“信疫”(Infodemic)的根源、规律及治理对策——新技术背景下国际信息传播秩序的失控与重建

面对智能时代第一场全球性疫情,人类除了要战胜病毒"瘟疫",还需要战胜"信疫"(Infodemic)"。信疫"问题的本质是新技术背景下社会信息传播的无序和失控,是民众、媒体、国家与国际社会整体对新形势不适应的集中、剧烈的爆发。其根源是随着互联网的发展,形成了大众传播、网络传播、自传播和智能传播等多种传播机制交错叠加的融合传播的复杂格局。以全民性社交媒体为基础的自下而上的大集市模式已经成为当今社会信息传播的主导性力量,要能够消除和有效治理"信疫",需要具备对当今传播格局和趋势准确认知的基本知识体系,以及对新的传播特性和规律的把握。在四种传播机制相互博弈的背景下,我们一方面需要有效抑制"信疫",另一方面要形成及时有效应对的反应机制,以及扬长避短的对冲机制,建立新的信息传播秩序。

《2021年美国图书馆行业现状特别报告:COVID-19》解读与启示

2021年4月5日,美国图书馆协会(ALA)发布的《2021年美国图书馆行业现状特别报告:COVID-19》,反映了美国图书馆在前所未有的环境下所展现的应变能力、决心和创新理念。文章围绕《2021版报告》中的图书馆开放概况、图书借阅情况、远程学习、图书馆活动、立法与筹资、打击虚假信息等六个方面的核心内容做了重点分析,并结合国内图书馆实践,提出完善图书馆应急服务体系、加强医药类特藏资源建设、提升馆员“嵌入式”决策咨询服务水平、多管齐下防治“信疫”危害等建议。

UBE2C as an Immune-Related Biomarker for Breast Cancer:A Study Based on Multiple Databases

Objective To screen the target genes that are associated with survival of breast cancer(BRCA) and explore their prognostic values and immune correlations with BRCA using multiple databases..Methods The microarray expression datasets of BRCA were downloaded from the Gene Expresssion Omnibus database(GEO) and analyzed to obtain differentially expressed genes(DEGs). Hub genes were obtained by constructing and visualizing the protein-protein interaction network of DEGs. The key gene was determined using R language, STRING, and Cytoscape, and the differential expression of the key gene was verified using external datasets The Cancer Genome Atlas(TCGA) and quantitative real-time PCR(q RT-PCR) for BRCA tissues of 37 patients. The prognostic value and immunological correlation of UBE2C in BRCA were explored using R language, TIMER, and Gene Set Enrichment Analysis(GSEA).Results Of 10 hub genes seleceed from 302 DEGS, UBE2C was identified as the gene associated with BRCA survival. The expression of UBE2C was differentially upregulated in BRCA, as verified by TCGA and q RT-PCR. Prognostic analysis revealed that UBE2C served as an independent prognostic factor. High expression of UBE2C was associated with decreased immune infiltration levels of B cells, CD4+ T cells, CD8+ T cells, macrophages, and myeloid dendritic cells in BRCA tissue. The expression of UBE2C in BRCA showed a significant correlation with immune checkpoints genes PDCD1, CD274, and CTLA4 expressions. There was a positive correlation between the expression of UBE2C and the tumor mutational burden and microsatellite instability. GSEA demonstrated that UBE2C expression significantly enriched 786 immune-related gene sets.Conclusions UBE2C expression in BRCA tissues is closely related to the BRCA immune microenvironment and showes predictive values on the survivals and prognosis of BRCA patients and the effecacy of immunotherapy. UBE2C may be an potential immune-related prognostic biomarker for BRCA.

Prognositic value of anoikis and tumor immune microenvironment-related gene in the treatment of osteosarcoma

Objective:Osteosarcoma is a highly aggressive primary malignant bone tumor commonly seen in children and adolescents,with a poor prognosis.Anchorage-dependent cell death(anoikis)has been proven to be indispensable in tumor metastasis,regulating the migration and adhesion of tumor cells at the primary site.However,as a type of programmed cell death,anoikis is rarely studied in osteosarcoma,especially in the tumor immune microenvironment.This study aims to clarify prognostic value of anoikis and tumor immune microenvironment-related gene in the treatment of osteosarcoma.Methods:Anoikis-related genes(ANRGs)were obtained from GeneCards.Clinical information and ANRGs expression profiles of osteosarcoma patients were sourced from the therapeutically applicable research to generate effective therapies and Gene Expression Omnibus(GEO)databases.ANRGs highly associated with tumor immune microenvironment were identified by the estimate package and the weighted gene coexpression network analysis(WGCNA)algorithm.Machine learning algorithms were performed to construct long-term survival predictive strategy,each sample was divided into high-risk and low-risk subgroups,which was further verified in the GEO cohort.Finally,based on single-cell RNA-seq from the GEO database,analysis was done on the function of signature genes in the osteosarcoma tumor microenvironment.Results:A total of 51 hub ANRGs closely associated with the tumor microenvironment were identified,from which 3 genes(MERTK,BNIP3,S100A8)were selected to construct the prognostic model.Significant differences in immune cell activation and immune-related signaling pathways were observed between the high-risk and low-risk groups based on tumor microenvironment analysis(all P<0.05).Additionally,characteristic genes within the osteosarcoma microenvironment were identified in regulation of intercellular crosstalk through the GAS6-MERTK signaling pathway.Conclusion:The prognostic model based on ANRGs and tumor microenvironment demonstrate good predictive power and provide more personalized treatment options for patients with osteosarcoma.

Inflammatory bowel disease requires the interplay between innate and adaptive immune signals

Inflammatory bowl disease （IBD） is a type 1 T helper cell （Th1）-mediated autoimmune disease. Various studies have revealed that environmental pathogens also play a significant role in the initiation and progression of this disease. Interestingly, the pathogenesis of IBD has been shown to be related to nitric oxide （NO） released from innate immune cells. Although NO is known to be highly toxic to the gut epithelia, there is very little information about the regulation of NO production, One major question in the etiology of IBD is how Thl cells and pathogens interact in the induction of IBD. In present study, we focused on the regulation of NO. We show that macrophages require both interferon-γ, （IFN-γ）-mediated and TLR4-mediated signals for the production of NO, which causes inflammation in the intestine and subsequently IBD. Thus, IBD is the result of concerted actions of innate immune signals, such as the binding of LPS to TLR-4, and adaptive immune signals, such as IFN-γ produced by Thl cells.

SPARCL1, Shp2, MSH2, E-cadherin, p53, ADCY-2 and MAPK are prognosis-related in colorectal cancer

AIM: To investigate the expression of markers that are correlated with the prognosis of colorectal cancer (CRC) patients. METHODS: One hundred and fifty-six CRC patientswere followed up for more than 3 years after radical surgery. Immunohistochemical (IHC) analysis was performed to detect the expression of 14 pathway-related markers (p53, APC, p21ras, E-cadherin, endothelin-B receptor, Shp2, ADCY-2, SPARCL1, neuroligin1, hsp27, mmp-9, MAPK, MSH2 and rho) in specimens from these patients. Bioinformatics analysis involving a Support Vector Machine (SVM) was used to determine the best prognostic model from combinations of these markers. RESULTS: Seven markers (SPARCL1, Shp2, MSH2, E-cadherin, p53, ADCY-2 and MAPK) were significantly related to the prognosis and clinical pathological features of the CRC patients (P < 0.05). Prognostic models were established through SVM from combinations of these 7 markers and proved able to differentiate patients with dissimilar survival, especially in stage Ⅱ/Ⅲ patients. According to the best prognostic model, the p53/SPARCL1 model, patients having high p53 and low SPARCL1 expression had about 50% lower 3-year survival than others (P < 0.001). CONCLUSION: SPARCL1, Shp2, MSH2, E-cadherin, p53, ADCY-2 and MAPK are potential prognostic markers in CRC. A p53/SPARCL1 bioinformatics model may be used as a supplement to tumor-nodes-metastasis staging.

Immunization with rPb27 Protects Mice from the Disruption of VEGF Signaling in Paracoccidioides brasiliensis Infection

VEGF （Vascular endothelial growth factor） signaling is critical for endothelial cell survival and maintenance of the vasculature. Deregulation of VEGF signaling contributes to the physiopathology of many diseases. However, the ways in which infection with Paracoccidioides brasiliensis affects VEGF signaling and the influence of immunization with rPb27 （recombinant protein Pb27） on VEGF signaling have not yet been studied. Animals were immunized with rPb27 and subsequently infected with a virulent strain of P. brasiliensis. The fungal load was evaluated by measuring CFU （colony-forming unit） and histology was performed to evaluate the inflammatory reaction. At the two time points analyzed, the PC （positive control） and TREAT （treated） animals had decreased levels of pulmonary VEGF compared to basal levels. However, in the immunized （Pb27） and treated mice （Pb27 ＋ TREAT）, VEGF expression remained unchanged after infection. In the case of VEGFR-2, the Pb27 and Pb27 ＋ TREAT groups showed increased levels of expression. Regarding the levels of the eNOS enzyme, only the Pb27 group did not reduce the expression levels relative to baseline. The immunization with rPb27 kept VEGF signaling, NO production and increased VEGFR-2 expression, after infection with P. brasiliensis. Thus, the authors infer that immunization with rPb27 protects mice from the disruption of VEGF signaling in Paracoccidioides brasiliensis infection.

Irradiation-induced EMT is associated with activation of TGF-β and restriction of BMP signaling in esophageal cancer cells

Objective: Irradiation may enhance migration and/or invasiveness of cancer cells in vitro and in vivo, the mechanism of which may be associated with epithelial-mesenchymal transition (EMT). The present study explored the mechanisms of EMT induced by irradiation in esophageal cancer cells. Methods: Human esophageal cancer cell line EC109 was treated with increased doses of irradiation (0 Gy, 20 Gy, 40 Gy and 60 Gy). Cell morphology was observed. Expressions of E-cadherin and vimentin were determined by immunofluorescence assay or western blot. Secretion of transforming growth factor-β1 (TGF-β1) by cells was determined by enzyme-linked immunosorbent assay (ELISA), and the expressions of Smad2/3 and phosphorated Smad2 (p-Smad2) were also examined by Western blot. The mRNA expressions of BMP-4, a bone morphogenetic protein (BMP) ligand, and two secreted BMP antagonists (Chordin and Gremlin), were detected with reverse transcription-polymerase chain reaction (RT-PCR). Cell migratory capacity was evaluated. Results: Irradiation induced EMT in EC109 cells in a dose-dependent manner as evidenced by morphological changes, decreased expression of E-cadherin and increased expression of vimentin, and increased cell motility. The secretion of TGF-β1 and expression of p-Smad2 were gradually increased in an irradiation dose-dependent manner, but the Smad2/3 protein levels remained stable. The mRNA expression of BMP-4 was gradually down-regulated, but the expressions of Chordin and Gremlin were gradually up-regulated in cells treated with increased doses of irradiation. Conclusion: Irradiation can induce EMT in esophageal cancer cells in a dose-dependent manner, and the mechanism may be associated with activation of TGF-β and restriction of BMP signaling.

Late SV40 factor:A key mediator of Notch signaling in human hepatocarcinogenesis

AIM:To investigate the relationship between late SV40 factor(LSF)and Notch signaling in the development and progress of hepatocellular carcinoma(HCC).METHODS:Liver cancer tissue specimens from 25 patients were analyzed for Notch-1 and LSF expression by immunohistochemistry.The correlation between expression and the biological effects of Notch-1 and LSF were analyzed using genetic and pharmacological strategies in HCC cell lines and human normal cell lines,including hepatic stellate cells(HSC)and human embryonic kidney epithelial cells(HEK).RESULTS:Immunohistochemistry showed that both Notch-1 and LSF were significantly upregulated in HCC samples(76%,19/25,P<0.0001 and 84%,21/25,P<0.0001,respectively)compared with non-cancer samples.Activation of Notch-1 by exogenous transfection of Notch1 intracellular domain increased LSF expression in HSC and HEK cells to levels similar to those seen in HepG2 cells.Furthermore,blocking Notch-1 activation with aγ-secretase inhibitor,DAPT,downregulated LSF expression in HepG2 cells.Additionally,a biological behavior assay showed that forced overexpression of LSF promoted HepG2 cell proliferation and invasion.CONCLUSION:LSF is a key mediator of the Notch signaling pathway,suggesting that it might be a novel therapeutic target for the treatment of HCC.

Application of geographical information system technology to epidemiological surveillance and prevention and cure decision-making for SARS

Objective:To expound geographical information system (GIS) technology is a very important tool when it was employed to assist to present the distribution by time and place and the model of transmission of infectious disease. Methods: We illustrated the assistant decision-making support function of GIS with an example of the spatial decision support system for SARS controlling in Shaanxi province of China which was developed by us. Results: The spatial decision support system established by applying GIS technology fulfilled the needs of real-time collection and management and dissemination SARS information and of surveillance and analysis the epidemic situation of SARS. Conclusion: Occurrence and epidemic of diseases, implement prevention and intervention measures and collocation hygienic resources are all with the characteristic of the variation of time and space, therefore, GIS technology has become a powerful tool for identifying risk factors of diseases, providing clues of causation of diseases , evaluating the effects of intervention measures and drawing a health management plan.

Changes of the cytokine profile in inflammatory bowel diseases

Cytokines are indispensable signals of the mucosaassociated immune system for maintaining normal gut homeostasis.An imbalance of their profile in favour of inflammation initiation may lead to disease states,such as that is observed in inflammatory bowel diseases(IBD).Although Crohn's disease(CD) is often described as a prototype of T-helper 1-type diseases,and ulcerative colitis(UC) is traditionally viewed as a T-helper 2-mediated condition,the classic paradigm,which categorises cytokines into pro-and anti-inflammatory groups,has recently been changed.The inflammation regulatory pathways may not be mutually exclusive as individual cytokines can have diverse and even opposing functions in various clinical and immunological settings.None the less there are many common immunological responses in IBD that are mediated by cytokines.Although they regulate and influence the development,course and recurrence of the inflammatory process,the concrete pathogenic role of these small signaling molecules is sometimes not unambiguous in the subtypes of the disease.Our aim is to review the current information about pro-and anti-inflammatory effects of traditionally studied and recently discovered cytokines in the pathogenesis of UC and CD.The better understanding of their production and functional activity may lead to the development of new therapeutic modalities.

AKT1 and AKT2 Promote Malignant Transformation in Human Brain Glioma LN229 Cells

OBJECTIVE To confirm the role played by AKT1 and AKT2 in the β- catenin/Tcf-4 signaling pathway in promoting malignant transfor- mation of glioma cells. METHODS LN229 cells were divided into five groups： a control group, acetone （ACE）group, acetylsalicylic acid （ASA; aspirin） group, ASA＋AKT1 plasmid group and ASA＋AKT2 plasmid group. Western blot and PCR were used to detect the expression of AKT1 and AKT2 after dealing with ASA and transferring AKTI/2 genes into LN229 cells. Cell proliferation was determined by flow cytometry, cell invasion was evaluated by transwell assay and cell apoptosis was detected with annexin V staining. The molecules regulating proliferation and invasion were examined by western blot analysis. RESULTS Aspirin down-regulates AKT1 and AKT2 expression by modulating β-cateninfrcf-4 activity. AKT1 and AKT2 can enhance cell proliferation and invasion by up-regulating the expression of cyclin-D and matrix metalloprotein-9 （MMP-9） in LN229 glioma cells. CONCLUSION AKT1 and AKT2 play an important role in the β- catenin/Tcf-4 signaling pathway promoting malignant transformation; AKT1 is more effective than AKT2. AKT1 and AKT2 may be potential targets for brain glioma therapy and an effective way to prevent metastasis of gliomas.

Mechanisms of HIV envelope-induced T lymphocyte apoptosis

Infection by the human immunodeficiency virus （HIV） is characterized by a progressive depletion of CD4 T lymphocytes, which leads to dysfunction of the immune system. Although a variety of mechanisms may contribute to the gradual T cell decline that occurs in H/V-infected patients, abnormal apoptosis of infected or bystander T lymphocytes is an important event leading to immunodeficiency. The HIV envelope glycoprotein plays a crucial role in HIV associated apoptosis through both death receptor-mediated and mitochondria-dependent pathways. This review summarizes current knowledge of Env-mediated T lymphocyte apoptosis.

Research on Application of RFID Technology in the Agricultural Product Quality and Safety Traceability System

Through the study of individual identification technology, the paper put forward the identification scheme for two-dimensional code ear tag ＋ RFID electronic tag, namely using Ministry of agriculture regulations two-dimensional code ear tag to identify individual animal in the breeding stage, and record the basic information and breeding, using the RFID electronic identification tag to record slaughter quarantine information; phase, and finally the ear tag code, RFID electronic tag and product number should be encode relatively to generate tracing code in the final agricultural products, realize the smooth flow of the information flow from the breeding stage to the final product. For fruits and vegetables, agricultural products are adopted the common identification for orchard （greenhouse） numbers units.

The expression and clinical significance of β-catenin and colorectal cancer stem cells marker EpCAM^(high)/CD44^+ in colorectal cancer

Objective： The aim of the study was to explore the role of Wnt βcatenin signalling pathway in the maintenance, invasion and metastasis of colorectal cancer stem cells. Methods： Double immunohistochemical staining was used to detect the expression of EpCAMhigh/CD44~ which is regarded as the marker of colorectal cancer stem cells in 80 cases of colorectal cancer and their corresponding liver metastases. The SP method of immunohistochemistry was used to detect the expression of the key protein βcatenin in the Wnt pathway in these tissue. The expression and correlation of ^-catenin and EpCAMh^gh/ CD44＋ in colorectal cancer were analyzed and their role on the biological behavior of colorectal cancer was explored. Results： The abnormal expression of βcatenin was significantly higher in colorectal cancer than in the paraneoplastic normal intes- tinal mucosa [55% （44/80） vs 10% （2/20）, P 〈 0.05]. The positive expression of EpCAMhigh/CD44＋ was significantly higher in colorectal cancer than in the paraneoplastic normal intestinal mucosa [66.25% （53/80） vs 0% （0/20）, P 〈 0.05]. In the 80 cases of colorectal cancer, the abnormal expression of ^-catenin has no correlation with gender （P = 0.079）, age （P = 0.416） and the magnitude （P = 0.816） of the tumor （P 〉 0.05）, but it was significantly correlated with degree of differentiation （P = 0.001）, depth of invasion （P = 0.001）, clinical stage （P = 0.000） and metastasis （P = 0.000）. In the colorectal cancer, the expression of EpCAMhi^h/CD44~ cells has no correlation with gender （P = 0.934） and the magnitude （P = 0.160） of the tumor （P 〉 0.05）, but was significantly correlated with age （P = 0.021）, degree of differentiation （P = 0.013）, depth of invasion （P = 0.000）, clinical stage （P = 0.000） and metastasis （P = 0.000）. In the corresponding liver metastases, we could also detecte EpCAMhih/CD44＋ cells. In cases with abnormal expression of βcatenin, the positive expression rate of EpCAMhigh/CD44＋ was significantly higher than those with normal expression of β-catenin （84.1% vs 44.4%）, and the difference was statistically significant （P 〈 0.05）. Conclusion： The abnormal activation of Wnt β-catenin signalling pathway may prompt the abnormal proliferation of the colorectal cancer stem cells, which leads to the recurrence and metastasis of the cancer.

Functional study of p38 mitogen-activated protein kinase based on cell-penetrating peptide delivery system

Objective p38 Mitogen-activated protein kinase （MAPK） is a crossing center of various pathways. In this study, protein transduction system based on human immunodeficiency virus （HIV）-1 transactivator of transcription （TAT）, which is an efficient delivery peptide of the foreign proteins into cells, was employed to study p38 MAPK functions in eukaryotic cells. Methods p38 And its dominant negative form, p38AF, were constructed into pET-His-TAT vector correctly to verify that the recombinant plasmids were well-founded through restriction enzyme digestion and DNA sequencing. The two proteins, His-TAT-p38 and His-TAT-p38AF, were expressed and purified in Escherichia coli by SDS-PAGE. Then they were incubated with ECV304 cells respectively and readily transduced into cells in a time-dependent and dose-dependent manner. The cells were stimulated by sorbitol. Activating transcription factor （ATF） 2 phosphorylation level was checked using Western blot to assess the activity of endogenous p38. Results Compared with controls, it was found that His-TAT-p38 increased the level ofATF2 phosphorylation in sorbitol-stimulated ECV304 cells, while His-TAT-p38AF inhibited it, indicating p38 MAPK protein delivery system based on TAT was constructed successfully. TAT-p38 and its dominant negative form possessed high biological activity after transduction into ECV304 cells by TAT protein delivery system. The results showed that p38AF fused with TAT could inhibit the transduction of endogenous p38 signal pathway in part, and other pathway might regulate p38 phosphorylation. Conclusions Our study provides a novel pathway to inhibit p38 signal pathway and establish a new method to study p38 function.

Immunohistochemical characterization of β-catenin in gynecologic tumor and its diagnostic value

β-catenin is a very unusual protein with multiple functions depending on its cellular localization. The β-catenin gene (CTNNB1) encodes for β-catenin and apart from its well-defined role in cellular adhesion,it is also a component of the Wnt signalling pathway. The Wnt/β-catenin pathway is involved in various normal cellular activities,including determination,proliferation,migration and differentiation in embryonic development and adult homeostasis. Deregulation or constitutive activation of the Wnt/β-catenin pathway may lead to cancer formation. Immunohistochemical expression of β-catenin in gynecologic tumor have been reported recently. In normal epithelia,immunoreactivity was strongly observed at the membrane,partially at cytoplasm,nuclear staining of β-catenin was rarely seen in normal cases; In ovarian carcinomas,β-catenin nuclear expression was found more commonly in endometrioid carcinomas,nuclear β-catenin staining seemed to be of prognostic importance; In endometrium carcinomas,β-catenin nuclear expression were more common in pure endometrioid tumors than in unendometrioid tumors,associated with favorable prognosis,the staining pattern was independent of the menopausal status; In synchronous primary cancers of the endometrium and ovary,activating mutations in β-catenin seemed to distinguish synchronous primary tumors from metastatic tumors.

Insulin-like growth factor binding protein-5 influences pancreatic cancer cell growth

AIM： To investigate the functional significance of insulin-like growth factor binding protein-5 （IGFBP-5） overexpression in pancreatic cancer （PaC）.METHODS： The effects of IGFBP-5 on cell growth were assessed by stable transfection of BxPC-3 and PANC-1 cell lines and measuring cell number and DNA synthesis. Alterations in the cell cycle were assessed by flow cytometry and immunoblot analyses. Changes in cell survival and signal transduction were evaluated after mitogen and phosphatidylinositol activated protein kinase 3-kinase （PI3K） inhibitor treatment.RESULTS： After serum deprivation, IGFBP-5 expression increased both cell number and DNA synthesis in BxPC-3 cells, but reduced cell number in PANC-1 cells. Consistent with this observation, cell cycle analysis of IGFBP-5-expressing cells revealed accelerated cell cycle progression in BxPC-3 and G2/M arrest of PANC-1 cells. Signal transduction analysis revealed that Akt activation was increased in BxPC-3, but reduced in PANC-1 cells that express IGFBP-5. Inhibition of PI3K with LY294002 suppressed extracellular signal-regulated kinase-1 and -2 （ERK1/2） activation in BxPC-3, but enhanced ERK1/2 activation in PANC-1 cells that express IGFBP-5. When MEK1/2 was blocked, Akt activation remained elevated in IGFBP-5 expressing PaC cells; however, inhibition of PI3K or MEK1/2 abrogated IGFBP-5-mediated cell survival.CONCLUSION： These results indicate that IGFBP-5 expression affects the cell cycle and survival signal pathways and thus it may be an important mediator of PaC cell growth.

ACRL《高校图书馆环境扫描报告》(2021版)解读与启示

对美国大学与研究图书馆学会(ACRL)《高校图书馆环境扫描报告》(2021版)的新冠疫情的挑战、发展原则、“信疫”之战、受控数字借阅、开放科学和研究数据服务、新兴技术发展带来的图书馆变革六方面核心内容进行介绍,并通过解读发现,美国高校图书馆重视环境扫描工作、数据管理和信息素养教育,信息技术变革对图书馆转型产生深远影响。借鉴其经验,结合我国国情,我国高校图书馆应重视环境扫描绘制图书馆“十四五”发展蓝图,开展数据管理服务促进图书馆转型发展,加强信息素养教育防治“信疫”。

Supramolecular organizing centers(SMOCs) as signaling machines in innate immune activation

Innate immunity offers the first line of defense against infections and other types of danger such as tumorigenesis. Its discovery provides tremendous therapeutic opportunities for numerous human diseases. Delving into the structural basis of signal transduction by innate immune receptors, our lab has recently helped to establish the new paradigm in which innate immune receptors transduce ligand-binding signals through formation of higher-order assemblies containing intracellular adapters, signaling enzymes and their substrates. These large signalosome assemblies may be visible under light microscopy as punctate structures in the μm scale, connecting to the underlying molecular structures in the nm scale. They drive proximity-induced enzyme activation, and provide a mechanism for signaling amplification by nucleated polymerization. These supramolecular signaling complexes also open new questions on their cellular organization and mode of regulation, pose challenges to our methodology, and afford valuable implications in drug discovery against these medically important pathways.