Science Signaling最新文献_第9页

Repetitive injury induces phenotypes associated with Alzheimer’s disease by reactivating HSV-1 in a human brain tissue model 在人脑组织模型中，重复性损伤通过重新激活HSV-1诱导与阿尔茨海默病相关的表型。

IF 6.7 1区生物学

Science Signaling Pub Date : 2025-01-07 DOI: 10.1126/scisignal.ado6430

Dana M. Cairns, Brooke M. Smiley, Jordan A. Smiley, Yasaman Khorsandian, Marilyn Kelly, Ruth F. Itzhaki, David L. Kaplan

{"title":"Repetitive injury induces phenotypes associated with Alzheimer’s disease by reactivating HSV-1 in a human brain tissue model","authors":"Dana M. Cairns, Brooke M. Smiley, Jordan A. Smiley, Yasaman Khorsandian, Marilyn Kelly, Ruth F. Itzhaki, David L. Kaplan","doi":"10.1126/scisignal.ado6430","DOIUrl":"10.1126/scisignal.ado6430","url":null,"abstract":"<div >Infection with herpes simplex virus type 1 (HSV-1) in the brains of <i>APOE4</i> carriers increases the risk of Alzheimer’s disease (AD). We previously found that latent HSV-1 in a three-dimensional in vitro model of <i>APOE4</i>-heterozygous human brain tissue was reactivated in response to neuroinflammation caused by exposure to other pathogens. Because traumatic brain injury also causes neuroinflammation, we surmised that brain injury might similarly reactivate latent HSV-1. Here, we examined the effects of one or more controlled blows to our human brain model in the absence or presence of latent HSV-1 infection. After repeated, mild controlled blows, latently infected tissues showed reactivation of HSV-1; the production and accumulation of β amyloid and phosphorylated tau (which promotes synaptic dysfunction and neurodegeneration); and activated gliosis, which is associated with destructive neuroinflammation. These effects are collectively associated with AD, dementia, and chronic traumatic encephalopathy (CTE) and were increased with additional injury but were absent in mock-infected tissue. Blocking the cytokine IL-1β prevented the induction of amyloid and gliosis in latently infected monolayer cultures after scratch wounding. We thus propose that after repeated mechanical injuries to the brain, such as from direct blows to the head or jarring motions of the head, the resulting reactivation of HSV-1 in the brain may contribute to the development of AD and related diseases in some individuals.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 868","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142957822","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

IRF1 cooperates with ISGF3 or GAF to form innate immune de novo enhancers in macrophages IRF1与ISGF3或GAF协同在巨噬细胞中形成先天免疫新生增强因子。

IF 6.7 1区生物学

Science Signaling Pub Date : 2025-01-07 DOI: 10.1126/scisignal.ado8860

Carolina Chavez, Kelly Lin, Alexis Malveaux, Aleksandr Gorin, Stefanie Brizuela, Quen J. Cheng, Alexander Hoffmann

{"title":"IRF1 cooperates with ISGF3 or GAF to form innate immune de novo enhancers in macrophages","authors":"Carolina Chavez, Kelly Lin, Alexis Malveaux, Aleksandr Gorin, Stefanie Brizuela, Quen J. Cheng, Alexander Hoffmann","doi":"10.1126/scisignal.ado8860","DOIUrl":"10.1126/scisignal.ado8860","url":null,"abstract":"<div >Macrophages exposed to immune stimuli reprogram their epigenomes to alter their subsequent functions. Exposure to bacterial lipopolysaccharide (LPS) causes widespread nucleosome remodeling and the formation of thousands of de novo enhancers. We dissected the regulatory logic by which the network of interferon regulatory factors (IRFs) induces the opening of chromatin and the formation of de novo enhancers. We found that LPS-activated IRF3 mediated de novo enhancer formation indirectly by activating the type I interferon (IFN)–induced ISGF3. However, ISGF3 was generally needed to collaborate with IRF1, particularly where chromatin was less accessible. At these locations, IRF1 was required for the initial opening of chromatin, with ISGF3 extending accessibility and promoting the deposition of H3K4me1, marking poised enhancers. Because <i>IRF1</i> expression depends on the transcription factor NF-κB, which is activated in infected but not bystander cells, IRF-regulated enhancers required activation of both the IRF3 and NF-κB branches of the innate immune signaling network. However, type II IFN (IFN-γ), which is typically produced by T cells, may also induce <i>IRF1</i> expression through the STAT1 homodimer GAF. We showed that, upon IFN-γ stimulation, IRF1 was also responsible for opening inaccessible chromatin sites that could then be exploited by GAF to form de novo enhancers. Together, our results reveal how combinatorial logic gates of IRF1-ISGF3 or IRF1-GAF restrict immune epigenomic memory formation to macrophages exposed to pathogens or IFN-γ–secreting T cells but not bystander macrophages exposed transiently to type I IFN.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 868","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142957821","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Erratum for the Research Article “Reciprocal regulation of mTORC1 signaling and ribosomal biosynthesis determines cell cycle progression in activated T cells” by T. Rosenlehner et al. 对 T. Rosenlehner 等人的研究文章 "mTORC1 信号传导和核糖体生物合成的相互调控决定了活化 T 细胞的细胞周期进程 "的勘误。

IF 6.7 1区生物学

Science Signaling Pub Date : 2024-12-17 DOI: 10.1126/scisignal.adu7437

引用次数: 0

Bile acid–induced metabolic changes in the colon promote Enterobacteriaceae expansion and associate with dysbiosis in Crohn’s disease 胆汁酸引起的结肠代谢变化会促进肠杆菌扩增，并与克罗恩病的菌群失调有关。

IF 6.7 1区生物学

Science Signaling Pub Date : 2024-12-17 DOI: 10.1126/scisignal.adl1786

Ravi Holani, Haggai Bar-Yoseph, Zakhar Krekhno, Antonio Serapio-Palacios, Kyung-Mee Moon, Richard G. Stacey, Katherine A. Donald, Wanyin Deng, Brian Bressler, Armando A. Magaña, Leonard J. Foster, Michael G. Atser, James D. Johnson, Barton Brett Finlay

{"title":"Bile acid–induced metabolic changes in the colon promote Enterobacteriaceae expansion and associate with dysbiosis in Crohn’s disease","authors":"Ravi Holani, Haggai Bar-Yoseph, Zakhar Krekhno, Antonio Serapio-Palacios, Kyung-Mee Moon, Richard G. Stacey, Katherine A. Donald, Wanyin Deng, Brian Bressler, Armando A. Magaña, Leonard J. Foster, Michael G. Atser, James D. Johnson, Barton Brett Finlay","doi":"10.1126/scisignal.adl1786","DOIUrl":"10.1126/scisignal.adl1786","url":null,"abstract":"<div >Bile acids (BAs) affect the growth of potentially pathogenic commensals, including those from the Enterobacteriaceae family, which are frequently overrepresented in inflammatory bowel disease (IBD). BAs are normally reabsorbed in the ileum for recycling and are often increased in the colonic lumina of patients with IBD, including those with Crohn’s disease (CD). Here, we investigated the influence of BAs on gut colonization by Enterobacteriaceae. We found increased abundance of Enterobacteriaceae in the colonic mucosae of patients with CD with a concomitant decrease in the transporters that resorb BAs in the ileum. The increase in Enterobacteriaceae colonization was greater in the colons of patients who had undergone terminal ileum resection compared with those with intact ileum, leading us to hypothesize that BAs promote intestinal colonization by Enterobacteriaceae. Exposure of human colonic epithelial cell lines to BAs reduced mitochondrial respiration, increased oxygen availability, and enhanced the epithelial adherence of several Enterobacteriaceae members. In a publicly available human dataset, mucosal Enterobacteriaceae was negatively associated with the expression of genes related to mitochondrial function. In a murine model, increased intestinal BA availability enhanced colonization by <i>Escherichia coli</i> in a manner that depended on bacterial respiration. Together, our findings demonstrate that BAs reduce mitochondrial respiration in the colon, leading to an increase in oxygen availability that facilitates Enterobacteriaceae colonization. This identification of BAs as facilitators of host-commensal interactions may be relevant to multiple intestinal diseases.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"17 867","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142848277","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

HIF-2α drives TH2 cells HIF-2α 驱动 TH2 细胞。

IF 6.7 1区生物学

Science Signaling Pub Date : 2024-12-17 DOI: 10.1126/scisignal.adv2653

John F. Foley

引用次数: 0

Castration-resistant prostate cancer is resensitized to androgen deprivation by autophagy-dependent apoptosis induced by blocking SKP2 通过阻断SKP2诱导的自噬依赖性凋亡，阉割耐药前列腺癌对雄激素剥夺再敏感。

IF 6.7 1区生物学

Science Signaling Pub Date : 2024-12-17 DOI: 10.1126/scisignal.adk4122

Sherly I. Celada, Guoliang Li, Lindsay J. Celada, Thanigaivelan Kanagasabai, Wenfu Lu, LaKendria K. Brown, Zaniya A. Mark, Michael G. Izban, Billy R. Ballard, Xinchun Zhou, Samuel E. Adunyah, Robert J. Matusik, Xiaofei Wang, Zhenbang Chen

{"title":"Castration-resistant prostate cancer is resensitized to androgen deprivation by autophagy-dependent apoptosis induced by blocking SKP2","authors":"Sherly I. Celada, Guoliang Li, Lindsay J. Celada, Thanigaivelan Kanagasabai, Wenfu Lu, LaKendria K. Brown, Zaniya A. Mark, Michael G. Izban, Billy R. Ballard, Xinchun Zhou, Samuel E. Adunyah, Robert J. Matusik, Xiaofei Wang, Zhenbang Chen","doi":"10.1126/scisignal.adk4122","DOIUrl":"10.1126/scisignal.adk4122","url":null,"abstract":"<div >Resistance to androgen receptor (AR)–targeted therapies for prostate cancer (PCa) is characteristic of an aggressive subtype called castration-resistant prostate cancer (CRPC) and is often associated with tumor relapse. Both relapse and poor prognosis in patients with CRPC are associated with increased abundance of the E3 ubiquitin ligase SKP2. Therefore, we investigated the therapeutic potential of combined inhibition of AR and SKP2 for CRPC. We found that combined targeting of AR and SKP2 with small-molecule inhibitors decreased proliferation in two CRPC cell lines in culture and in xenografts in humanized mice. Furthermore, combined therapy in mice markedly decreased the growth of <i>Pten/Trp53</i> double-knockout tumors, a particularly invasive model of CRPC, whereas disruption of either AR or SKP2 alone only modestly suppressed their growth. Mechanistically, the inhibition of SKP2 in CRPC cells induced autophagy-dependent apoptosis and promoted luminal-associated phenotypes, which promoted responsiveness to AR-targeted therapy. These effects were further enhanced by coinhibition of AR and were not induced by the AR inhibitor alone. Our findings indicate that targeting both AR and SKP2 signaling pathways is necessary to treat CRPC.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"17 867","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142848279","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

AXL-TBK1 driven AKT3 activation promotes metastasis AXL-TBK1 驱动的 AKT3 激活可促进转移。

IF 6.7 1区生物学

Science Signaling Pub Date : 2024-12-17 DOI: 10.1126/scisignal.ado6057

Emily N. Arner, Dina Alzhanova, Jill M. Westcott, Stefan Hinz, Crina Elena Tiron, Magnus Blø, Anja Mai, Reetta Virtakoivu, Natalie Phinney, Silje Nord, Kristina Y. Aguilera, Ali Rizvi, Jason E. Toombs, Tanner C. Reese, Vidal Fey, David Micklem, Gro Gausdal, Johanna Ivaska, James B. Lorens, Rolf A. Brekken

{"title":"AXL-TBK1 driven AKT3 activation promotes metastasis","authors":"Emily N. Arner, Dina Alzhanova, Jill M. Westcott, Stefan Hinz, Crina Elena Tiron, Magnus Blø, Anja Mai, Reetta Virtakoivu, Natalie Phinney, Silje Nord, Kristina Y. Aguilera, Ali Rizvi, Jason E. Toombs, Tanner C. Reese, Vidal Fey, David Micklem, Gro Gausdal, Johanna Ivaska, James B. Lorens, Rolf A. Brekken","doi":"10.1126/scisignal.ado6057","DOIUrl":"10.1126/scisignal.ado6057","url":null,"abstract":"<div >The receptor tyrosine kinase AXL promotes tumor progression, metastasis, and therapy resistance through the induction of epithelial-mesenchymal transition (EMT). Here, we found that activation of AXL resulted in the phosphorylation of TANK-binding kinase 1 (TBK1) and the downstream activation of AKT3 and Snail, a transcription factor critical for EMT. Mechanistically, we showed that TBK1 directly bound to and phosphorylated AKT3 in a manner dependent on the multiprotein complex mTORC1. Upon activation, AKT3 interacted with and promoted the nuclear accumulation of Snail, which led to increased EMT as assessed by marker abundance. In human pancreatic ductal adenocarcinoma tissue, nuclear AKT3 colocalized with Snail and correlated with worse clinical outcomes. Primary mouse pancreatic cancer cells deficient in AKT3 showed reduced metastatic spread in vivo, suggesting selective AKT3 inhibition as a potential therapeutic avenue for targeting EMT in aggressive cancers.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"17 867","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142848276","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Erratum for the Research Article “The Tyrosine Kinase Syk Differentially Regulates Toll-like Receptor Signaling Downstream of the Adaptor Molecules TRAF6 and TRAF3” by Y.-C. Lin et al. y.c .研究文章“酪氨酸激酶Syk对接头分子TRAF6和TRAF3下游toll样受体信号传导的差异调节”的更正。Lin等人。

IF 6.7 1区生物学

Science Signaling Pub Date : 2024-12-10 DOI: 10.1126/scisignal.adu7156

引用次数: 0

Revealed at last: Structure of the antibody-receptor complex common to all IgE-mediated allergic hypersensitivity reactions 终于揭晓了：所有 IgE 介导的过敏超敏反应中常见的抗体-受体复合物的结构。

IF 6.7 1区生物学

Science Signaling Pub Date : 2024-12-10 DOI: 10.1126/scisignal.adu0382

Brian Sutton

引用次数: 0

The polarizing nature of fructose 果糖的两极分化特性

IF 6.7 1区生物学