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One of the most critical tasks in Vehicular Ad-hoc Networks (VANETs) is broadcasting Emergency Messages (EMs) at considerable data delivery rates (DDRs). The enhanced spider-web-like Transmission Mechanism for Emergency Data (TMED) is based on request spiders and authenticated spiders to create the shortest route path between the source vehicle and target vehicles. However, the adjacent allocation is based on the DDR only and it is not clear whether each adjacent vehicle is honest or not. Hence, in this article, the Improved Restricted Greedy Forwarding (IRGF) scheme is proposed for adjacent allocation with the help of trust computation in TMED. The trust and reputation score value of each adjacent vehicle is estimated based on successfully broadcast emergency data. The vehicles’ position, velocity, direction, density, and the reputation score, are fed to a fuzzy logic (FL) scheme, which selects the most trusted adjacent node as the forwarding node for broadcasting the EM to the destination vehicles. Finally, the simulation results illustrate the TMED-IRGF model’s efficiency compared to state-of-the-art models in terms of different network metrics.

Numerous trafficking and quality control pathways evolved to handle the diversity of proteins made by eukaryotic cells. However, at every step along the biosynthetic pathway, there is the potential for quality control system failure. This review focuses on the mechanisms of disrupted proteostasis. Inspired by diseases caused by misfolded proteins in the kidney (mucin 1 and uromodulin), we outline the general principles of protein biosynthesis, delineate the recognition and degradation pathways targeting misfolded proteins, and discuss the role of cargo receptors in protein trafficking and lipid homeostasis. We also discuss technical approaches including live-cell fluorescent microscopy, chemical screens to elucidate trafficking mechanisms, multiplexed single-cell CRISPR screening platforms to systematically delineate mechanisms of proteostasis, and the advancement of novel tools to degrade secretory and membrane-associated proteins. By focusing on components of trafficking that go awry, we highlight ongoing efforts to understand fundamental mechanisms of disrupted proteostasis and implications for the treatment of human proteinopathies. [ABSTRACT FROM AUTHOR]

One of the most critical tasks in Vehicular Ad-hoc Networks (VANETs) is broadcasting Emergency Messages (EMs) at considerable data delivery rates (DDRs). The enhanced spider-web-like Transmission Mechanism for Emergency Data (TMED) is based on request spiders and authenticated spiders to create the shortest route path between the source vehicle and target vehicles. However, the adjacent allocation is based on the DDR only and it is not clear whether each adjacent vehicle is honest or not. Hence, in this article, the Improved Restricted Greedy Forwarding (IRGF) scheme is proposed for adjacent allocation with the help of trust computation in TMED. The trust and reputation score value of each adjacent vehicle is estimated based on successfully broadcast emergency data. The vehicles' position, velocity, direction, density, and the reputation score, are fed to a fuzzy logic (FL) scheme, which selects the most trusted adjacent node as the forwarding node for broadcasting the EM to the destination vehicles. Finally, the simulation results illustrate the TMED-IRGF model's efficiency compared to state-of-the-art models in terms of different network metrics. [ABSTRACT FROM AUTHOR]

Under ER stress conditions, the ER form of transmembrane proteins can reach the plasma membrane via a Golgi‐independent unconventional protein secretion (UPS) pathway. However, the targeting mechanisms of membrane proteins for UPS are unknown. Here, this study reports that TMED proteins play a critical role in the ER stress‐associated UPS of transmembrane proteins. The gene silencing results reveal that TMED2, TMED3, TMED9 and TMED10 are involved in the UPS of transmembrane proteins, such as CFTR, pendrin and SARS‐CoV‐2 Spike. Subsequent mechanistic analyses indicate that TMED3 recognizes the ER core‐glycosylated protein cargos and that the heteromeric TMED2/3/9/10 complex mediates their UPS. Co‐expression of all four TMEDs improves, while each single expression reduces, the UPS and ion transport function of trafficking‐deficient ΔF508‐CFTR and p.H723R‐pendrin, which cause cystic fibrosis and Pendred syndrome, respectively. In contrast, TMED2/3/9/10 silencing reduces SARS‐CoV‐2 viral release. These results provide evidence for a common role of TMED3 and related TMEDs in the ER stress‐associated, Golgi‐independent secretion of transmembrane proteins. [ABSTRACT FROM AUTHOR]

Vehicular Ad-Hoc Network (VANET) is a new technology in the Internet of Things (IoT). It is broadly used in intelligent transport system. VANET provides V2V communication and V2R communication in real time. Intelligent Transport System (ITS) is used for road safety, information service and traffic efficiency. Greedy Perimeter Stateless Routing (GPSR) protocol and Greedy Perimeter Coordinate Routing (GPCR) protocol are proposed. However, transmission of emergency data packets can be risky since Packet Delivery Ratio (PDR) is not guaranteed as GPCR link connectivity is not considered; hence, they are not suitable for emergency data transmission. The algorithms Destination Sequenced Distance Vector (DSDV) and Ad-hoc On-demand Distance Vector (AODV) are proposed to resolve problems like end-to-end delay, average PDR, and routing overhead. It is observed that AODV algorithm improves throughput and PDR, and reduces end-to-end delay in transmission of emergency data packets. [ABSTRACT FROM AUTHOR]

Background: Head and neck squamous carcinoma (HNSC) is one of the most common malignant tumors with high incidence and poor prognosis. Transmembrane emp24 structural domain (TMED) proteins are involved in protein transport and vesicle budding processes, which have implicated various malignancies' progression. However, the roles of TMEDs in HNSC, especially in terms of development and prognosis, have not been fully elucidated. Methods: We applied TIMER 2.0, UALCAN, GEPIA 2, Kaplan-Meier plotter, GEO, The Human Protein Atlas (HPA), cBioPortal, Linkedomics, Metascape, GRNdb, STRING, and Cytoscape to investigate the roles of TMED family members in HNSC. Results: Compared with normal tissues, the mRNA expression levels of TMED1/2/4/5/7/8/9/10 were significantly increased in the TCGA HNSC dataset. And we combined GEPIA 2 and Kaplan-Meier Plotter to select TMED2/9/10 with prognostic value. Then we detected the levels of mRNA in the GEO HNSC database and the protein expression in HPA. It was found that the mRNA and protein expression levels of TMED2/9/10 were increased in HNSC. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that TMED2/9/10 and their co-expressed genes promoted the malignant behavior of tumors by participating in biological processes such as intracellular transferase complex, protein transport, focal adhesion, intracellular protein processing. Single-cell analysis and immune infiltration analysis suggested that immune responses of cancer-associated fibroblasts and endothelial cells might be associated with prognosis. Finally, the transcription factors-genes network and protein-protein functional interaction network pointed to genes such as X-box binding protein 1 (XBP1) and TMED7, which might cooperate with TMED2/9/10 to change the progression of HNSC. Conclusions: Our study implied that TMED2/9/10 and related genes mightjointly affect the prognosis of HNSC, providing specific clues for further experimental research, personalized diagnosis strategies, and targeted clinical therapy for HNSC. [ABSTRACT FROM AUTHOR]

Background: Head and neck squamous carcinoma (HNSC) is one of the most common malignant tumors with high incidence and poor prognosis. Transmembrane emp24 structural domain (TMED) proteins are involved in protein transport and vesicle budding processes, which have implicated various malignancies’ progression. However, the roles of TMEDs in HNSC, especially in terms of development and prognosis, have not been fully elucidated.Methods: We applied TIMER 2.0, UALCAN, GEPIA 2, Kaplan-Meier plotter, GEO, The Human Protein Atlas (HPA), cBioPortal, Linkedomics, Metascape, GRNdb, STRING, and Cytoscape to investigate the roles of TMED family members in HNSC.Results: Compared with normal tissues, the mRNA expression levels of TMED1/2/4/5/7/8/9/10 were significantly increased in the TCGA HNSC dataset. And we combined GEPIA 2 and Kaplan-Meier Plotter to select TMED2/9/10 with prognostic value. Then we detected the levels of mRNA in the GEO HNSC database and the protein expression in HPA. It was found that the mRNA and protein expression levels of TMED2/9/10 were increased in HNSC. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that TMED2/9/10 and their co-expressed genes promoted the malignant behavior of tumors by participating in biological processes such as intracellular transferase complex, protein transport, focal adhesion, intracellular protein processing. Single-cell analysis and immune infiltration analysis suggested that immune responses of cancer-associated fibroblasts and endothelial cells might be associated with prognosis. Finally, the transcription factors-genes network and protein-protein functional interaction network pointed to genes such as X-box binding protein 1 (XBP1) and TMED7, which might cooperate with TMED2/9/10 to change the progression of HNSC.Conclusions: Our study implied that TMED2/9/10 and related genes mightjointly affect the prognosis of HNSC, providing specific clues for further experimental research, personalized diagnosis strategies, and targeted clinical therapy for HNSC.

The transmembrane emp24 domain-containing (TMED) proteins, also called p24 proteins, are members of a family of sorting receptors present in all representatives of the Eukarya and abundantly present in all subcompartments of the early secretory pathway, namely the endoplasmic reticulum (ER), the Golgi, and the intermediate compartment. Although essential during the bidirectional transport between the ER and the Golgi, there is still a lack of information regarding the TMED's structure across different subfamilies. Besides, although the presence of a TMED homo-oligomerization was suggested previously based on crystallographic contacts observed for the isolated Golgi Dynamics (GOLD) domain, no further analyses of its presence in solution were done. Here, we describe the first high-resolution structure of a TMED1 GOLD representative and its biophysical characterization in solution. The crystal structure showed a dimer formation that is also present in solution in a salt-dependent manner, suggesting that the GOLD domain can form homodimers in solution even in the absence of the TMED1 coiled-coil region. A molecular dynamics description of the dimer stabilization, with a phylogenetic analysis of the residues important for the oligomerization and a model for the orientation towards the lipid membrane, are also presented. - The structure and solution characterization of a TMED1 GOLD were firstly presented - The GOLD domain can form homodimers in solution in a salt-dependent fashion - Molecular Dynamics unravelled the net of interactions inside the dimer interface - Residues important for the oligomerization are conserved inside the γ-subfamily - A model for the γ-subfamily GOLD orientation towards the membrane surface is proposed [ABSTRACT FROM AUTHOR]

Autosomal dominant tubulointerstitial kidney diseases (ADTKDs) are a group of rare genetic diseases that lead to kidney failure. Mutations in the MUC1 gene cause ADTKD-MUC1 (MUC1 kidney disease, MKD), a disorder with no available therapies. Recent studies have identified the molecular and cellular mechanisms that drive MKD disease pathogenesis. Armed with patient-derived cell lines and pluripotent stem cell (iPSC)-derived kidney organoids, it was found that MKD is a toxic proteinopathy caused by the intracellular accumulation of misfolded MUC1 protein in the early secretory pathway. We discuss the advantages of studying rare monogenic kidney diseases, describe effective patient-derived model systems, and highlight recent mechanistic insights into protein quality control that have implications for additional proteinopathies beyond rare kidney diseases. Kidney diseases collectively pose a major health crisis, and represent an area of unmet need in large part owing to disease complexity, a lack of biomarkers, and several challenges on the path to the clinic. Studying rare monogenic kidney diseases provides a way forward for teasing apart specific molecular pathways and targets that can lead to mechanism-based therapies. Patient-derived tools, including kidney organoids and high-throughput screens, have identified a novel chemical probe that ultimately revealed a membrane protein quality-control mechanism that is responsible for epithelial cell injury in the kidney. Lessons learned from studying a rare genetic kidney disease have uncovered shared mechanisms of cargo quality control that are operative in many different cell types and tissues, and that have implications for a diversity of toxic proteinopathies well beyond the kidney. [ABSTRACT FROM AUTHOR]

Regulated transport through the secretory pathway is essential for embryonic development and homeostasis. Disruptions in this process impact cell fate, differentiation and survival, often resulting in abnormalities in morphogenesis and in disease. Several congenital malformations are caused by mutations in genes coding for proteins that regulate cargo protein transport in the secretory pathway. The severity of mutant phenotypes and the unclear aetiology of transport protein-associated pathologies have motivated research on the regulation and mechanisms through which these proteins contribute to morphogenesis. This review focuses on the role of the p24/transmembrane emp24 domain (TMED) family of cargo receptors in development and disease. [ABSTRACT FROM AUTHOR]

The members of the transmembrane emp24 domain-containing protein (TMED) family are summarized in human as four subfamilies, α (TMED 4, 9), β (TMED 2), γ (TMED1, 3, 5, 6, 7) and δ (TMED 10), with a total of nine members, which are important regulators of intracellular protein transport and are involved in normal embryonic development, as well as in the pathogenic processes of many human diseases. Here we systematically review the composition, structure and function of TMED family members, and describe the progress of TMED family in human diseases, including malignancies (head and neck tumors, lung cancer, breast cancer, ovarian cancer, endometrial cancer, gastrointestinal tumors, urological tumors, osteosarcomas, etc.), immune responses, diabetes, neurodegenerative diseases, and nonalcoholic fatty liver disease, dilated cardiomyopathy, mucin 1 nephropathy (MKD), and desiccation syndrome (SS). Finally, we discuss and prospect the potential of TMED for disease prognosis prediction and therapeutic targeting, with a view to laying the foundation for therapeutic research based on TMED family causative genes., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Stepwise flowchart delineating the overall strategies employed in this study. [Display omitted] • TMED4 and TMED9 Genes are highly expressed in low-grade glioma (LGG) and glioblastoma multiforme (GBM) tissues. • TMED4 and TMED9 gene expression is negatively associated with the overall survival of LGG and GBM patients. • Differential methylation and presence of somatic mutations in TMED4 and TMED9 genes provides assurance in glioma diagnosis. Here, we utilized a database mining approach to unfold the prognostic and therapeutic potentials of Transmembrane EmP24 Trafficking Protein 4 (TMED4) and 9 (TMED9) coding gene expressions in glioma. Both the genes were found to be overexpressed at the mRNA and protein levels in low grade glioma (LGG) and glioblastoma multiforme (GBM) tissues including different glioma cell lines. Significant increase in the expression level of these genes with advancing glioma patients' age, glioma grades and histological subtypes was observed. Differential and distinct promoter and coding sequence methylation pattern of TMED4 and TMED9 was reported in LGG and GBM tissues that may aid in methylation-sensitive diagnosis of glioma patients. The presence of multiple heterozygous genetic alterations (frequency: 0.4–1.1%) in those genes unveiled their potentials in high-throughput screening of glioma patients. The overexpression of TMED4 and TMED9 genes was associated with poor overall survival (OS) of LGG and GBM patients (HR: >1.6). Association of the expression levels of these genes with different immune cell infiltration levels i.e., B cell and T cell and modulators like CD274 and IL10RB was observed providing assurance in TMED -based diagnostic measure and therapeutic intervention discovery for glioma. Furthermore, functional enrichment analysis of the neighbor genes of TMED4 and TMED9 revealed that they are involved in metal ion binding, focal adhesion of cells and protein processing, and the deregulation of these activities are associated with gliomagenesis. The scientific findings of this study should guide clinical development of TMED -based therapeutic and diagnostic measures development against glioma. [ABSTRACT FROM AUTHOR]

Abstract: During vesicular transport between the endoplasmic reticulum and the Golgi, members of the TMED/p24 protein family form hetero-oligomeric complexes that facilitate protein-cargo recognition as well as vesicle budding. In addition, they regulate each other''s level of expression. Despite analyses of TMED/p24 protein distribution in mammalian cells, yeast, and C. elegans, little is known about the role of this family in vertebrate embryogenesis. We report the presence of a single point mutation in Tmed2/p24β 1 in a mutant mouse line, 99J, identified in an ENU mutagenesis screen for recessive developmental abnormalities. This mutation does not affect Tmed2/p24β 1 mRNA levels but results in loss of TMED2/p24β1 protein. Prior to death at mid-gestation, 99J homozygous mutant embryos exhibit developmental delay, abnormal rostral–caudal elongation, randomized heart looping, and absence of the labyrinth layer of the placenta. We find that Tmed2/p24β 1 is normally expressed in tissues showing morphological defects in 99J mutant embryos and that these affected tissues lack the TMED2/p24β1 oligomerization partners, TMED7/p24γ3 and TMED10/p24δ1. Our data reveal a requirement for TMED2/p24β1 protein in the morphogenesis of the mouse embryo and placenta. [Copyright &y& Elsevier]

Objective: To present operative details and clinical follow-up of a series of patients with thoracic disk herniation treated with the minimally invasive technique of thoracic microendoscopic diskectomy (TMED)., Methods: TMED was performed in 16 consecutive patients (age range, 18-79 years old) with 18 thoracic disk herniations. One patient with a calcified herniation in a direct ventral location was not included in this series. Patients were positioned prone, and a tubular retractor system was placed through a muscle dilating approach. The procedure was performed with endoscopic visualization. Outcomes were assessed using modified McNab criteria., Results: There were no complications, and no case required conversion to an open procedure. The mean operative time was 153 minutes per level, and mean blood loss was 69 mL per level. Mean hospital stay was 21 hours. At a mean follow-up of 24 months (median, 22 months), 13 patients (81%) had excellent or good outcomes, 1 patient (6%) had a fair outcome, and 2 patients (13%) had poor outcomes. The two patients with poor outcomes had neurologic diagnoses (multiple sclerosis and multiple systems atrophy) that were ultimately found to be responsible for their symptoms and deficits., Conclusions: TMED is a safe and effective minimally invasive posterolateral approach for the treatment of thoracic disk herniations that lacks the morbidity associated with traditional approaches., (Copyright © 2013 Elsevier Inc. All rights reserved.)