Ruhi Polara,Briony L Gliddon,Raja Ganesan,Lorena T Davies,John Toubia,Sakthi Lenin,Ghizal Siddiqui,Olivia Morris-Hanon,Melinda N Tea,Paul A B Moretti,Dung A Nguyen,Chung Hoow Kok,Chloe Shard,Alexander H Staudacher,Michael P Brown,Darren J Creek,Guillermo A Gomez,Daniel Thomas,Stuart M Pitson,Nirmal Robinson
CD47 is an innate immune checkpoint that inhibits phagocytosis by myeloid cells, contributing to immune evasion by cancer cells. CD47-blocking antibodies have limited efficacy in glioblastoma (GBM), and the cell-intrinsic role of CD47 is poorly understood. In this study, we show that CD47 is highly expressed at the invasive edge of GBM tumors, and its elevated expression correlates with poor patient survival. We demonstrate that CD47 loss impairs GBM cell proliferation, migration, and invasion, independent of immune activity, and leads to reduced tumor burden and prolonged survival in vivo. Our study identifies ROBO2 signaling as a key downstream effector of CD47 and demonstrates that loss of ROBO2 similarly reduces GBM cell proliferation and migration. Importantly, we have uncovered that CD47 stabilizes ROBO2 by sequestering the E3 ubiquitin ligase ITCH, thereby blocking ubiquitination and proteasomal degradation of ROBO2. These findings establish CD47 as a key regulator of GBM cell plasticity and highlight the therapeutic potential of targeting CD47-ROBO2 signaling in GBM.
{"title":"CD47 stabilizes ROBO2 to regulate glioblastoma progression by preventing ITCH-mediated ubiquitination.","authors":"Ruhi Polara,Briony L Gliddon,Raja Ganesan,Lorena T Davies,John Toubia,Sakthi Lenin,Ghizal Siddiqui,Olivia Morris-Hanon,Melinda N Tea,Paul A B Moretti,Dung A Nguyen,Chung Hoow Kok,Chloe Shard,Alexander H Staudacher,Michael P Brown,Darren J Creek,Guillermo A Gomez,Daniel Thomas,Stuart M Pitson,Nirmal Robinson","doi":"10.1073/pnas.2602460123","DOIUrl":"https://doi.org/10.1073/pnas.2602460123","url":null,"abstract":"CD47 is an innate immune checkpoint that inhibits phagocytosis by myeloid cells, contributing to immune evasion by cancer cells. CD47-blocking antibodies have limited efficacy in glioblastoma (GBM), and the cell-intrinsic role of CD47 is poorly understood. In this study, we show that CD47 is highly expressed at the invasive edge of GBM tumors, and its elevated expression correlates with poor patient survival. We demonstrate that CD47 loss impairs GBM cell proliferation, migration, and invasion, independent of immune activity, and leads to reduced tumor burden and prolonged survival in vivo. Our study identifies ROBO2 signaling as a key downstream effector of CD47 and demonstrates that loss of ROBO2 similarly reduces GBM cell proliferation and migration. Importantly, we have uncovered that CD47 stabilizes ROBO2 by sequestering the E3 ubiquitin ligase ITCH, thereby blocking ubiquitination and proteasomal degradation of ROBO2. These findings establish CD47 as a key regulator of GBM cell plasticity and highlight the therapeutic potential of targeting CD47-ROBO2 signaling in GBM.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"92 1","pages":"e2602460123"},"PeriodicalIF":11.1,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147502366","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Justin P Gwynn,Hilde Elise Heldal,Hans-Christian Teien,Andrey Volynkin,Simon M Jerome,Ole Christian Lind
The study documents in detail the extent of damage to the exterior of the sunken nuclear submarine Komsomolets and that previous remedial action carried out by Russia was still in place. No evidence was found of any plutonium in the near environment around the damaged forward section of the submarine from the nuclear warheads that were reported to be part of Komsomolets armament in the torpedo compartment. It was confirmed that releases from the reactor were still occurring, but not continuously, with maximum activity concentrations of 90Sr and 137Cs that were 400,000 and 800,000 times higher, respectively, than typical levels of these radionuclides in the Norwegian Sea. Elevated levels of 239Pu, 240Pu, and 236U were also detected in the releases from the reactor, with atom ratios of 240Pu/239Pu and 236U/239Pu that indicate that the nuclear fuel in the reactor is corroding. Despite that releases from the reactor have occurred for over 30 y, there is little evidence of any accumulation of radionuclides in the near environment around the submarine as the released radionuclides appear to be rapidly diluted in the surrounding seawater. Releases from the reactor in Komsomolets can be expected to continue, so further investigations should be carried out to determine the mechanisms behind the observed releases, the corrosion processes that are occurring within the reactor and the implications of these for further releases and the fate of the remaining nuclear material in the reactor.
{"title":"Status of the sunken nuclear submarine Komsomolets in the Norwegian Sea.","authors":"Justin P Gwynn,Hilde Elise Heldal,Hans-Christian Teien,Andrey Volynkin,Simon M Jerome,Ole Christian Lind","doi":"10.1073/pnas.2520144123","DOIUrl":"https://doi.org/10.1073/pnas.2520144123","url":null,"abstract":"The study documents in detail the extent of damage to the exterior of the sunken nuclear submarine Komsomolets and that previous remedial action carried out by Russia was still in place. No evidence was found of any plutonium in the near environment around the damaged forward section of the submarine from the nuclear warheads that were reported to be part of Komsomolets armament in the torpedo compartment. It was confirmed that releases from the reactor were still occurring, but not continuously, with maximum activity concentrations of 90Sr and 137Cs that were 400,000 and 800,000 times higher, respectively, than typical levels of these radionuclides in the Norwegian Sea. Elevated levels of 239Pu, 240Pu, and 236U were also detected in the releases from the reactor, with atom ratios of 240Pu/239Pu and 236U/239Pu that indicate that the nuclear fuel in the reactor is corroding. Despite that releases from the reactor have occurred for over 30 y, there is little evidence of any accumulation of radionuclides in the near environment around the submarine as the released radionuclides appear to be rapidly diluted in the surrounding seawater. Releases from the reactor in Komsomolets can be expected to continue, so further investigations should be carried out to determine the mechanisms behind the observed releases, the corrosion processes that are occurring within the reactor and the implications of these for further releases and the fate of the remaining nuclear material in the reactor.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"31 1","pages":"e2520144123"},"PeriodicalIF":11.1,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147502368","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Antarctic sea ice extent (SIE) has experienced unprecedented variability in recent decades, with record expansion through 2015, followed by an abrupt transition to sustained decline. Using over two decades of under-ice Argo float observations, we show that changes in ocean heat ventilation have modulated these extreme sea ice variations on interannual timescales. Between 2007 and 2015, the ocean thermocline warmed and shoaled within the Weddell Sea and off East Antarctica, with the former accounting for most of the interannual variability in Antarctic SIE. After 2016, as Antarctic SIE declined, surface salinity increased, enhancing exchange between the sharpened thermocline and surface waters. Idealized modeling of the Weddell Sea indicates that these upper ocean trends were due to concurrent variations in wind-driven Ekman upwelling and precipitation. During the sea ice expansion phase, increased precipitation enhanced ocean stratification, suppressing the upward flux of subsurface heat while promoting sea ice growth. However, between 2014 and 2016, a nearly three-fold increase in upwelling rates weakened the upper ocean stratification, releasing the accumulated subsurface heat. Though a similar sequence of events occurred along the East Antarctic margin, distinct upper-ocean trends and surface forcing in the Pacific sector of the Southern Ocean imply alternative drivers of recent sea ice loss in that region. Nevertheless, these results suggest that future multiyear Antarctic SIE variability will depend on the competing influences of wind-driven upwelling and surface freshwater fluxes.
{"title":"Recent extremes in Antarctic sea ice extent modulated by ocean heat ventilation.","authors":"Earle A Wilson,Lexi Arlen,Ethan C Campbell","doi":"10.1073/pnas.2530832123","DOIUrl":"https://doi.org/10.1073/pnas.2530832123","url":null,"abstract":"Antarctic sea ice extent (SIE) has experienced unprecedented variability in recent decades, with record expansion through 2015, followed by an abrupt transition to sustained decline. Using over two decades of under-ice Argo float observations, we show that changes in ocean heat ventilation have modulated these extreme sea ice variations on interannual timescales. Between 2007 and 2015, the ocean thermocline warmed and shoaled within the Weddell Sea and off East Antarctica, with the former accounting for most of the interannual variability in Antarctic SIE. After 2016, as Antarctic SIE declined, surface salinity increased, enhancing exchange between the sharpened thermocline and surface waters. Idealized modeling of the Weddell Sea indicates that these upper ocean trends were due to concurrent variations in wind-driven Ekman upwelling and precipitation. During the sea ice expansion phase, increased precipitation enhanced ocean stratification, suppressing the upward flux of subsurface heat while promoting sea ice growth. However, between 2014 and 2016, a nearly three-fold increase in upwelling rates weakened the upper ocean stratification, releasing the accumulated subsurface heat. Though a similar sequence of events occurred along the East Antarctic margin, distinct upper-ocean trends and surface forcing in the Pacific sector of the Southern Ocean imply alternative drivers of recent sea ice loss in that region. Nevertheless, these results suggest that future multiyear Antarctic SIE variability will depend on the competing influences of wind-driven upwelling and surface freshwater fluxes.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"219 1","pages":"e2530832123"},"PeriodicalIF":11.1,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147502312","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Himanshu Batra,Sai Luo,Kevin O Saunders,Jaclyn S Higgins,Fanchong Jian,Jun Zhang,Md Golam Kibria,G M Jonaid,Qingchen J Zhou,Amanda Eaton,Kenneth Cronin,Michael L Mallory,Melissa Mattocks,Robert J Edwards,Robert Parks,Esther M Lee,Adam Yongxin Ye,Aimee Chapdelaine Williams,Geeyoun Jung,Katayoun Mansouri,S Munir Alam,David C Montefiori,Ming Tian,Ralph S Baric,Yunlong Cao,Barton F Haynes,Bing Chen,Frederick W Alt
During V(D)J recombination, antibody diversity is enhanced by nontemplated junctional modifications that generate immensely diverse heavy chain (HC) and light chain (LC) complementarity-determining 3 antigen-contact regions (CDR3s). We previously developed a mouse model that generates diverse antibody repertoires by rearranging a single human VH1-2 and Vκ1-33, associated with highly diverse CDR3s generated by V(D)J recombination with mouse Ds and/or Js. Immunization of this model with SARS-CoV-2 D614G spike elicited an antibody that potently neutralized SARS-CoV-2 variants through Omicron BA.2.754. Here, we report a related mouse model in which a single VH1-2 rearranges to human D3-3 and JH6, generating diverse HC-CDR3s much longer on average than those of our prior model. Omicron BA.4/.5 spike-ferritin nanoparticle-immunization of the new model elicited four highly related humanized antibodies that potently neutralize downstream Omicron subvariants. All four antibodies had 12 AA HC-CDR3s with two aromatic amino acids that engage an epitope comprising a hydrophobic patch opened-up by early Omicron lineage mutations and conserved in subsequent variants. Immunization of our prior, shorter CDR3-based model, elicited slightly less potent neutralizing antibodies that bound the same Omicron epitope, and were similar in all other aspects to those from the long, fully human CDR3 model. One tested antibody from each set reduced lung viral titers in a mouse-adapted BQ1.1 challenge. The antibodies we describe are related in their epitope recognition to recently described antibodies from Omicron-infected humans. These studies validate the utility of single human VH- and Vκ-rearranging mice for discovering humanized antibodies that neutralize emerging pathogens.
{"title":"Recurrent SARS-CoV-2 Omicron broadly neutralizing humanized antibodies in different single human VH1-2-rearranging mouse models.","authors":"Himanshu Batra,Sai Luo,Kevin O Saunders,Jaclyn S Higgins,Fanchong Jian,Jun Zhang,Md Golam Kibria,G M Jonaid,Qingchen J Zhou,Amanda Eaton,Kenneth Cronin,Michael L Mallory,Melissa Mattocks,Robert J Edwards,Robert Parks,Esther M Lee,Adam Yongxin Ye,Aimee Chapdelaine Williams,Geeyoun Jung,Katayoun Mansouri,S Munir Alam,David C Montefiori,Ming Tian,Ralph S Baric,Yunlong Cao,Barton F Haynes,Bing Chen,Frederick W Alt","doi":"10.1073/pnas.2537053123","DOIUrl":"https://doi.org/10.1073/pnas.2537053123","url":null,"abstract":"During V(D)J recombination, antibody diversity is enhanced by nontemplated junctional modifications that generate immensely diverse heavy chain (HC) and light chain (LC) complementarity-determining 3 antigen-contact regions (CDR3s). We previously developed a mouse model that generates diverse antibody repertoires by rearranging a single human VH1-2 and Vκ1-33, associated with highly diverse CDR3s generated by V(D)J recombination with mouse Ds and/or Js. Immunization of this model with SARS-CoV-2 D614G spike elicited an antibody that potently neutralized SARS-CoV-2 variants through Omicron BA.2.754. Here, we report a related mouse model in which a single VH1-2 rearranges to human D3-3 and JH6, generating diverse HC-CDR3s much longer on average than those of our prior model. Omicron BA.4/.5 spike-ferritin nanoparticle-immunization of the new model elicited four highly related humanized antibodies that potently neutralize downstream Omicron subvariants. All four antibodies had 12 AA HC-CDR3s with two aromatic amino acids that engage an epitope comprising a hydrophobic patch opened-up by early Omicron lineage mutations and conserved in subsequent variants. Immunization of our prior, shorter CDR3-based model, elicited slightly less potent neutralizing antibodies that bound the same Omicron epitope, and were similar in all other aspects to those from the long, fully human CDR3 model. One tested antibody from each set reduced lung viral titers in a mouse-adapted BQ1.1 challenge. The antibodies we describe are related in their epitope recognition to recently described antibodies from Omicron-infected humans. These studies validate the utility of single human VH- and Vκ-rearranging mice for discovering humanized antibodies that neutralize emerging pathogens.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"25 1","pages":"e2537053123"},"PeriodicalIF":11.1,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147502370","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Spinning carbon and sinking phosphorus: Misaligned cycles in the sea.","authors":"Matthew J Church,Katie N Coates","doi":"10.1073/pnas.2602952123","DOIUrl":"https://doi.org/10.1073/pnas.2602952123","url":null,"abstract":"","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"19 1","pages":"e2602952123"},"PeriodicalIF":11.1,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147502314","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The identification of functional ligand-membrane protein interactions under native conditions remains a major challenge in cancer biology. Using cell-systematic evolution of ligands by exponential enrichment, we identified a high-affinity DNA aptamer, CW06, against breast cancer cells. To precisely identify its native membrane target, we developed Aptamer-mediated Metabolic Glycan-labeling Proximity Hybridization (Apt-MGPH), which revealed the mitochondrial solute carrier SLC25A24 as the specific target. Unexpectedly, CW06 treatment upregulated SLC25A24 expression, disrupting methionine metabolism, depleting cytosolic SAM, and inducing G1 cell cycle arrest and senescence via the p21-HMGA1 axis. In mouse xenograft models, CW06 significantly inhibited tumor growth without affecting healthy tissues. Targeted degradation of SLC25A24 reverses these effects, confirming its regulatory role in the metabolism-senescence axis. Our study establishes Apt-MGPH as a robust tool for membrane target identification and highlights aptamer-induced target overexpression as a strategy for cancer therapy.
{"title":"Identifying a cancer therapeutic target: Cell-SELEX identifies a membrane protein for aptamer-mediated growth suppression.","authors":"Wei Cui,Hang Xiao,Xiaohong Wen,Chen Li,Suxia Bao,Jiahao Zeng,Yangbing Li,Yan Qiao,Kemin Wang,Honghui Wang,Jin Huang,Qiuping Guo","doi":"10.1073/pnas.2514681123","DOIUrl":"https://doi.org/10.1073/pnas.2514681123","url":null,"abstract":"The identification of functional ligand-membrane protein interactions under native conditions remains a major challenge in cancer biology. Using cell-systematic evolution of ligands by exponential enrichment, we identified a high-affinity DNA aptamer, CW06, against breast cancer cells. To precisely identify its native membrane target, we developed Aptamer-mediated Metabolic Glycan-labeling Proximity Hybridization (Apt-MGPH), which revealed the mitochondrial solute carrier SLC25A24 as the specific target. Unexpectedly, CW06 treatment upregulated SLC25A24 expression, disrupting methionine metabolism, depleting cytosolic SAM, and inducing G1 cell cycle arrest and senescence via the p21-HMGA1 axis. In mouse xenograft models, CW06 significantly inhibited tumor growth without affecting healthy tissues. Targeted degradation of SLC25A24 reverses these effects, confirming its regulatory role in the metabolism-senescence axis. Our study establishes Apt-MGPH as a robust tool for membrane target identification and highlights aptamer-induced target overexpression as a strategy for cancer therapy.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"235 1","pages":"e2514681123"},"PeriodicalIF":11.1,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147502410","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Diyendo Massilani,Stéphane Peyrégne,Leonardo N M Iasi,Cesare de Filippo,Fabrizio Mafessoni,Alba Bossoms Mesa,Arev P Sümer,Yaniv Swiel,Divyaratan Popli,Shahar Silverman,Michael James Boyle,Maxim B Kozlikin,Michael V Shunkov,Anatoly P Derevianko,Tom Higham,Katerina Douka,Matthias Meyer,Hugo Zeberg,Janet Kelso,Svante Pääbo
We present a genome sequenced to ~37-fold genomic coverage from an approximately 110,000-y-old male Neandertal from Denisova Cave in the Altai Mountains and analyze it together with previously published Neandertal genomes of high quality. We show that he belonged to a population more closely related to a ~120,000-y-old Neandertal from Denisova Cave than to Neandertals in Europe or to a ~80,000-y-old Neandertal from Chagyrskaya Cave in the Altai Mountains. Both Neandertals from Denisova Cave show evidence of gene flow from Denisovans, a pattern not seen in later Neandertals from the Altai region or from Western Europe. The extent of chromosomal regions of homozygosity in Neandertals from the Altai region between 120,000 and 80,000 y ago indicates that they lived in smaller and more isolated groups than later Neandertals in Europe (54,000 to 40,000 y ago). We estimate the extent of allele frequency differentiation among Neandertal populations and find that the older Eastern Neandertals in the Altai region and younger Western Neandertals in Europe were as differentiated as the most differentiated present-day human populations worldwide.
{"title":"A high-coverage Neandertal genome from the Altai Mountains reveals population structure among Neandertals.","authors":"Diyendo Massilani,Stéphane Peyrégne,Leonardo N M Iasi,Cesare de Filippo,Fabrizio Mafessoni,Alba Bossoms Mesa,Arev P Sümer,Yaniv Swiel,Divyaratan Popli,Shahar Silverman,Michael James Boyle,Maxim B Kozlikin,Michael V Shunkov,Anatoly P Derevianko,Tom Higham,Katerina Douka,Matthias Meyer,Hugo Zeberg,Janet Kelso,Svante Pääbo","doi":"10.1073/pnas.2534576123","DOIUrl":"https://doi.org/10.1073/pnas.2534576123","url":null,"abstract":"We present a genome sequenced to ~37-fold genomic coverage from an approximately 110,000-y-old male Neandertal from Denisova Cave in the Altai Mountains and analyze it together with previously published Neandertal genomes of high quality. We show that he belonged to a population more closely related to a ~120,000-y-old Neandertal from Denisova Cave than to Neandertals in Europe or to a ~80,000-y-old Neandertal from Chagyrskaya Cave in the Altai Mountains. Both Neandertals from Denisova Cave show evidence of gene flow from Denisovans, a pattern not seen in later Neandertals from the Altai region or from Western Europe. The extent of chromosomal regions of homozygosity in Neandertals from the Altai region between 120,000 and 80,000 y ago indicates that they lived in smaller and more isolated groups than later Neandertals in Europe (54,000 to 40,000 y ago). We estimate the extent of allele frequency differentiation among Neandertal populations and find that the older Eastern Neandertals in the Altai region and younger Western Neandertals in Europe were as differentiated as the most differentiated present-day human populations worldwide.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"15 1","pages":"e2534576123"},"PeriodicalIF":11.1,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147502413","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Taylor A DePauw,Kexin Gai,Jian Shen,Nicholas J Maurice,Ka Hyun Rhee,William J Valente,Christine H O'Connor,Weiguo Cui,Changwei Peng,Stephen C Jameson
Numerous transcriptional regulators have been associated with the differentiation pathways that lead to recirculating vs. tissue-resident memory T cells. However, it is unclear whether independent, coordinated expression of these regulators is required to determine residency vs. recirculation or whether there is a hierarchy, with some factors playing a dominant role in controlling T cell trafficking. We report that ablation of the gene encoding Kruppel-like factor 2 (KLF2) during CD8+ T cell activation leads to rapid transcriptional reprogramming, such that effector T cells fail to recirculate and prematurely acquire canonical phenotypic and transcriptional characteristics of resident memory cells (TRM). Klf2-deficient memory CD8+ T cells retained the capacity to undergo recall responses, including in vivo pathogen control. These data suggest that KLF2 diverts CD8+ T cells from the TRM differentiation program. In contrast, ablation of another member of the KLF family, KLF3, enhanced differentiation of some recirculating T cell subsets and limited production of TRM in lymphoid tissues. However, both KLF2 and KLF3 were required for differentiation of long-lived effector cells, suggesting cooperation between these factors in some situations. These findings indicate that KLFs occupy a central nexus in coordinating activated CD8+ T cell differentiation and trafficking.
{"title":"KLF2 overrides the resident memory CD8 T cell differentiation program, in opposition to KLF3.","authors":"Taylor A DePauw,Kexin Gai,Jian Shen,Nicholas J Maurice,Ka Hyun Rhee,William J Valente,Christine H O'Connor,Weiguo Cui,Changwei Peng,Stephen C Jameson","doi":"10.1073/pnas.2533700123","DOIUrl":"https://doi.org/10.1073/pnas.2533700123","url":null,"abstract":"Numerous transcriptional regulators have been associated with the differentiation pathways that lead to recirculating vs. tissue-resident memory T cells. However, it is unclear whether independent, coordinated expression of these regulators is required to determine residency vs. recirculation or whether there is a hierarchy, with some factors playing a dominant role in controlling T cell trafficking. We report that ablation of the gene encoding Kruppel-like factor 2 (KLF2) during CD8+ T cell activation leads to rapid transcriptional reprogramming, such that effector T cells fail to recirculate and prematurely acquire canonical phenotypic and transcriptional characteristics of resident memory cells (TRM). Klf2-deficient memory CD8+ T cells retained the capacity to undergo recall responses, including in vivo pathogen control. These data suggest that KLF2 diverts CD8+ T cells from the TRM differentiation program. In contrast, ablation of another member of the KLF family, KLF3, enhanced differentiation of some recirculating T cell subsets and limited production of TRM in lymphoid tissues. However, both KLF2 and KLF3 were required for differentiation of long-lived effector cells, suggesting cooperation between these factors in some situations. These findings indicate that KLFs occupy a central nexus in coordinating activated CD8+ T cell differentiation and trafficking.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"17 1","pages":"e2533700123"},"PeriodicalIF":11.1,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147502415","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Rethinking same-sex sexual behavior: From sensory error to social function.","authors":"Viraj R Torsekar","doi":"10.1073/pnas.2600926123","DOIUrl":"https://doi.org/10.1073/pnas.2600926123","url":null,"abstract":"","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"402 1","pages":"e2600926123"},"PeriodicalIF":11.1,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147502362","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Matthew Wei Ming Tan,Guodong Nian,Zheqi Chen,Xianyang Bao,Yakov Kutsovsky,Zhigang Suo
Natural rubber outperforms synthetic rubbers because of its long chains and strain-induced crystallization (SIC). However, these advantages are largely lost when the natural rubber chains are masticated during processing, and silica particles are added for reinforcement. Mastication eases mixing but shortens chains and lowers performance. Silica particles require covalent interlinks with rubber chains, but these interlinks restrict chain stretch and alignment, reducing SIC. Here, we show that the performance of silica-reinforced natural rubber can be markedly enhanced by preserving long natural rubber chains. We use a solvent to dissolve natural rubber latex into individual rubber chains and use the solution to uniformly disperse silica particles. After drying, the uncured compound can be stored and molded prior to curing. The long rubber chains are then sparsely crosslinked with one another and interlinked with the silica particles. The long strands readily align under stretch and increase SIC. Preserving long chains elevates toughness by an order of magnitude, from ~2 to 44 kJ m-2. High toughness arises from energy dissipation across multiple length scales, over long rubber strands, silica particles, and a zone of SIC. High modulus of ~19 MPa arises from two interpenetrating networks: the network of densely entangled rubber chains and the network of percolated silica particles. The resulting material achieves high toughness while maintaining high modulus, a combination uncommon in silica-reinforced synthetic and natural rubbers.
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