The BK virus has become a substantial threat to transplanted kidneys. Yet, the present understanding of the clinical course and postoperative management of BK virus infections remains inadequate. Here, we report a case of a male transplant recipient with rapid graft loss due to BK virus-associated nephropathy after the second renal transplant, who had previously experienced failure of his first kidney allograft for the same reason. The posttransplant period was uneventful until serum creatinine rose to 2.30 mg/dL on postoperative day 59. Puncture biopsy was postponed because of swelling in the transplanted kidney, and acute rejection was considered as a source of the swelling because the repetitive results of blood BK virus DNA tests were negative. Methylprednisolone 500 mg was administered empirically for 3 days, followed by a 5-day course of anti-thymocyte globulin 100 mg. On postoperative day 83, SV40 T-antigen antibody immunostaining confirmed the diagnosis of BK virus nephropathy. However, it took only 28 days for this patient to progress from abnormal kidney function to the loss of the secondary transplanted kidney, and dialysis was initiated on postoperative day 87. To our knowledge, this is the first report of BK virus resulting in acute failure of a transplanted kidney. An early biopsy is crucial, and a negative test for viremia is not sufficient to exclude the recurrence of BK virus.

Background and Objectives: Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease with few effective treatments. In its pathogenesis, damage-associated molecular patterns are released and recognized by Toll-like receptors (TLRs); all TLRs except TLR3 transduce signals through MyD88. Research has shown that autophagy participates in the progression of pulmonary fibrosis, and MyD88 is closely associated with autophagy. However, whether targeting MyD88 can affect fibrosis progression by regulating autophagy during lung fibrosis remains unclear. Materials and Methods: TJ-M2010-5 (TJ-5) is a small molecular derivative of aminothiazole that inhibits MyD88 homodimerization. A bleomycin-induced pulmonary fibrosis model in mice was established, and a human lung fibroblast cell line MRC-5 was cultured, and the mechanism of fibrosis induced by TGF-β1 was studied. TJ-5 and the autophagy inhibitor 3-MA were used to intervene. Results: Our study indicated that TJ-5 suppressed fibrosis foci formation and collagen deposition in fibrotic lungs, effectively increased the survival rate of bleomycin-stimulated mice from 40.0% to 80.0%, and repressed lung fibroblast activation in vitro. Subsequently, TJ-5 could trigger autophagy, as indicated by increased autophagosomes, LC3B-II and Beclin-1 promotion, and p62 degradation. Moreover, inhibition of TJ-5-induced autophagy by 3-MA reversed the anti-fibrosis effect of TJ-5. Furthermore, the autophagy-related pathways PI3K/AKT/mTOR and MAPK/mTOR were inhibited under TJ-5 intervention. Conclusions: Our findings demonstrated that the mechanism of TJ-5 in alleviating lung fibrosis was through triggering MyD88-related autophagy, and TJ-5 may be therapeutically useful for the clinical treatment of IPF.

Ethnopharmacological relevance: Wutou Decoction (WTD), a classic traditional Chinese prescription, is widely used for orthopedic disorders and has shown favorable clinical efficacy. Aim of the study: To investigate the effects of WTD on osteoarthritis (OA) and urine-derived stem cell (USC) differentiation. Materials and methods: USCs were isolated and induced to undergo chondrogenic differentiation using WTD (0.4, 0.8, 1.2 mu g/mL). Cell viability (MTT assay) and chondrogenic capacity (SOX9, Collagen II, Aggrecan expression; Alcian blue staining) were assessed. ESR1-NDRG3 interactions were examined via ChIP and dual-luciferase assays. (3-catenin signaling activity was evaluated by TOPFlash and immunofluorescence. An OA rat model was established to assess cartilage damage via H&E, Safranin O-fast green staining, micro-CT, and IHC. Results: WTD promoted USC chondrogenesis by upregulating chondrogenic markers and downregulating ESR1. ESR1 overexpression reversed WTD's effects. ESR1 bound to the NDRG3 promoter to enhance transcription, which was suppressed by WTD. NDRG3 interacted with (3-catenin and promoted nuclear translocation, while WTD inhibited this process via ESR1 downregulation. Knockdown of NDRG3 or (3-catenin reversed the effects of ESR1 overexpression. In OA rats, WTD alleviated cartilage damage through ESR1 downregulation and inhibition of (3-catenin signaling. Conclusion: WTD promotes USC chondrogenic differentiation and alleviates OA by downregulating ESR1, which reduces NDRG3 transcription, thereby inhibiting (3-catenin nuclear translocation and suppressing (3-catenin signaling activity.

Background: The classic anxiolytics have adverse effects in the treating anxiety disorders. Aim: To identify the anxiolytic polysaccharide from Sargentodoxa cuneata. Materials and Methods: The water-soluble Polysaccharide Fraction (PSC) was purified from S. cuneata, as well as its subfractions PSCA-1 and PSCB-1. The antioxidant effect of PSC against rotenone induced PC12 cell excitotoxicity, stimulating telomerase effect in HEK293Tcell and anxiolytic effect on zebrafish were evaluated. Results: The pretreatment of PC12 with PSC obviously increased cell survival and SOD level. PSC also down-regulated the LDH release, ROS level and cell apoptosis rate. PSC promoted the 293T cell proliferation, associated with the mechanism of stimulating telomerase. Additionally, PSC alleviated the anxiety level in zebrafish induced by mCPP. Conclusion: These findings suggested that the PSC could possess the anxiolytic potential via antioxidant and telomerase activation.

Metabolic inflammation is an important link in exacerbating obesity and insulin resistance, and the M1 polarization of macrophages is the key to the generation and maintenance of metabolic inflammation. As an inflammatory regulator, the toll-like receptor 4 (TLR4) / myeloid differentiation factor 88 (MyD88) signaling pathway plays an important role in the M1 polarization of macrophages. We previously proved that TJ-M2010-5 is a novel MyD88 inhibitor. However, the protective effect and underlying mechanisms of the MyD88 inhibitor TJ-M2010-5 against obesity induced by high fat diet (HFD) have not been reported. This study revealed that TJ-M2010-5 significantly improved the body weight, blood glucose and lipid levels of HFD mice. Histologically, TJ-M2010-5 alleviated lipid deposition in liver and adipose tissue. The proportion of M1 macrophages and the protein levels of TLR4, MyD88 and the phosphorylation ratio of nuclear factor-κB (NF-κB) in liver and epididymis adipose tissue of HFD mice were decreased after TJ-M2010-5 intervention. In vitro, TJ-M2010-5 inhibited the activation of TLR4 and MyD88 in bone marrow-derived macrophage (BMDM), significantly reduced the proportion of M1 polarization of BMDM. TJ-M2010-5 can improve obesity and its related glucose and lipid metabolism abnormalities induced by HFD through alleviating M1 polarization of macrophages and metabolic inflammation via inhibiting TLR4/MyD88 pathway.

Survival of transplanted hearts is often limited by cold ischemia time. Here, we assessed the effects of the small molecular compound TJ-M2010-5 on graft preservation. In a cardiac cold ischemia/reperfusion model, TJ-M2010-5 ameliorated myocardial ischemia/reperfusion injury (MIRI) in histidine-tryptophan-ketoglutarate (HTK) organ preservation solution. When applied in HTK solution and on donors/recipients respectively, TJ-M2010-5 exerted optimal effects when applied as an additive in the HTK solution. TJ-M2010-5-administered mice exhibited shorter rebeating time; higher beating score; stronger and more regular sinus heart rate; and amelioration of apoptosis, inflammatory reactions, and myocardial injury. Mechanistically, TJ-M2010-5 inhibited the expression of key molecules in the toll-like receptor (TLR) signaling pathway and affected downstream proteins by inhibiting myeloid differentiation factor 88 homodimerization, thereby decreasing myocardial injury. Thus, TJ-M2010-5 may exert protective effects against MIRI by blocking the TLR signaling pathway. Our findings may lead to novel approaches for organ preservation, thereby reducing organ abandonment and improving recipient prognosis. The role of the TLR signaling pathway in MIRI progress and operation procedure of the MIRI model in vivo are presented in a graphical abstract (Online Abstract Figure).

BACKGROUND:Acute vascular rejection (AVR) and systemic inflammation in xenograft recipients (SIXR) negatively impact the xenografts survival, and novel immunosuppressants are required to improve survival outcomes. We previously reported that TJ-M2010-5, a myeloid differentiation factor 88 (MyD88) inhibitor, exerts excellent anti-rejection effects in allogeneic transplantation. The aim of the present study was to evaluate the efficacy of TJ-M2010-5 in preventing AVR and SIXR and to investigate whether combined treatment of TJ-M2010-5 with anti-CD154 antibody (MR1) could prolong xenograft survival furthermore.METHODS:A model involving heart transplantation from Sprague-Dawley rats to BALB/c mice was established in vivo, and the xenografts developed typical AVR. Bone marrow-derived dendritic cells and macrophages were cultured to study the underlying mechanisms induced by rat cardiomyocyte lysate stimulation in vitro.RESULTS:TJ-M2010-5 monotherapy prolonged xenograft survival, although combination treatment with MR1 further enhanced the anti-AVR and anti-SIXR effects with about 21 days graft survival, compared to monotherapy. TJ-M2010-5 reduced dendritic cell and macrophage activation induced by xenotransplantation, downregulated CD80/CD86 expression, suppressed B-cell activation and anti-donor antibody generation, reduced pro-inflammatory cytokine production and tissue factor expression, and attenuated epigenetic modifications underlying interleukin-6 and tumor necrosis factor-α production in macrophages by inhibiting nuclear factor kappa B nuclear translocation.CONCLUSIONS:TJ-M2010-5 attenuated AVR and SIXR and contributed to xenograft survival by inhibiting dendritic cell and macrophage activation. A dual-system inhibition strategy combining TJ-M2010-5 with anti-CD154 antibody achieved better results in xenotransplantation.

Background. With the development of medical technology and increased surgical experience, the number of patients receiving liver transplants has increased. However, restoration of liver function in patients is limited by the occurrence of hepatic ischemia-reperfusion injury (IRI). Previous studies have reported that the Toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88) signaling pathway and pyroptosis play critical roles in the development of hepatic IRI. Methods. A mouse model of segmental (70%) warm hepatic IRI was established using BALB/c mice in vivo. The mechanism underlying inflammation in mouse models of hepatic IRI was explored in vitro using lipopolysaccharide- and ATP-treated bone marrow-derived macrophages. This in vitro inflammation model was used to simulate inflammation and pyroptosis in hepatic IRI. Results. We found that a MyD88 inhibitor conferred protection against partial warm hepatic IRI in mouse models by downregulating the TLR4/MyD88 signaling pathway. Moreover, TJ-M2010-5 (a novel MyD88 inhibitor, hereafter named TJ-5) reduced hepatic macrophage depletion and pyroptosis induction by hepatic IRI. TJ-5 treatment inhibited pyroptosis in bone marrow-derived macrophages by reducing the nuclear translocation of nuclear factor kappa-light-chain-enhancer of activated B cells, decreasing the release of high-mobility group box-1, and promoting endocytosis of lipopolysaccharide-high-mobility group box-1 complexes. Conclusions. Inhibition of MyD88 may protect the liver from partial warm hepatic IRI by reducing pyroptosis in hepatic innate immune cells. These results reveal the mechanism underlying the development of inflammation in partially warm hepatic IRI and the induction of cell pyroptosis.

Background:Human aortic valve stenosis (AS) and insufficiency (AI) are common diseases in aging population. Identifying the molecular regulatory networks of AS and AI is expected to offer novel perspectives for AS and AI treatment.Methods:Highly correlated modules with the progression of AS and AI were identified by weighted genes co-expression network analysis (WGCNA). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed by the clusterProfiler program package. Differentially expressed genes (DEGs) were identified by the DESeqDataSetFromMatrix function of the DESeq2 program package. The protein-protein interaction (PPI) network analyses were implemented using the STRING online tool and visualized with Cytoscape software. The DEGs in AS and AI groups were overlapped with the top 30 genes with highest connectivity to screen out ten hub genes. The ten hub genes were verified by analyzing the data in high throughput RNA-sequencing dataset and real-time PCR assay using AS and AI aortic valve samples.Results:By WGCNA algorithm, 302 highly correlated genes with the degree of AS, degree of AI, and heart failure were identified from highly correlated modules. GO analyses showed that highly correlated genes had close relationship with collagen fibril organization, extracellular matrix organization and extracellular structure organization. KEGG analyses also manifested that protein digestion and absorption, and glutathione metabolism were probably involved in AS and AI pathological courses. Moreover, DEGs were picked out for 302 highly correlated genes in AS and AI groups relative to the normal control group. The PPI network analyses indicated the connectivity among these highly correlated genes. Finally, ten hub genes (CD74, COL1A1, TXNRD1, CCND1, COL5A1, SERPINH1, BCL6, ITGA10, FOS, and JUNB) in AS and AI were found out and verified.Conclusion:Our study may provide the underlying molecular targets for the mechanism research, diagnosis, and treatment of AS and AI in the future.

Hepatocellular carcinoma (HCC) is the main histologic type of liver cancer. It accounts for the majority of all diagnoses and deaths due to liver cancer. The induction of tumor cell death is an effective strategy to control tumor development. Pyroptosis is an inflammatory programmed cell death caused by microbial infection, accompanied by activation of inflammasomes and release of pro-inflammatory cytokines, interleukin-1β (IL-1β), and interleukin-18 (IL-18). The cleavage of gasdermins (GSDMs) promotes the occurrence of pyroptosis leading to cell swelling, lysis, and death. Accumulating evidence has indicated that pyroptosis influences the progression of HCC by regulating immune-mediated tumor cell death. Currently, some researchers hold the view that inhibition of pyroptosis-related components may prevent the incidence of HCC, but more researchers have the view that activation of pyroptosis exerts a tumor-inhibitory effect. Growing evidence indicates that pyroptosis can prevent or promote tumor development depending on the type of tumor. In this review, pyroptosis pathways and pyroptosis-related components were discussed. Next, the role of pyroptosis and its components in HCC was described. Finally, the therapeutic significance of pyroptosis in HCC was discussed.

目的 探讨肾移植术后多瘤病毒相关性肾病(PyVN)的临床病理学特征及预后.方法 回顾性分析 44 例肾移植术后确诊PyVN患者的临床资料,分析患者穿刺原因及病理学诊断时间.按Banff 2018 标准进行组织学分级,比较各级患者临床资料及病理特征.分析患者血、尿BK病毒DNA载量及移植肾功能.比较各组患者的预后情况,分析影响预后的危险因素.结果 患者病理诊断PyVN距肾移植手术时间为16(8,29)个月,血清肌酐升高为穿刺的主要原因.44例患者中,PyVN 1 级19例、2级21例、3级4例,各组光学显微镜下病毒包涵体阳性率差异无统计学意义(P=0.148),2 级患者炎症细胞浸润、间质纤维化、肾内多瘤病毒载量均多于或高于 1 级患者,3 级患者炎症细胞浸润及肾内多瘤病毒载量多于或高于 1 级患者,3 级患者肾内多瘤病毒载量多于或高于 2 级患者,差异均有统计学意义(均为P<0.05/3).确诊时 39 例患者具有血、尿BK病毒DNA载量检测记录,其中 38 例尿BK病毒阳性,30 例血BK病毒阳性.患者确诊PyVN时血清肌酐较术后 1 个月升高,末次随访时血清肌酐较确诊PyVN时升高,差异均有统计学意义(P<0.001、P=0.049).不同级别PyVN患者术后1 个月血清肌酐差异无统计学意义(P=0.554),确诊时 2 级患者血清肌酐水平高于 1 级患者(P=0.007).肾移植术后1、3、5年移植肾累积存活率分别为95％、69％、62％,不同分级PyVN间移植肾存活率差异有统计学意义,分级越高,存活率越低(P=0.014).单因素和多因素Cox回归分析提示肾内多瘤病毒载量、确诊时血清肌酐水平为移植肾失功的独立危险因素(均为P<0.05).结论 PyVN多发生在肾移植术后 2 年内,临床表现以血清肌酐升高、BK病毒血症和BK病毒尿症为主,术后常规监测BK病毒有利于早期诊断并保护移植肾,Banff 2018 分级标准可有效预测移植肾预后.

Background: Cerebral ischemia-reperfusion injury (CIRI) inevitably occurs after vascular recanalization treatment for ischemic stroke. The accompanying inflammatory cascades have a major impact on outcome and regeneration after ischemic stroke. Evidences have demonstrated that TLR/MyD88/NF-κB signaling contributes to CIRI. This study aimed to investigate the druggability of MyD88 in the central nervous system (CNS) and the neuroprotective and anti-neuroinflammatory effects of the MyD88 inhibitor TJ-M2010-5 on CIRI.Methods: A middle cerebral artery occlusion (MCAO) model was used to simulate CIRI in mice. BV-2 cells were stimulated with oxygen glucose deprivation/reoxygenation (OGD/R) or lipopolysaccharide, and SH-SY5Y cells were induced by OGD/R in vitro. Neurological deficit scores and cerebral infarction volumes were evaluated. Immunofluorescence staining was performed to measure neuronal damage and apoptosis in the brain. The anti-neuroinflammatory effect of TJ-M2010-5 was evaluated by analyzing the expression of inflammatory cytokines, activation of microglia, and infiltration of peripheral myeloid cells. The expression of proteins of the MyD88/NF-κB and ERK pathway was detected by Simple Western. The concentrations of TJ-M2010-5 in the blood and brain were analyzed by liquid chromatography-mass spectrometry.Results: The cerebral infarction volume decreased in mice treated with TJ-M2010-5, with the most prominent decrease being approximately 80% of the original infarction volume. Neuronal loss and apoptosis were reduced following TJ-M2010-5 treatment. TJ-M2010-5 inhibited the infiltration of peripheral myeloid cells and the activation of microglia. TJ-M2010-5 also downregulated the expression of inflammatory cytokines and inhibited the MyD88/NF-κB and ERK pathway. Furthermore, TJ-M2010-5 showed good blood-brain barrier permeability and no neurotoxicity.Conclusion: TJ-M2010-5 has an excellent therapeutic effect on CIRI as a novel CNS drug candidate by inhibiting excessive neuroinflammatory responses.

Ischemia-reperfusion injury (IRI) is an inevitable pathological process during donation after circulatory death (DCD) liver transplantation, which contributes to serious damage to the graft. Oxidative stress, inflammation and apoptosis are all fatal causes of IRI of the liver. Hypothermic oxygenated perfusion (HOPE), as an emerging dynamic preservation technology, has a more significant effect on reducing DCD liver IRI than static cold storage (CS) mainly by regulating oxidative stress and inflammation. To further enhance the effect of HOPE and reveal its underlying mechanisms, investigators have recently combined HOPE with various methods. Excessive activation of the TLR/MyD88 signaling pathway can lead to severe immune inflammatory response. TJ-M2010-5 (TJ-5), a novel thiazaol-aminoramification MyD88 inhibitor, plays an essential role in the treatment of various diseases or pathological injuries in mice, such as hepatocellular carcinoma, acute liver injury and myocardial IRI. However, little is known about the role of TJ-5 in HOPE alleviating DCD liver IRI. Herein, we sought to investigate the role of HOPE combined with TJ-5 in reducing DCD liver IRI. We found that HOPE combined with TJ-5 significantly reduced oxidative stress, lessened inflammation, and decreased apoptosis during DCD liver IRI. Furthermore, HOPE combined with TJ-5 exerted their effects by inhibiting the TLR/MyD88 signaling pathway. Overall, these results demonstrated that HOPE combined with TJ-5 has a significant effect on alleviating DCD liver IRI. Therefore, the combined application of HOPE and TJ-5 may be an available and valid treatment option for DCD liver IRI.

Liver fibrosis is the result of most chronic inflammatory liver damage and seriously endangers human health. However, no drugs have been approved to treat this disease. Previous studies showed that the Toll‐like receptors (TLRs)/myeloid differentiation factor-88 (MyD88)/nuclear factor-κB (NF-κB) pathway plays a key role in liver fibrosis. TJ-M2010-5 is a self-developed small molecule MyD88 inhibitor, which has been proven to have a good protective effect in a variety of inflammatory disease models. In the present study, to investigate the anti-fibrotic effect of TJ-M2010-5, mice were injected with carbon tetrachloride (CCl4) in vivo and LX2 cells (a human hepatic stellate cell line) were treated with TGF-β1 in vitro to induce liver fibrosis. In vivo studies showed that TJ-M2010-5 attenuated the CCl4-induced liver damage, collagen accumulation, and the activation of hepatic stellate cells by inhibiting the nuclear transfer of NF-κB. Moreover, in vitro experiments of LX2 cells stimulated with TGF-β1 further indicated that the NF-κB pathway is involved in the development of liver fibrosis. TJ-M2010-5 significantly inhibited the proliferation and activation of LX2 cells. In addition, TJ-M2010-5 upregulated the expression of bone morphogenetic protein and membrane-bound inhibitor (BAMBI) in LX2 cells by blocking the activation of MyD88/NF-κB, thereby inhibiting the phosphorylation of Smad2/3 and the expression of collagen I (COL1A1) induced by TGF-β1. In conclusion, this study illustrates the anti-hepatic fibrosis effect of TJ-M2010-5 and provides a new treatment method for liver fibrosis.

Increasing evidence supports the pathogenic role of neuroinflammation in psychiatric diseases, including major depressive disorder (MDD) and neuropsychiatric symptoms of Coronavirus disease 2019 (COVID-19); however, the precise mechanism and therapeutic strategy are poorly understood. Here, we report that myeloid differentiation factor 88 (MyD88), a pivotal adaptor that bridges toll-like receptors to their downstream signaling by recruiting the signaling complex called 'myddosome', was up-regulated in the medial prefrontal cortex (mPFC) after exposure to chronic social defeat stress (CSDS) or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein. The inducible expression of MyD88 in the mPFC primed neuroinflammation and conferred stress susceptibility via amplifying immune danger signals, such as high-mobility group box 1 and SARS-CoV-2 spike protein. Overexpression of MyD88 aggravated, whereas knockout or pharmacological inhibition of MyD88 ameliorated CSDS-induced depressive-like behavior. Notably, TJ-M2010-5, a novel synthesized targeting inhibitor of MyD88 dimerization, alleviated both CSDS- and SARS-CoV-2 spike protein-induced depressive-like behavior. Taken together, our findings indicate that inhibiting MyD88 signaling represents a promising therapeutic strategy for stress-related mental disorders, such as MDD and COVID-19-related neuropsychiatric symptoms.

Background: The acute ischemia-reperfusion injury that occurs after an ischemic stroke is almost inevitable. In treating ischemic stroke, the prevention and treatment of cerebral ischemia-reperfusion injury (CIRI) is an undeniable difficulty clinically. Despite increasing studies being done on the subject, medicines showing effective neurological improvements after reperfusion is still minimal. This study aims to investigate the effects of a self-developed MyD88 inhibitor (TJ-M2010-5) on CIRI and its mechanism. Methods: The middle cerebral artery occlusion (MCAO) model was used to simulate CIRI in mice. BV-2 cells were cultured for the mechanism study by LPS stimulation in vitro. Neurological deficit score and cerebral infarction volume were studied. Immunofluorescence staining was used to measure neuronal damage and apoptosis in the brain. The anti-inflammation effect of TJ-M2010-5 was evaluated by analyzing the expression of inflammatory cytokines, activation of microglia and infiltration of peripheral myeloid cells. The expression of TLR4/Myd88/NF-κB signaling pathway protein was detected by Simple Western. The concentrations of TJ-M2010-5 in blood and brain were analyzed by LC-MS methods. Results: The cerebral infarction volume decreased in mice treated with TJ-M2010-5, with the most prominent decrease in approximately 80% of the original infarction volume. Moreover, the downregulation of apoptosis and NeuN protein expression in the brain of infarction area further indicated that neuronal damage was alleviated. TJ-M2010-5 treatment also reduced the infiltration ratio of peripheral myeloid cells in the cerebral infarction area and increased the proportion of inactive microglia. The inflammatory cytokines decreased after TJ-M2010-5 treatment in infarction area and supernatant. TJ-M2010-5 downregulated the expression of iNOS and inhibited TLR4/MyD88/NF-κB signaling pathway in vivo and in vitro. In addition, TJ-M2010-5 could freely pass through the blood-brain barrier. Conclusions: TJ-M2010-5 has shown to have an excellent therapeutic effect on CIRI by inhibiting TLR4/Myd88/NF-κB signaling pathway to decrease excessive inflammatory response, showing the potential to change the history that there is no effective medicine for the treatment of CIRI. and also has the potential to be utilized in brain neuroinflammatory diseases.

The unified management of IoT devices with interoperability can be inspired by cloud computing. In addition, sinking the 5G core network to the edge brings chances for the deployment of end-to-end ultralow-latency services. However, the resource efficiency brought by heterogeneous computing devices in 5G spectrum multiplexing environments has encountered challenges. To discuss this issue from a comprehensive perspective, this article first proposes an ultralow-latency service deployment architecture in 5G heterogeneous networks, and three cognitive engines are the key components for efficient service communication across the terminal/edge/cloud computing structure. Then we give an analysis of application task model in the proposed architecture, and following the service response time models are established. In addition, it is efficient to deploy multiuser tasks with constraint resources when the differentiated user requirements are met. Finally, we conducted some experiments and the result statistics are up to our expectations. The first one is the system performance under two microcloud covered cells, and the second one is the performance comparison of the proposed solution with three single scenes of terminal computing, edge computing and cloud computing.

纯音测听一直是临床上用于听力检测的核心技术，是评估听力损失程度的重要指标。本文追溯了纯音听阈测试的技术演变过程，并结合近年来利用智能终端上的应用程序（App）实现自动化测听的趋势，对纯音测听技术的起源、演变与未来方向做一综述。