The emergence of the Internet of Vehicles (IoV) aims to facilitate the next generation of intelligent transportation system (ITS) applications by combining smart vehicles and the internet to improve traffic safety and efficiency. On the other hand, mobile edge computing (MEC) technology provides enormous storage resources with powerful computing on the edge networks. Hence, the idea of IoV edge computing (IoVEC) networks has grown to be an assuring paradigm with various opportunities to advance massive data storage, data sharing, and computing processing close to vehicles. However, the participant’s vehicle may be unwilling to share their data since the data-sharing system still relies on a centralized server approach with the potential risk of data leakage and privacy security. In addition, vehicles have difficulty evaluating the credibility of the messages they received because of untrusted environments. To address these challenges, we propose consortium blockchain and smart contracts to accomplish a decentralized trusted data sharing management system in IoVEC. This system allows vehicles to validate the credibility of messages from their neighboring by generating a reputation rating. Moreover, the incentive mechanism is utilized to trigger the vehicles to store and share their data honestly; thus, they will obtain certain rewards from the system. Simulation results substantially display an efficient network performance along with forming an appropriate incentive model to reach a decentralized trusted data sharing management of IoVEC networks. With the rapid movement of urbanization and industrialization, the number of registered vehicles worldwide is estimated to reach two billion within the next 10–20 years [However, the conventional IoV system has difficulty overcoming the increasing complexity of ITS applications that exponentially led to the demand for the enormous data storage volumes with high computation and communication processing requirements. Hence, the notion of IoV edge computing (IoVEC) is introduced to enhance user experience with low latency, high bandwidth, and real-time communications with the help of mobile edge computing (MEC) technology . IoVEC iDespite the potentials mentioned above, the conventional architecture of IoVEC with a centralized approach has crucial challenges related to user’s data security and privacy. In this sense, the potential exposure of user information with single point of failure (SPoF) challenges still will reasonably occur since the IoVEC framework’s data is centralized on a central server. Hence, the IoV network participants might be hesitant in the data sharing process that contains private information, such as customer identities, vehicle numbers, and driving preference. Moreover, the risk of selfish behaviors might diminish participants’ enthusiasm to cooperate with each other in the system. This problem becomes more serious when there exists a malicious vehicle in the network. The various adversarial actions may threaten the privacy security to gather the user’s private information for personal benefit, as well as endanger traffic safety and efficiency, by giving the incorrect report to the system. Consequently, IoVEC needs to construct a reliable and trusted data sharing management model by removing a centralized intermediary scheme.Previous work considers that vehicle may share their data voluntarily . UnfortuIn recent years, since Nakamoto introduced Bitcoin  in 2008,1.We design a decentralized trusted data sharing management framework for IoVEC networks by utilizing a consortium blockchain and smart contracts. This framework proposes a secure data sharing scenario among vehicles without relies on trusted intermediaries in distributed, verifiable, and immutable ledgers.2.We present an information credibility assessment scenario to minimize irrelevant information data and against malicious behaviors of the vehicle on the data sharing process.3.We design an appropriate incentive mechanism based on the vehicle’s contribution by leveraging smart contracts’ self-execution nature. This scheme aims to motivate vehicles to participate positively in maintaining trusted data sharing activities and ensuring the system’s security and sustainability.4.We formulate a decentralized data sharing of IoV networks prototype and evaluate its performance based on simulation results.The remainder of this paper is organized as follows. In this section, we review relevant literature on conventional data sharing management on vehicular network and centralized incentive mechanism to position the existing approach in relation to our research.Mobile edge computing (MEC) technology is introduced in 2014 by the European Telecommunications Standards Institute (ETSI), aiming to heighten user experiences with low latency, high bandwidth, and real-time communications . MEC levIn the vehicular network environment, the primary entities in the data sharing process are vehicles and roadside units (RSUs), which form two types of communication, namely vehicle-to-vehicle (V2V) and vehicle-to-infrastructure (V2I). Vehicles interact with other neighboring vehicles by using onboard units (OBUs) equipped with several sensing devices with simple computation and communication capabilities. OBUs are also used to automatically recognize traffic-related information and facilitate the vehicles to send notification messages to others using V2V communication standards to improve traffic safety and efficiency. On the other hand, V2I provides a single or multi-hop communication between vehicle and RSU, supported by dedicated short-range communication (DSRC) standards . RSUs, aMoreover, conventional VN data management relies on a cloud service platform with a centralized database approach. In this sense, the centralized server is employed to collect and store all vehicles’ shared data centrally. However, the centralized approach is still facing the threat of security and privacy risk, where the attackers can easily forge or tamper with the data sent by OBUs in an open wireless communication environment . FurtherSince the VN system relies on a centralized approach, vehicles might be reluctant to share their data due to data security and privacy protection issues. Moreover, the SPoF is likewise a significant problem for centralized networks. Another challenge is that vehicle participation in the data sharing process remains low due to self-interest characteristics, and the vehicles do not obtain the compensation or benefit from the system. Hence, the incentive scheme is used to boost vehicle participation with positive contribution and maintain the system’s reliability and sustainability. The existing incentive mechanism with a centralized approach allows simple transactions between vehicles and a trusted third party. In this case, a trusted third party holds the entire data transaction and provides transaction incentives among participants involved. In short, as a data provider, the trusted third party controls the whole system orchestration (including incentive scheme).Current works that represent centralized incentive approach are monetary-based incentive  and repuBlockchain is considered as a solution to improve security and privacy protection since it is suitable to overcome the centralized problem approach. Blockchain is a distributed ledger technology that enables participator entities to accept and share recorded activities with a time-stamp to the network. The particular consensus mechanism validates those activities before it is filed in a changeless database. Generally, blockchain can be utilized to achieve three objectives: managing distributed services relying on smart contracts, operating a distributed ledger, and accomplishing decentralized storage . There eMoreover, the authors in Reference  proposedFurthermore, several efforts study employing consortium blockchain’s advantages to minimize malicious entities’ existence during the consensus mechanism. The authors of Reference  proposedThis section explains our proposed model, blockchain-based secure and trusted data sharing management in IoVEC networks. Inspired by Reference , our arcUser network layer manages vehicle enrollment and authentication, the road-related message broadcasting, and the message credibility assessment process.In our scenario, vehicles represent the user network that communicates with other vehicles and RSUs to improve traffic safety and efficiency. Before entering and accessing the network service, all vehicles must be authorized by a trusted party (TP), e.g., the Department of Transportation, to guarantee vehicle identity legitimation by binding their real identities . Then, a legitimate vehicle eference . The sysk and time t and encrypts those messages before being broadcasted to the network by utilizing V2V and V2I communication. Nevertheless, k. We consider that the message sent by vehicles near the event location is more trusted compared to the vehicle in a far distance. Therefore, the message credibility is defined based on Equation  and validation block smart contract (VBSC). MRSC collects, records, and aggregates the number of message information ψPt,A consensus mechanism is utilized to achieve the required agreement between the authorized participant entities to generate a new block transaction into a blockchain network using a particular set of rules. Here, only authorized RSUs are eligible to be the nodes participants  in the consensus mechanism with more extensive storage and computation capability compared to the OBUs. We use the PBFT algorithm to conduct a consensus mechanism due to its advantages, including small resource consumption, high efficiency, consistency, and maturity, making it proper for our proposed scheme. Moreover, PBFT permits the presence of anomalous nodes =(n−1)/3 . Figure n edge nodes RSUs k, where r, a leader is responsible for storing Leader selection step: In consortium blockchain, RSUs are selected as validators to verify the block Request step: The request step represents a new candidate block generation Pre-prepare step: In this step, as shown in Prepare step: Each validator verifies the commit message after receiving over prepare-step.Commit step: Then, the validators broadcast the r is finished after the consensus reaches over commit message and then uploads the verified block Reply step: Finally, the leader t according to the message credibility assessment from We designed a trusted data sharing management IoVEC network based on the proposed model, consisting of three layers, i.e., user network layer, blockchain edge layer, and blockchain network layer. Each layer has its setting that distinct from one another. Using the OSMWebWizard package provided in the simulation of urban mobility (SUMO), we modeled a highway traffic scenario to prototype and evaluate IoVEC networks’ efficiency. Here, NS3 as a discrete-event network simulator is used to verify the result, analyzing a trace file for vehicle mobility and message credibility.To form an IoVEC, we use an optimized link-state routing protocol (OLSR) as one of the protocol standards in the wireless access for the vehicular environments (WAVE). This protocol enables the system to provide better performance in terms of vehicle mobility, speed, and delay communication . Here, vFurthermore, we also observed the relationship between the distance of After the MRSC aggregates the trust value rating, its result is then validated using a consensus mechanism in the VBSC consortium blockchain. To construct a consortium blockchain, we use Hyperledger Sawtooth as part of the Hyperledger platform. Hyperledger Sawtooth platform is suitable for our proposed model because it supports the PBFT consensus mechanism equipped by several validators. We utilized Docker containers to facilitate the main core components of Hyperledger Sawtooth architecture, such as transaction processors, validators that represent preselected edge nodes, and Sawtooth Representational State Transfer (REST) server. The consensus mechanism is then conducted by preselected RSUs  to validate a new block transaction. Before that block is stored in the blockchain network layer, the PBFT algorithm requires the agreement over To support an adequate incentive for the information provider (vehicle HTTP://127.0.0.1:7545 (accessed on 11 January 2021) with an auto mining mode. The address for all vehicles is derived from Ganache that holds 100.00 ETH each (publicly available). In a real-world implementation, the address does not depend on a single user interface, and the address is managed in the private wallet of each entity.We utilized a smart contract feature in the Ethereum platform through Ganache Truffle (v.2.4.0) graphical user interface (GUI). The default setting is applied where the gas limit is set to be 6,721,975 units, with the gas price is 20,000,000,000 wei running on a remote procedure call (RPC) server We performed the incentive distribution with a different number of vehicles (the message providers) Recently, blockchain has been widely studied to form a secure, trusted, and decentralized data management in the vehicular network. Several works have proposed blockchain-based IoV solutions to protect road-related information sharing among vehicles to improve traffic safety and efficiency ,15,16. HCompared to the proposals by Yang et al.  and ZhanKang et al.  also makFurthermore, we employ consortium blockchain to avoid SPoF attacks in a centralized system and prevent data modification attacks that may broadcast and create a modified block transaction in the consensus process conducted by compromised RSUs. Compared to other works which mainly use a joint PoW and PoS mechanisms  wBy leveraging the several advantages of our proposed framework as discussed above, the blockchain-based IoVEC framework can be utilized to address the limitation of ITS application , especially in terms of enhancing system performance and security protection. In IoVEC, MEC can improve the system performance; providing low latency, high bandwidth, and real-time communication by placing its server in the edge network to be closer to the user. Furthermore, the blockchain can form a decentralized and trusted data management system, as well as to provide the users with privacy and security. Nevertheless, future discussions are encouraged to address relevant issues in the blockchain-based IoVEC. For instance, the construction of a robust message authentication mechanism in order to strengthen privacy and security protection in the blockchain-based IoVEC would be of great importance. In Reference , the autWe have introduced a consortium blockchain and smart contracts to achieve a decentralized trusted data sharing management system in IoVEC. In this paper, smart contracts are exploited to accomplish an efficient, reliable, and secure data management system. Here, two smart contracts, MRSC and VBSC, are employed and placed on RSUs as the distributed edge network infrastructure. MRSC is used to collect and aggregate the trust value rating, while VBSC performs the consensus mechanism. Furthermore, this framework permits vehicles to validate the credibility of messages from their neighboring vehicles by generating a reputation rating. Additionally, we utilized an incentive mechanism based on Ethereum smart contract to motivate and propel the vehicles to contribute and sincerely share their data to obtain certain rewards from the system. Packet delivery ratio, considered to represent trust value rating of data sharing efficiency in IoVEC-Blockchain, shows a favorably positive performance and feasible to form a decentralized trusted data management system. Lastly, further studies are still required to apply a robust message authentication mechanism and cope with the blockchain scalability issue.


U test. There was a tendency towards higher expression of ER α in LF fibroblasts in the hypertrophy group (p = 0.065). The Sairyo and Okuda scores were more severe for the hypertrophy group but, in general, not statistically relevant. There was no statistically relevant correlation between the expression of ER α and sex (p = 0.326). ER α expression was higher in patients with osteochondrosis but not statistically significant (p = 0.113). In patients with scoliosis, ER α expression was significantly lower (p = 0.044). LF hypertrophy may be accompanied by a higher expression of ER α in fibroblasts. No difference in ER α expression was observed regarding sex. Further studies are needed to clarify the biological and clinical significance of these findings.The most common spinal disorder in elderly is lumbar spinal stenosis (LSS), resulting partly from ligamentum flavum (LF) hypertrophy. Its pathophysiology is not completely understood. The present study wants to elucidate the role of estrogen receptor α (ER α) in fibroblasts of hypertrophied LF. LF samples of 38 patients with LSS were obtained during spinal decompression. Twelve LF samples from patients with disk herniation served as controls. Hematoxylin & Eosin (H&E) and Elastica stains and immunohistochemistry for ER α were performed. The proportions of fibrosis, loss and/or degeneration of elastic fibers and proliferation of collagen fibers were assessed according to the scores of Sairyo and Okuda. Group differences in the ER α and Sairyo and Okuda scores between patients and controls, male and female sex and absence and presence of additional orthopedic diagnoses were assessed with the Mann–Whitney  One of the most common spinal disorder in the elderly is LSS , with LFFifty patients  were prospectively included in our study. Study approval was obtained from the Ethics Committee of the Medical Faculty of the Philipps University of Marburg (study reference 191/09). Thirty-eight patients with LSS necessitating decompressive surgery comprised the study group, and LF specimens were harvested from the L4/L5 spinal level. The control group consisted of 12 patients with disk herniation at the L4/L5 level. None of the controls had signs of degeneration on preoperative magnetic resonance imaging (MRI). Care was taken to remove as little LF as possible.Tissues were fixed in 4% formalin solution, embedded in paraffin, cut at a thickness of 4 μm, and stained with H&E and Elastica van Gieson (EvG) stains, as established for routine histopathological diagnosis. Immunohistochemistry was performed using heat-induced antigen retrieval (employing citrate buffer pH 6.0) and the Leica Bond Polymer Refine Detection System with 3,3′-diaminobenzidine (DAB) as the chromogen . All immunostainings were run on an automated immunostaining apparatus . ER α was detected by the monoclonal mouse antibody NCL-ER6F11 .The expression of ER α was semiquantitatively assessed as the nuclear staining of fibroblasts in LF according to the standardized procedures in breast cancer diagnostics by experienced senior pathologists (CCW and AR). The immunoreactive score (IRS) was calculated according to Remmele by multiplying the staining intensity  with the proportion of positive cells among all LF fibroblasts  . The proU, Kruskal–Wallis-, t-test, or Fisher’s exact test using R [Differences with regards to sex, age, additional orthopedic diagnosis, ER α and proportion of fibrosis, loss and/or degeneration of elastic fibers, and proliferation of collagen fibers, according to Sairyo and Okuda between the groups of patients and controls, male and female study participants, and among LSS patients were evaluated with the Mann–Whitney  using R  and comp using R  where app = 0.088). The LSS patients were significantly older than the study participants in the control group (p = 0.009), reflecting the typical age of onset for lumbar spinal stenosis (LSS patient group) and disk herniation (control group).The clinical characteristics, ER α expression data, and pathological findings of the control and the LSS patient groups are displayed in p = 0.065). In the LF specimens, the Sairyo and Okuda scores were in general more severe for the LSS patient group but, with regards to the differences between the control and LSS patient groups, not statistically relevant. Immunohistochemical staining for ER α in the nuclei of LF fibroblasts could be demonstrated for both sexes, along with a partly impressive staining intensity for the male probes c,f. Therp = 0.127), additional orthopedic diagnosis (p = 0.365), or ER α (p= 0.326) and sex. Furthermore, in both sexes, the same range of ER α expression was found , especially among LSS patients (patients . No statp = 0.113) (p = 0.932). However, in patients with scoliosis, the ER α expression was significantly lower (p = 0.044). When evaluating the absolute fibrosis and loss of elastic fibers on the basis of the score of Sairyo among the LSS patient group (p = 0.04), but there was no difference for structural instability (p = 0.124) or scoliosis (p = 0.125). There was also a trend for less of a loss of elastic fibers in patients with osteochondrosis (p = 0.076). No statistically significant effect was seen for the loss of elastic fibers in patients with structural instability (p = 0.308) or scoliosis (p = 0.765). The scores of fibrosis and the loss of elastic fibers according to Sairyo and the scores according to Okuda showed no statistically significant effects with regards to additional diagnoses  . In patint group , there wiagnoses .Hypertrophy of the LF is an important contributing factor in LSS , being oIn previous studies, expression of the ER was demonstrated on different tendons and ligaments via immunohistochemistry or reverse transcription-polymerase chain reaction (RT-PCR) ,20,21,22In our study population, we found a tendency toward higher ER α expression in LF fibroblasts of LSS patients among both sexes, accompanied by a higher variation among LSS patients . ER α haSince the LSS patients were much older than the study participants of the control group, it should be considered whether age alone could lead to a higher ER α expression. However, in previous studies on ER α in mesenchymal cells, no such correlation was found. In smooth muscle cell nuclei of the uterosacral ligament, the ER was detected immunohistochemically in all 25 patients studied regardless of variations in patient ages, which ranged from 34 to 68 years . In meseAmong LSS patients, the ER α expression was higher with the additional diagnosis of osteochondrosis, with a tendency toward statistical significance, whereas ER α expression was significantly lower in patients with the additional diagnosis of scoliosis. To date, no correlation regarding estrogen/ER and osteochondrosis has been found in the pertinent literature. With respect to scoliosis, ER α is considered a candidate gene for idiopathic scoliosis . FurtherThere have been a number of studies investigating the histopathological basis of LF hypertrophy and its correlation with clinical findings. However, no generally approved score exists to quantify histopathological changes in LF pathology. Therefore, we used the scores proposed by Sairyo et al.  and OkudOkuda et al. found no significant relationship between the loss of elastic fibers, degeneration of elastic fibers, or proliferation of collagen fibers and clinical symptoms or image findings. Although they examined materials from 50 patients, they did not include a control group without degenerative changes but analyzed only patients with LSS or spondylolisthesis.In a gender-matched case–control study of 30 patients with LSS or disc herniation, respectively, Park et al. identified a statistically significant correlation of elastin degradation and fibrosis with LSS  while grIn our study population—being slightly larger with respect to LSS patients than Park’s cohort—the scores according to Sairyo and Okuda, respectively, were, in general, more severe for the LSS patient group but, with regard to the differences between the control and LSS patient groups, not statistically relevant.Sairyo et al. demonstrated increased fibrosis and loss of elastic fibers, particularly in the dorsal portion of the LF . In ParkWhile our results on the histopathological changes in LF hypertrophy are in-line with previous findings and promising, further studies are warranted, with preferably more patient samples examined and LF tissues gained and processed in an oriented manner, e.g., for the differentiation of dural and dorsal LF. Further, larger studies may aid in elucidating the potential clinical consequences of our findings.n = 12) compared with the hypertrophy group, we only used LF samples from patients with an indication for discectomy without visible signs of degenerative lumbar spine disease, being a rare clinical situation. Additionally, only a few male control samples were available (n = 2), representing a potential bias. However, care was taken to recruit an equivalent number of male and female patients (n = 19 each).Concerning the small number of control samples in our study (Our study is the first published to examine ER α on LSS patient materials with a relevant number of cases and clearly indicating both sexes. LF hypertrophy may be accompanied by a higher expression of ER α. More severe fibrosis, loss of elastic fibers, and the proliferation of collagen fibers, according to Sairyo and Okuda, were observed in the hypertrophy group. No statistically relevant correlation was seen between ER α and sex. Among the LSS patients, ER α expression was higher with the additional diagnosis of osteochondrosis, with a tendency toward statistical significance, whereas the ER α expression was significantly lower in LSS patients with the additional diagnosis of scoliosis. Further, larger studies with some technical modifications in material processing may help to clarify the biological and clinical significances of these findings.


The incretin hormone glucagon-like peptide-1 (GLP-1) has received enormous attention during the past three decades as a therapeutic target for the treatment of obesity and type 2 diabetes. Continuous improvement of the pharmacokinetic profile of GLP-1R agonists, starting from native hormone with a half-life of ~2–3 min to the development of twice daily, daily and even once-weekly drugs highlight the pharmaceutical evolution of GLP-1-based medicines. In contrast to GLP-1, the incretin hormone glucose-dependent insulinotropic polypeptide (GIP) received little attention as a pharmacological target, because of conflicting observations that argue activation or inhibition of the GIP receptor (GIPR) provides beneficial effects on systemic metabolism. Interest in GIPR agonism for the treatment of obesity and diabetes was recently propelled by the clinical success of unimolecular dual-agonists targeting the receptors for GIP and GLP-1, with reported significantly improved body weight and glucose control in patients with obesity and type II diabetes. Here we review the biology and pharmacology of GLP-1 and GIP and discuss recent advances in incretin-based pharmacotherapies. Obesity decades Figure 1 decades .While traditionally recognized primarily as a disease of the elderly, T2D is currently one of the most frequently diagnosed preventable chronic diseases in middle age, as well as children and adolescents , 6. ExceLifestyle modifications, such as balanced nutrition, calorie restriction and physical exercise, remain the cornerstone of any weight loss intervention. However, lifestyle changes alone are insufficiently efficacious and sustainable as a stand-alone therapy, possibly because physiological adaptations conspire to promote weight regain following diet-induced weight loss . Genetic® Novo Nordisk, Copenhagen, Denmark), a long-acting agonist at the glucagon-like peptide-1 receptor (GLP-1R)  , and the(GLP-1R) . Each of(GLP-1R) –28. WhilGLP-1 is encoded by proglucagon, a 158 amino acid precursor protein, that is predominantly expressed in the gut, pancreas, and distinct neuronal populations of the hindbrain . In the via the Gαs pathway, and hence accelerates intracellular levels of cAMP (via the Gαq and β-arrestin pathways and knockdown of β-arrestin-1 in rat insulinoma (INS1) cells decreases the ability of GLP-1 to promote GSIS , a 7 transmembrane G protein-coupled receptor of the class B family . GLP-1R  of cAMP . GLP-1R ote GSIS . Immunohote GSIS . These dote GSIS . Consistote GSIS , 29, expote GSIS , 46. In ote GSIS . No exprote GSIS .2), with a low proportion produced as GLP-1(7-37) and an even a lower portion as GLP-1(1-37) or GLP-1(1-36NH2) (in vivo proteolysis by the dipeptidylpeptidase-4 (DPP-4) and fast renal elimination. DPP-4 cleaves GLP-1(7-36NH2) and GLP-1(7-37) at the second N-terminal amino acid (Ala8) position, leading to metabolically metabolites GLP-1(9-36NH2) and GLP-1(9-37) of much reduced potency  , 57. Nat1-36NH2) –60, whic potency . Despite potency , 62. The potency , 64, it’ potency .2) at a rate of 4.8 pmol-1 kg-1 min-1 improved glycemic control and insulin sensitivity in patients with T2D   , and the recruitment of GLP-1 into unimolecular pharmacology with GIP, glucagon (and others)   and moreDenmark) , 28. AlsDenmark) –85 or glDenmark) , 87 have others) , 29, 88  others) .in vivo action and potency  to protect from degradation by DPP-4. Such structural modification has been applied to exenatide, lixisenatide, semaglutide, dulaglutide, and albiglutide.heloderma suspectum). Both exenatide and lixisenatide contain the full sequence of exendin-4, but lixisenatide is extended on the C-terminus to possess six additional lysine residues  is a sixty amino acid tandem of two DPP-4 protected GLP-1 molecules that are covalently fused to human albumin . The chevia a gamma glutamic acid spacer at the lysine residue at position 26  and semaglutide . Liraglutide is linked to palmitic acid (C16:0) ition 26 . The fatition 26 . Semagluition 26 . Of notein vivo proteolysis, and enhance toxicological safety and potentially even its non-immunogenic resilience  which was approved by the FDA in 1990 for adenosine deaminase deficiency associated with severe combined immunodeficiency disease (SCID). The PEG modification can, in rare cases, lead to vacuolation or the generation of antibodies against the PEG. As it pertains to drugs to control body weight and/or glycemia, preclinically tested pegylated anorectics include leptin (Polyethylene glycol (PEG) is a synthetic water-soluble inert polymer with the potential to enhance a drug’s half-life by slowing down its rate of renal clearance. Pegylation of a drug can also enhance its aqueous solubility, protect against silience . The linsilience –110. Thie leptin , FGF21  has been applied for dulaglutide. The sixty amino acid molecule comprises two Gly8-modified DPP-4 protected GLP-1 molecules in which the C-termini are fused at a Gly36 residue to IgG4 Fc fragments. Notably, while dulaglutide carries a glycine at position 8 to protect from DPP-4 cleavage, Fc fusion to native GLP-1 is sufficient to reduce DPP-4 degradation by 4-5-fold relative to native GLP-1  in the acidic endosomal compartments with the consequence that the FcRn-bound Fc complex is recycled back to the plasma membrane and secreted back into general circulation  is an extended-release (ER) formulation of exenatide. The drug is self-applied on a weekly basis independent of meal patterns. The extended release is achieved through incorporation of exenatide (exendin-4) into 0.06 mm-diameter biodegradable microspheres, which comprise a 50:50 poly (PLG) polymer along with sucrose  weeks, yielding therapeutic levels after two weeks and a steady state after 6–7 weeks . The relThe prolonged rise to achieve steady state plasma concentrations seems to have beneficial effects on tolerability since the frequency of nausea and vomiting is reduced in patients treated with exenatide ER relative to treatment with exenatide BID , 133. Exvia the GI-tract and quick degradation by proteolytic enzymes and the acidic environment of the stomach. For this reason, peptide GLP-1R agonists are not available as oral preparations and rather have to be subcutaneously self-injected by the patient. Difficulties and discomfort with self-injected medication is a factor that negatively affects patient compliance and quality of life . In Rybelsus®, semaglutide is co-formulated with sodium N-[8-(2-hydroxybenzoyl)aminocaprylate] (SNAC), which shields the molecule from enzymatic and acidic degradation and accelerates its site-directed release and absorption in the stomach  was approved in 2014 for the treatment of obesity in adults and in 2020 for the treatment of obesity in children aged 12 and older  in adjunct to lifestyle programs for the treatment of obesity in adults (vs. 31.5% in placebo controls), while 69.1% (vs. 12.0% in placebo controls) lost >10%, 50.5% (vs. 4.9% in placebo controls) >15% and 32% (vs. 1.7% in placebo controls) >20%  >20% . Similarls) >20% , 143, pals) >20% . Like wils) >20% . Notablyls) >20% , 146–1482), is produced in the intestine and the pancreatic α-cells by cleavage of proGIP by PC2    . Body wecontrols  and is de tissue  and the e tissue . However of Gipr –179, indue (BAT)  or the pue (BAT) .Gipr protects from diet-induced obesity , fatty-acyl GIP decreases body weight and food intake in HFD-fed wildtype mice but not in mice with CNS deletion of Gipr  has been developed by Eli Lilly . The molIn recent phase III clinical trials, tirzepatide showed profound ability to improve body weight and glycemia in patients with obesity and T2D. Depending on the dose , 40-52 weeks of treatment with tirzepatide, decreased HbA1c between -1.87 and – 2.59%, with 81 – 97% of patients achieving a HbA1c <7%, and 23 – 62% of patients achieving HbA1c <5.7% –27, 196.The results of completed tirzepatide trials are quite exciting. However, some effort is still required to ensure such therapeutic advance will be applicable to all populations for whom it is intended. Racial and ethnic minorities carry a disproportionate burden of obesity and T2D in the general population, but their enrolment in the completed tirzepatide trials was lower than expected, which raises concerns regarding the generalizability of these trials. Female participants were reasonably represented in the completed trials, but no assessment of biological sex differences in drug efficacy and safety profiles was made –27, 196.It is well recognized that T2D and obesity treatments may be best suited for precision medicine approaches rather than a “one size fits all” paradigm. While considerable effort continues to be invested into developing more pharmacotherapies for T2D and diabetes, it is of paramount importance that use of the currently available medications is optimized—that is, to provide the right treatment to the right patient, at the right time. The completed trials of tirzepatide demonstrate meaningful improvement of glycemic and weight control with this drug. However, as with any medical therapy, there are large inter-individual differences in response among participants, including the possibility of less than 5% weight loss to 20% or greater weight loss –27, 196,QT and SA co-wrote sections and edited the manuscript. CO made the figures and edited the manuscript. RW edited the manuscript. RD edited and revised the manuscript and co-wrote sections. TM conceptualized and wrote the manuscript. AH co-conceptualized the manuscript, co-wrote sections, and edited the manuscript. All authors contributed to the article and approved the submitted version.QT received research funding from the International Helmholtz Research School for Diabetes and the Alberta Diabetes Institute. SA received research funding from the Helmholtz Association (Helmholtz Diabetes School). TM received research funding from the German Research Foundation (TRR152 and TRR296). AH received research funding from the Canadian Institutes of Health Research and Weston Family Foundation (Pro00069477 and Pro00100067).AH is an investigator on clinical trials for Rhythm Pharmaceuticals, Inc., and Levo Therapeutics, has received grant funding from the W. Garfield Weston Foundation, and has served as a speaker for Rhythm Pharmaceuticals, Inc. TM receives research funding by Novo Nordisk, but these funds are unrelated the here described work. TM further received speaking fees from Eli Lilly, Novo Nordisk, Mercodia, AstraZeneca, Berlin Chemie, and Sanofi Aventis. RD is a co-inventor on intellectual property owned by Indiana University and licensed to Novo Nordisk. He was recently employed by Novo Nordisk and previously Lilly Research Laboratories.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.The handling editor declared a shared affiliation with several of the authors SA and TM.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The membrane showed permeation behavior, wherein the permeance reduced with the molecular size, attributed to the effect of molecular sieving. The separation performances were also determined using the equimolar mixtures of N2–SF6, CO2–N2, and CO2–CH4. As a result, the N2/SF6 and CO2/CH4 selectivities were as high as 710 and 240, respectively. However, the CO2/N2 selectivity was only 25. These results propose that the high-silica CHA-type zeolite membrane is suitable for the separation of CO2 from CH4 by the effect of molecular sieving.The polycrystalline CHA-type zeolite layer with Si/Al = 18 was formed on the porous α-Al Some kinds of zeolite membranes are available for the dehydration of many kinds of organic solvents in industries [Zeolites are microporous aluminosilicate compounds, and they have been attracted much attention as the potential material for membranes. Zeolite membranes have been studied since the 1990s, and the MFI-type zeolite membranes were formed on the substrates by deposition and intergrowth of crystallites, which were nucleated in synthesis mixtures ,7,8,9,10dustries ,21,22.2/CH4 selectivity was as high as 2000 below 250 K. However, the selectivity decreased to 220 around 300 K. Noble and coworkers investigated CHA-type silica-aluminophosphate zeolite (SAPO-34) membranes [2–CH4, CO2–N2, Kr–Xe, and N2–CH4 mixtures. The CO2/CH4 selectivity was 171 at 295 K [2 separation performances were determined [N-methyl-2-pyrrolidone (NMP) [−2 h−1 and 1100, respectively. Imasaka et al. developed high-silica CHA-type zeolite membranes with Si/Al = 23, and they applied them to the CO2 separation [2 permeance (1.5 × 10−6 mol m−2 s−1 Pa−1) and CO2/CH4 selectivity (115) at 313 K. AEI-type zeolite is one of the aluminophosphate-type zeolites and contains no exchangeable cations. Since the crystal structure is similar to CHA-type zeolite, the identical CO2/CH4 selectivities were obtained [These mechanism studies have established that DDR-, CHA-, and AEI-type zeolite has favorable characteristics for the membrane material, such as small micropore diameter, large micropore volume, and the composition variability . These fembranes ,28,29,30termined ,32. Satone (NMP) . For a 5obtained ,34,35.2, CO2, N2, CH4, n-C4H10, and SF6 at 303–473 K. The gas separation tests were also examined for binary mixtures of N2-SF6, CO2-N2, and CO2-CH4 at 303–473 K. Furthermore, the gas permeation and separation mechanisms of the CHA-type zeolite membrane were discussed in this paper.Recently, we developed the rapid preparation technique for high-silica CHA-type zeolite membranes using the structure conversion of Y-type zeolite ,37,38. T2O3 support tube by the combination of the secondary growth of seed particles and the structure conversion of FAU-type zeolite [N,N,N-trimethyl-1-adamantammonium hydroxide solution , and ultra-stable Y-type zeolite particles . The molar composition of the solution was 40 SiO2:1 Al2O3:4 Na2O:8 SDA:800 H2O. The mixture was poured into a Teflon-lined stainless-steel autoclave, and a hydrothermal reaction was carried out at 433 K for 4 days. Solids were recovered by filtration, washed with distilled water, and dried overnight at 383 K to obtain seed particles. For the secondary growth, a synthesis solution was prepared by the same procedures as that for the seed particles, and the mixture was stirred at room temperature for 4 h. The molar composition of the mixture was 45 SiO2:1 Al2O3:4.5 Na2O:3.4 SDA:4500 H2O. The α-Al2O3 tube was used as the support, and the properties were as follows: outer diameter = 2.0 mm; inside diameter = 1.5 mm; mean pore diameter = 0.3 μm; and porosity = 45%. The outer surface of the support tube was rubbed with the seed particles to implant seeds for nucleation, and the tube was added to the autoclave filled with 30 g of the synthesis solution. The autoclave was placed horizontally in an oven at 433 K for 20 h to form the polycrystalline high-silica CHA-type zeolite layer. After the autoclave was cooled to room temperature, the support tube was recovered, washed with distilled water, and dried at room temperature overnight. Finally, the tube was calcined in air at 773 K for 10 h to remove the SDA to obtain the high-silica CHA-type zeolite membrane.A high-silica CHA-type zeolite membrane was prepared on the outer surface of a porous α-Al zeolite ,37,38. TThe morphology was observed using a scanning electron microscope , and the composition was analyzed by an energy-dispersive X-ray (EDX) analyzer attached with the SEM. The crystal structure of the membrane was identified by X-ray diffraction .2. The membrane was fixed to a permeation cell, as shown in 2, CO2, N2, CH4, n-C4H10, and SF6, as well as binary mixtures of N2–SF6, CO2–N2, and CO2–CH4, were fed onto the outer surface of the membrane (feed side) at 100 mL min−1, and either argon (for H2) or helium (for the others) was introduced into the inside of the membrane (permeate side) at 10–50 mL min−1 as the sweep gas. The total pressures of the feed and permeate sides were kept at 300 and 101 kPa, respectively. In this study, the membrane was treated under N2 flow at 473 K for 30 min to remove adsorbed water, and the test gas was fed onto the feed side. The pretreatment was carried out before each measurement. The gas composition was analyzed using a gas chromatograph with a thermal conductivity detector (Shimadzu GC-8A), and the gas flow rate was determined by a soap-film flowmeter. The permeance for component i, iQ, was calculated using the following equation:Np is the molar flow rate of the outlet from the permeate side; S, the effective membrane area for permeation; iy, the mole fraction of component i in the outlet gas of the permeate side; Pif, the partial pressure of component i on the feed side; and Pip, the partial pressure of component i on the permeate side. The selectivity was defined as the ratio of the permeances in this study.Both the ends of the support tube were connected to stainless-steel tubes with silicon resin , and the outer surfaces of resin were wrapped with thermally shrinking tetrafluoroethylene and hexafluoropropylene copolymer (FEP) tubes . The effective membrane area for permeation was 1.2 cm2O3 tube with high reproducibility.2 was 5.1 × 10−7 mol m−2 s−1 Pa−1 at 303 K. The permeance, except for H2, decreased, with increase in the diameter, and that reached 4.1 × 10−11 mol m−2 s−1 Pa−1 for SF6. The diameter of the crystallographic channel aperture of the CHA-type zeolite is 0.38 nm [2, CO2, N2, CH4, n-C4H10, and SF6 are 0.289, 0.33, 0.364, 0.38, 0.43, and 0.55 nm, respectively [2, CO2, and N2 molecules are smaller than the channel diameter, those molecules can penetrate into and diffuse within the zeolite channels. Although the molecular diameter of SF6 is clearly larger than the channel sizes, SF6 was detected on the permeate side of the membrane. The marginal permeance of SF6 proposes that the membrane had intercrystalline boundaries. The unit cell of the high-silica CHA-type zeolite was shrunk by the air calcination, and the volume shrinkage degree was 0.6 vol % [ 0.38 nm , and theectively . Since H.6 vol % . The sma2 was 1.8 × 10−8 mol m−2 s−1 Pa−1 at 473 K. After nine times heating and cooling treatment for determination of the permeation properties of single-component gases and binary mixtures, the permeance was 1.7 × 10−8 mol m−2 s−1 Pa−1. The identical permeances of N2 indicates that the high-silica CHA-type zeolite membrane was stable for the thermal treatment.Moreover, the permeance of N2, CO2, N2, CH4, n-C4H10, and SF6 at 303–473 K. The permeance of CO2 was 5.1 × 10−7 mol m−2 s−1 Pa−1 at 303 K and decreased with temperature. As a result, it was 1.3 × 10−7 mol m−2 s−1 Pa−1 at 473 K. The permeances of H2 and N2 showed similar dependencies. Since these molecules are smaller than the channel diameter of the CHA-type zeolite, these molecules can adsorb on the zeolite channels. The adsorption amount decreased with temperature. Therefore, the permeances of H2, CO2, and N2 were decreased with temperature by the reduction of the concentration difference between both the sides of the membrane.4, n-C4H10, and SF6, the diameters of which are identical or larger than the zeolite channels, the permeances increased with temperature. The effect of temperatures is described using the Arrhenius equation as follows:iQ* and Ep are the pre-exponential factor and activation energy for permeation, respectively. The pre-exponential factors and activation energies of single-component gas permeation are listed in n-C4H10 and SF6 were higher than those of the other gases. It is well known that the difference in the diffusivities is important for the permeation through membranes [n-C4H10 and SF6 suggest that it is difficult for these molecules to permeate through the intercrystalline boundaries. Therefore, the high-silica CHA-type zeolite membrane had small and minimal intercrystalline boundaries.In contrast, for CHembranes ,15,16,172 < N2 < CH4 < SF6. This suggests that the CO2/N2, CO2/CH4, and N2/SF6 selectivities are higher at lower temperatures. The separation performances for these mixtures are examined in the next subsection.As shown in 2 and SF6 for the equimolar mixture of them at 303–473 K. As same as for the single gas, the permeance of N2 for the binary mixture decreased with temperature, while that of SF6 showed the reverse dependency. Therefore, the N2/SF6 selectivity was the highest (=710) at 303 K. The permeance of SF6 for the mixture was the same as that for single gas, and the permeance of N2 for the mixture was also identical at temperatures higher than 363 K. However, below 363 K, the permeances of N2 for the mixture was lower than that for the single gas. As a result, the N2/SF6 selectivity was 440 for the mixture. The lower N2 permeances for the mixture was attributed to the weaker interaction of N2 with the zeolite than SF6. The interaction potential of individual molecules can be described using the Lennard–Jones 12-6 equation. The depths of interaction potential are 0.59 kJ mol−1 and 1.85 kJ mol−1 for N2 and SF6, respectively [6 proposes that SF6 molecules interact with zeolites more strongly than N2. In addition, SF6 molecules permeated through the boundaries, as discussed above. Therefore, N2 molecules, permeated through the boundaries, were inhibited by the SF6 molecules, and the permeance of N2 became lower compared to the single gas.ectively . The dee2 and N2 for the equimolar mixture of them at 303–473 K. Although the permeance of N2 became the maximum at 343 K for the mixture, that of CO2 decreased with temperature. The CO2/N2 selectivity for the mixture was the highest at 303 K (=25) and decreased with temperature. As a result, the selectivity became only 9 at 473 K.2 for the mixture was similar, although the permeance for the mixture was slightly higher at all temperatures. The permeance of N2 was almost the same that for the single gas at higher temperatures than 373 K, while it was lower below 363 K. These are typical permeation properties when molecules are transferred and separated by the preferential adsorption of CO2. Similar properties were also observed for the CO2–N2 separation using FAU-type zeolite membranes [2 adsorption and the overtaking N2 by CO2 [Compared to the single gas, the temperature dependency of COembranes ,16. Moro2 by CO2 .2 and CH4 for the equimolar mixture of them. The permeances of CO2 and CH4 for the mixture were 5.3 × 10−7 and 2.2 × 10−9 mol m−2 s−1 Pa−1 at 303 K, respectively. The CO2/CH4 selectivity was 240 for the mixture. The permeance of CO2 decreased with temperature, although that of CH4 showed the reverse dependency. As a result, the CO2/CH4 selectivity reduced to 43 at 473 K. Comparing to the single gases, the permeances of CO2 and CH4 for the mixture were almost identical. The permeation properties cannot be explained by only the preferential CO2 adsorption, as discussed in 4 is similar to the channel diameter of the CHA-type zeolite, the diffusion of CH4 within the zeolite channel was slower than N2, as show in i-C4H10 molecules hinder the diffusion of n-C4H10 for the separation of butane isomers using MFI-type zeolite membranes [4 molecules within the zeolite channels may hinder the diffusion of CO2 molecules.embranes . The CH42 concentration in the feed mixture was determined to check the interaction between CO2 and CH4 molecules during the permeation. 2 concentration in the feed mixtures on the permeation properties of CO2 and CH4 for binary mixtures of them at 303 K. If CH4 inhibits the permeation of CO2, the permeance of CO2 would be reduced at the dilute CO2 concentration. However, the permeances of CO2 and CH4 were independent of the CO2 concentration in the feed mixture, and the selectivity was almost constant at 200–260. The constant permeances of CO2 and CH4 propose that the CO2 and CH4 molecules did not interact each other during the membrane permeation. Therefore, it is considered that CO2 and CH4 molecules diffuse in the different passes, such as zeolite micropores and inter-crystalline boundaries.The influence of the CO2 separation performance to previous reports [2 permeance and selectivity of our membrane were relatively high for CO2–CH4 mixtures, and the performances could be plotted on the trade-off line of SAPO-34, CHA-, and AEI-type zeolite membranes [2 separation performances of the membranes are attributed to the similar crystal structures [2 selectivity below 300 K, the selectivity at temperature higher than 300 K was almost the same as those of CHA- and AEI-type zeolite membranes [2 selectivities of the FAU-type zeolite membranes were lower compared to those membranes [2 permeance and selectivity for CO2–N2 mixtures [2 separation from CH4, while the selective adsorption of CO2 is necessary for CO2–N2 mixtures. reports ,34,42,43embranes ,32,33,34ructures . Althougembranes . The CO22O3 tube in this study, and the gas permeation properties were determined using single-component H2, CO2, N2, CH4, n-C4H10, and SF6 at 303–473 K. The permeance was 5.1 × 10−7 mol m−2 s−1 Pa−1 for CO2 at 303 K and the permeance reduced with increasing the molecular size. Moreover, the permeances of H2, CO2, and N2 decreased with temperature, while those of CH4, n-C4H10, and SF6 showed reverse trends. The gas separation tests were also carried out using binary mixtures of N2-SF6, CO2-N2, and CO2-CH4. The membrane showed the high separation performance for the mixtures, and the N2/SF6, CO2/N2, and CO2/CH4 selectivities were 710, 25, and 240, respectively.The polycrystalline CHA-type zeolite layer with Si/Al = 18 was formed on the porous α-Al


The objective of this study was to identify potential biomarkers and possible metabolic pathways of malignant and benign thyroid nodules through lipidomics study. A total of 47 papillary thyroid carcinomas (PTC) and 33 control check (CK) were enrolled. Plasma samples were collected for UPLC-Q-TOF MS system detection, and then OPLS-DA model was used to identify differential metabolites. Based on classical statistical methods and machine learning, potential biomarkers were characterized and related metabolic pathways were identified. According to the metabolic spectrum, 13 metabolites were identified between PTC group and CK group, and a total of five metabolites were obtained after further screening. Its metabolic pathways were involved in glycerophospholipid metabolism, linoleic acid metabolism, alpha-linolenic acid metabolism, glycosylphosphatidylinositol (GPI)—anchor biosynthesis, Phosphatidylinositol signaling system and the metabolism of arachidonic acid metabolism. The metabolomics method based on PROTON nuclear magnetic resonance (NMR) had great potential for distinguishing normal subjects from PTC. GlcCer(d14:1/24:1), PE-NME (18:1/18:1), SM(d16:1/24:1), SM(d18:1/15:0), and SM(d18:1/16:1) can be used as potential serum markers for the diagnosis of PTC. Thyroid cancer is the most common endocrine-related malignancy and the most prevalent cancer of the head and neck in the past decades . It accoAt the same time, researchers have been searching for molecular markers that are valuable in diagnosing thyroid cancer, such as BRAF, RET/PTC, RAS, PAX8/PPARδ, P53, NTRK1, galectin-3. CK19, VEGF, Aurora-A, P16, AR, HBME-1, etc. , but disLipids played critical roles in cellular structures and functions, including cellular barriers, membrane matrices, signaling and energy storage. They undergo constant changes in physiological, pathological, and environmental conditions. Lipids play essential roles in cell growth and metabolism, therefore they are associated with carcinogenic pathways. Lipidomics, the metabolism of lipids, is defined as “the full characterization of lipid molecular species and of their biological roles with respect to expression of proteins involved in lipid metabolism and function, including gene regulation” . First iE (UPLC-QTOF-MSE)-based technique for determination of total lipids present in patient plasma to identify the potential diagnostic biomarkers for thyroid cancer. UPLC-Q-TOF-MS has been used in systems analysis of complicated metabolome (Recent advances in mass spectrometry (MS), nuclear magnetic resonance (NMR) and other spectroscopic methods have greatly facilitated the development and application of lipidomics , and MS tabolome . Differen = 47) and control check (CK) (n = 33) were collected from the First Hospital of Tsinghua University from August 2016 to September 2019. The patients were selected according to the following criteria: (1) all patients with papillary thyroid carcinoma were diagnosed by pathology; (2) no patients received preoperative treatment, including adjuvant chemotherapy and radiotherapy; and (3) patients do not have hyperlipidemia, diabetes, and other diseases that might affect lipid metabolism. (4) Patients with a history of other malignancies or recurrent tumors were excluded. The selected healthy controls include age and gender-matched healthy subjects with no metabolic diseases and were proven to lack any lesions in thyroid after the physical examination followed by ultrasonography of the thyroid.Serum samples from PTC (Fasting venous blood samples were collected in EDTA anticoagulant tube. The fresh blood samples were transported to the laboratory for 20 min by cold chain (4°C), and the plasma was obtained by centrifugation at 1,000 g and 4°C. The plasma was cold extracted in a liquid nitrogen tank for 15 min, and then put into the –80°C freezer for analysis.Mass spectrometry was an analytical method which ionizes the substance to be measured, separated it according to the mass/charge ratio of ions, and measured the intensity of various ion spectrum peaks to achieve the purpose of analysis. Mass was one of the inherent characteristics of substances. Different substances had different MS. Use this property, qualitative analysis  can be carried out. The peak intensity was also related to the content of the compound it represented and can be used for quantitative analysis.t-test was used for age variables. Metabolic changes in Plasma extract were analyzed by using UPLC-Q-TOF MS system and its software Progenesis QI (Waters). The original tandem mass spectrometry datasets were generated on the Waters XEVO-G2XS QTOF instrument and processed by the commercial software Progenesis QI 2.0, including raw data import, selection of possible adducts, peak set alignment, peak detection, deconvolution, dataset filtering, noise reduction, compound identification, and normalization with some method. The original data was preprocessed and the linear model was adjusted. Orthogonal Partial least squares discriminant analysis (OPLS-DA) was first used for classification discrimination. OPLS-DA was a supervised statistical method for discriminant analysis. OPLS-DA was used to establish a model of the relationship between the metabolite expression and the sample type, so as to realize the prediction of sample type , VIP value (VIP > 1), and FDR value (FDR < 0.05) Standard potential difference marker is selected. The best truncation value was determined by using The Youden index. Finally, potential biomarkers were correlated with metabolic pathways through KEGG.Statistical analysis was conducted on clinical data, gender variables were analyzed using the chi-square test, and independent ple type . The relP < 0.05 was considered statistically significant.All statistical analyses were performed used R version 3.6.3, and There were 47 PTC patients , and 33 healthy controls . The clinical information of the samples was shown in validation set and a training set. To describe the changes between PTC group and CK group, an OPLS-DA model was developed .As can be seen in the figure, the plasma lipid profile of the two groups changed significantly. In addition, we obtained the S-plot showing a good curve, and the further away the metabolites from the origin in the figure, the greater the contribution to the grouping . Thirty P < 0.05 were selected by the classic one-stage method , Recursive Partitioning (RPART), Support Vector Machine (SVM), Random Forest (RF), Gradient Boosting Machine (GBM) as the alternative algorithm. Through the 7-fold cross-validation, the indexes of each model were calculated, including accuracy, sensitivity, specificity and AUC. Statistical analysis of the results of 7-fold cross- validation showed that the classification effect of Logistic Regression was similar to that of SVM, which showed high AUC valued and high accuracy . Validatp-value or pathway impact, were associated with Glycerophospholipid metabolism (a), Linoleic acid (b), alpha-Linolenic acid metabolism (c), Glycosylphosphatidylinositol (GPI) (d), Glycerolipid metabolism (e), Phosphatidylinositol signaling system (f), and Arachidonic acid metabolism (g). Metabolomics Pathway Analysis (MetPA) is a part of many functions of MetaboAnalyst network database. It can visualize the metabolic pathway information of potential biomarkers with the help of METLIN, HMDB, and KEGG database. As shown in In our study, UPLC-Q-TOF MS metabolomics technology was used to analyze the plasma of PTC group and CK group. Based on the classical statistical method, appropriate metabolites were selected for pathway analysis to determine the potential metabolic pathways and mechanisms.Tumor progression is a complex process involving proliferation, hypoxia, angiogenesis, apoptosis, metastasis, immunity, and increased tolerance to reactive oxygen species . These tPhospholipids are divided into two main groups, glycerophospholipids (GPs) and sphingophospholipids. Depending on the different substituents at the sn-3 position of the glycerol backbone, GPs fall into phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidyl glycerol (PG), phosphatidylserine (PS), phosphatidylinositol (PI), phosphatidic acid (PA), and cardiolipins. There is evidence that PC, PE and sphingomyelin (SM) are major components of eukaryotic cell membranes.PE is a key phospholipid that helps maintain cell membrane fluidity. SM is an important component of biofilm composition. SM and its metabolites such as ceramide (Cer), sphingosine (Sph), and sphingosinephosphate (S1P) are an important class of biologically active signaling molecules involved in the regulation of many important signal transduction processes such as cell growth, differentiation, senescence and death are involved . Among tIn cells, PC is mediated by phospholipase A2 (PLA2), a family of enzymes that hydrolyze glycerophospholipids to fatty acids and lysophosphatidylcholine. PLA2 is significantly more active in thyroid cancer cells than in normal thyroid tissue, and thus PC, along with its choline metabolites produced during metabolism, has an important role in tumor proliferation and survival . Guo et de novo synthesis of ceramide pathway Enzymes can reverse drug resistance in cancer cells  mainly exists in body tissues in the form of complex lipids. The research results of Linoleic acid, as an unsaturated fatty acid, has many functions. First, LA inhibits tumors by inducing the formation of lipid peroxidation products . FurtherGlycosylated phosphatidylinositol (GPI) proteins are proteins that are anchored to the surface of eukaryotic cell membranes by a glycosylated phosphatidylinositol-anchored structure at the carboxyl terminus. GPI ethanolamine phosphate transferase participates in glycosylphosphatidylinositol biosynthesis. The relationship between GPI and tumor. First, GPI-anchored proteins are associated with tumor markers . GPI-ancAccording to the current study, sphingolipids are the most recognized lipid markers. Sphingolipids play an important role in cell proliferation, migration, inflammatory response to anticancer drugs and other cancer-related functions as well as in preventing the occurrence and development of cancer . but no We didn’t find the sphingolipid pathway in our metabolic pathway, but phospholipids and glycolipids are complex lipids composed of simple lipids and non-lipid components . Phospholipids are lipids containing phosphoric acid. They can be divided into glycerol phospholipids and sphingosine phospholipids according to the different alcohols in the molecules. In addition, these two pathways can be interrelated through phosphoethanolamine and ceramide. In future experiments, we will expand the sample size and carefully screen the samples for further verification of the results. We would like to explore the role and association of sphingolipid metabolism in cancer.This study culminated in the design of a predictive model that was constructed using altered lipid metabolites found previously in several patients with thyroid cancer, which will hopefully help in future work to diagnose thyroid cancer. Early diagnosis can enable PTC patients to receive more effective follow-up monitoring, especially high-risk patients to receive timely treatment to reduce the higher medical costs and physical injuries caused by delayed progression of the disease. Although ultrasound is the preferred method for the diagnosis of thyroid nodules, its application in the differential diagnosis of benign thyroid nodules and papillary thyroid carcinoma is controversial, and the diagnostic accuracy range is between 20 and 76% . The appThe limitations of our study include a relatively small sample size and a study group. Follicular, anaplastic, and poorly differentiated tumor samples were not included in our study because of their low incidence. In this study, we did not compare the changes in the lipid spectra of rai-refractory and rai-responsive. The samples selected in this study were patients with papillary thyroid carcinoma confirmed by pathology. There is no clear distinction between early-stage (I-II) and late-stage (III-IV) tumors. Another limitation of this study is the small data set. In the future, the sample size should be enlarged.The lipids in the serum of patients with PTC and in the healthy control groups were comprehensively analyzed using UPLC-QTOF/MS. Thirteen lipid species are proposed as potential biomarkers for the diagnosis of PTC. These species showed significant differences between the PTC and healthy control group. The identified biomarker or panels showed excellent diagnostic accuracies for distinguishing among PTC patients, and normal individuals. The predictive model showed good diagnostic performance and it could be gradually incorporated as a support method for the diagnosis of PTC.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.The study was performed according to the standards of the Institutional Ethical Committee and the Helsinki Declaration of 1975, as revised in 1983, and was approved by the Institutional Review Board of the Tsinghua University. The patients/participants provided their written informed consent to participate in this study.NJ, ZZ, and XC were involved in the study concept and design. NJ, ZZ, GZ, LP, CY, GY, and LZ provided the tools and patient specimens. XC and YW performed the experiments. XC, JH, and TX analyzed and interpreted the results and edited the manuscript. JH and TX organized the results and drafted the manuscript. NJ and XC approved the final version. All authors participated in the critical revision of the manuscript for important intellectual content.XC and JH were employed by the BaoFeng Key Laboratory of Genetics and Metabolism. TX was employed by the Zhongguancun Biological and Medical Big Data Center. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


In uncertainty, the existing t-test of a correlation coefficient is unable to investigate the significance of correlation. The study presents a modification of the existing t-test of a correlation coefficient using neutrosophic statistics. The test statistic is designed to investigate the significance of correlation when imprecise observations or uncertainties in the level of significance are presented. The test is applied to data obtained from patients with diabetes. From the data analysis, the proposed t-test of a correlation coefficient is found to be more effective than existing tests.The existing  In the t-test for correlation, the null hypothesis that there is no association between two variables is tested against the alternative hypothesis that two variables are associated. Values of the statistic of the t-test for correlation are calculated from given data and compared with tabulated values. The null hypothesis of no association between two variables is accepted if the calculated value is less than the tabulated value. Bartroff and Song  to be pair data and let rN = rL+rUIrN; IrNϵ be a neutrosophic correlation, where rL is a determinate part, the rUIrN is an indeterminate part, and IrNϵ is the measure of correlations. The neutrosophic correlation rNϵ, by following Aslam and Albassam , the probability of accepting HN0: no correlation between G1 and G2 is 0.95 (true), and the measure of indeterminacy is 0.0027. The t-test using fuzzy logic will give information only about the measures of falseness and truth. Based on the analysis, it is concluded that the proposed t-test for correlation is better than the existing tests.The proposed rN = 0.99−0.9899IrN; IrNϵ. It is interesting to note that the correlation between the two groups, G1 and G2, varies from 0.99 to 0.9899, with the measure of indeterminacy IrN= 0.001. From this correlation analysis, it can be seen that there is a strong positive correlation between fasting of 8 h and after 2 h of drinking the glucose solution. It means that if an 8-h fasting blood sugar level is high, then the blood sugar level after 2 h of drinking the glucose solution is also high and vice versa. It is important to note that after the 8-h fasting, the minimum blood sugar level of those aged 45 is 159. The value 159 indicates that these patients should take some energy drink before 2 h before sleeping, so that blood sugar can be utilized properly by the body. In addition, with an increase in 8-h fasting sugar, patients aged 45 to 60 should avoid taking carbohydrate or glucose items.As the data is collected from a group having 20 people at the fasting time and then after two hours of drinking glucose solution about 237 milliliters contained 75-gram. The neutrosophic form of the correlation between G1 and G2 is t-test of a correlation coefficient under neutrosophic statistics was presented in the article. The proposed t-test of a correlation coefficient was a generalization of the existing t-test of a correlation coefficient under classical statistics. From the real example, the proposed t-test of a correlation coefficient was found to be effective for investigating the significance of correlation in an indeterminate environment. The simulation study showed that measures of indeterminacy affect the decision on the significance of correlation. The proposed test can be applied to investigate correlations in the fields of economics, business, medicine, and industry. The proposed t-test of a correlation coefficient using a double sampling scheme can be considered as future research. Further statistical properties can be studied in future research. The proposed study can be extended for blood sugar measurement under different conditions and validation methods as future research. In addition, some disturbances can also be considered for blood glucose measurement in future studies.The The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.Both authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.This work was funded by the Deanship of Scientific Research at King Abdulaziz Univesity.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.