rusunawa UNNES APEFwas in not-good category.Suggestions needs for the manager enhance the safety aspects that form the Emergency Action PlanFire, by conducting periodic evaluation of the readiness of the system and the existing equipment.