Conventional semiconductor device engineering regards intrinsic device nonidealities as reliability concerns to be minimized or eliminated. Here, we demonstrate the strategic repurposing of these nonidealities as functional resources for advanced stochastic analog computing. We leverage two underutilized phenomena—deep-level channel trap-induced generation-recombination (G-R) noise and impact ionization–induced negative differential resistance (NDR) in body current—which have received limited attention compared to the extensively studied 1/f noise and monotonic drain current behavior in logic-centric transistors. By exploiting G-R noise with controllable temporal correlation and NDR with an unprecedented peak-to-valley ratio (2.78 × 104) within fully depleted silicon-on-insulator transistors fabricated in industry silicon complementary metal-oxide semiconductor (CMOS) process, we achieve multifunctional analog computation at the single-device level. Our transistor seamlessly performs stochastic encryption, deterministic signal readout, and analog inversion simply through reconfiguration of applied bias conditions, thereby eliminating the need for peripheral random-number generators, dedicated analog inverters, or amplifiers. This approach not only reveals the previously unrecognized computational potential embedded in mature CMOS technologies but also presents a scalable and energy-efficient alternative to architecture based on exotic materials, laying the foundation for next-generation analog computing systems.
{"title":"Repurposing Si CMOS nonidealities for stochastic and analog image processing","authors":"Been Kwak, Ryun-Han Koo, Changhyeon Han, Yunho Shin, Joonhyeok Choi, Dongbin Kim, Jongwoo Lee, Jiseong Im, Youngchan Cho, Jong-Ho Lee, Wonjun Shin, Daewoong Kwon","doi":"","DOIUrl":"","url":null,"abstract":"<div >Conventional semiconductor device engineering regards intrinsic device nonidealities as reliability concerns to be minimized or eliminated. Here, we demonstrate the strategic repurposing of these nonidealities as functional resources for advanced stochastic analog computing. We leverage two underutilized phenomena—deep-level channel trap-induced generation-recombination (G-R) noise and impact ionization–induced negative differential resistance (NDR) in body current—which have received limited attention compared to the extensively studied 1/<i>f</i> noise and monotonic drain current behavior in logic-centric transistors. By exploiting G-R noise with controllable temporal correlation and NDR with an unprecedented peak-to-valley ratio (2.78 × 10<sup>4</sup>) within fully depleted silicon-on-insulator transistors fabricated in industry silicon complementary metal-oxide semiconductor (CMOS) process, we achieve multifunctional analog computation at the single-device level. Our transistor seamlessly performs stochastic encryption, deterministic signal readout, and analog inversion simply through reconfiguration of applied bias conditions, thereby eliminating the need for peripheral random-number generators, dedicated analog inverters, or amplifiers. This approach not only reveals the previously unrecognized computational potential embedded in mature CMOS technologies but also presents a scalable and energy-efficient alternative to architecture based on exotic materials, laying the foundation for next-generation analog computing systems.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 8","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146224575","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}
Katherine A. Legg, Giovanni Gonzalez-Gutierrez, Katherine A. Edmonds, Philip G. Shushkov, David P. Giedroc
Many bacteria harbor an ATP-binding cassette (ABC) transporter named EgtU specific for the human dietary antioxidant and 2-thioimidazole–containing low–molecular weight thiol ergothioneine (ET). How the solute binding domain, EgtUC, discriminates among ET and other similar molecules is unknown. Here, we use a “chimeric” mutagenesis strategy and two distantly related EgtUCs from Streptococcus pneumoniae and Helicobacter pylori to show that a suite of EgtUC alkyl CH•••S hydrogen bonds to the ET thione S atom are central determinants of molecular recognition. Small perturbations in CH•••S distance and angle give rise to sharply attenuated transport-competent ET-bound “closed” state lifetimes and increased motional disorder in the binding pocket, not around the S atom itself, but distally in weakening NH•••O hydrogen bonds. This work highlights the impact of alkyl CH•••S H bonding in a biological protein-ligand complex in water.
{"title":"CH•••S hydrogen bonds drive molecular recognition of ergothioneine by the microbial transporter","authors":"Katherine A. Legg, Giovanni Gonzalez-Gutierrez, Katherine A. Edmonds, Philip G. Shushkov, David P. Giedroc","doi":"","DOIUrl":"","url":null,"abstract":"<div >Many bacteria harbor an ATP-binding cassette (ABC) transporter named EgtU specific for the human dietary antioxidant and 2-thioimidazole–containing low–molecular weight thiol ergothioneine (ET). How the solute binding domain, EgtUC, discriminates among ET and other similar molecules is unknown. Here, we use a “chimeric” mutagenesis strategy and two distantly related EgtUCs from <i>Streptococcus pneumoniae and Helicobacter pylori</i> to show that a suite of EgtUC alkyl CH•••S hydrogen bonds to the ET thione S atom are central determinants of molecular recognition. Small perturbations in CH•••S distance and angle give rise to sharply attenuated transport-competent ET-bound “closed” state lifetimes and increased motional disorder in the binding pocket, not around the S atom itself, but distally in weakening NH•••O hydrogen bonds. This work highlights the impact of alkyl CH•••S H bonding in a biological protein-ligand complex in water.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 8","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146224606","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}
Sabrina Y. Camp, Meng Xiao He, Michael S. Cuoco, Amanda E. Garza, Sherin Xirenayi, Ziad Bakouny, Eddy Saad, Jad El Masri, Erica Pimenta, Kevin Meli, Chris Labaki, Breanna M. Titchen, Yun Jee Kang, Jack Horst, Rachel Trowbridge, Erin Shannon, Karla Helvie, Aaron R. Thorner, Sébastien Vigneau, Angie Mayorga, Jahnavi Kodali, Hannah Lachmayr, Meredith Bemus, Pengsheng Chen, Haiteng Deng, Jihye Park, Toni K. Choueiri, Kevin Bi, Eliezer M. Van Allen
Transcriptional programs in renal cell carcinoma (RCC) have been linked to tumor heterogeneity and clinical outcomes, but analogous efforts to define chromatin programs shaping disease biology have been limited. Here, we generated single-cell ATAC-seq profiles from patients with RCC and integrated them with three previously published datasets to identify chromatin programs in tumor cells. We identified an interferon response program enriched in BAP1 -mutant tumors, and, in bulk ATAC-seq cohorts with linked clinical data, this program was associated with poor prognosis. Mechanistic analyses in isogenic models suggested that BAP1 loss induces a tumor-intrinsic interferon response, with dysregulated endogenous retroviruses as a potential upstream trigger. We further characterized the BAP1 mutation–associated tumor microenvironment across single-cell, bulk, and multiplex immunofluorescence data, identifying features of both inflammation and immune evasion. Together, our findings nominate tumor-intrinsic interferon signaling as a candidate driver of BAP1 -associated aggressiveness in RCC and highlight immune evasion pathways as potential therapeutic targets.
{"title":"Single-cell epigenetic profiling reveals a tumor-intrinsic interferon response program in ccRCC tied to poor prognosis and BAP1 loss","authors":"Sabrina Y. Camp, Meng Xiao He, Michael S. Cuoco, Amanda E. Garza, Sherin Xirenayi, Ziad Bakouny, Eddy Saad, Jad El Masri, Erica Pimenta, Kevin Meli, Chris Labaki, Breanna M. Titchen, Yun Jee Kang, Jack Horst, Rachel Trowbridge, Erin Shannon, Karla Helvie, Aaron R. Thorner, Sébastien Vigneau, Angie Mayorga, Jahnavi Kodali, Hannah Lachmayr, Meredith Bemus, Pengsheng Chen, Haiteng Deng, Jihye Park, Toni K. Choueiri, Kevin Bi, Eliezer M. Van Allen","doi":"10.1126/sciadv.adv5457","DOIUrl":"https://doi.org/10.1126/sciadv.adv5457","url":null,"abstract":"Transcriptional programs in renal cell carcinoma (RCC) have been linked to tumor heterogeneity and clinical outcomes, but analogous efforts to define chromatin programs shaping disease biology have been limited. Here, we generated single-cell ATAC-seq profiles from patients with RCC and integrated them with three previously published datasets to identify chromatin programs in tumor cells. We identified an interferon response program enriched in <jats:italic toggle=\"yes\">BAP1</jats:italic> -mutant tumors, and, in bulk ATAC-seq cohorts with linked clinical data, this program was associated with poor prognosis. Mechanistic analyses in isogenic models suggested that <jats:italic toggle=\"yes\">BAP1</jats:italic> loss induces a tumor-intrinsic interferon response, with dysregulated endogenous retroviruses as a potential upstream trigger. We further characterized the <jats:italic toggle=\"yes\">BAP1</jats:italic> mutation–associated tumor microenvironment across single-cell, bulk, and multiplex immunofluorescence data, identifying features of both inflammation and immune evasion. Together, our findings nominate tumor-intrinsic interferon signaling as a candidate driver of <jats:italic toggle=\"yes\">BAP1</jats:italic> -associated aggressiveness in RCC and highlight immune evasion pathways as potential therapeutic targets.","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"4 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2026-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146222924","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}
Min Li, Fantao Kong, Hao Zhuo, Wenshu Luo, Xiangzhi Cui, Jianlin Shi
The electrochemical conversion of oxalic acid (OX) to glycolic acid (GC) offers a sustainable route for biomass valorization yet suffers from inefficient proton-coupled electron transfer and competitive hydrogen evolution. We report an oxygen vacancy (O V )–mediated atomic interface strategy to construct Fe δ- -O V -Ti 3+ dual-active sites in TiO 2 , enabling tandem activation of H + and C═O bond through a (2e − + 2e − ) relay mechanism. The Fe-TiO X /titanium paper electrocatalyst achieves a faradaic efficiency of 74.3% with >60% GC selectivity at industrially relevant current densities (~100 milliamperes per square centimeter), stable for ~60 hours, which is a record high in electrochemical conversion of OX to GC. In situ spectroscopy and density functional theory calculations reveal that the Fe δ- sites dynamically stabilize H* intermediates while inhibiting H 2 formation, while Ti 3+ sites form a σ─π coordination bond with the carbonyl oxygen in OX, lowering the energy barrier of the rate-determining step. This work provides a paradigm for designing a dual site in electrochemical tandem reactions, offering fundamental insights in sustainable chemical synthesis.
草酸（OX）到乙醇酸（GC）的电化学转化为生物质增值提供了一条可持续的途径，但存在质子耦合电子转移效率低和竞争性析氢的问题。我们报道了一种氧空位（O V）介导的原子界面策略，在tio2中构建了Fe δ- -O V - ti 3+双活性位点，通过（2e−+ 2e−）接力机制实现了H +和C = O键的串联活化。在工业相关电流密度（~100毫安/平方厘米）下，Fe-TiO X /钛纸电催化剂的法拉第效率为74.3%，GC选择性为60%，稳定时间约为60小时，这是OX到GC的电化学转化的最高记录。原位光谱和密度泛函理论计算表明，Fe δ-位点在抑制h2生成的同时动态稳定H*中间体，而Ti 3+位点与氧羰基形成σ─π配位键，降低了速率决定步骤的能垒。这项工作为设计电化学串联反应中的双位点提供了范例，为可持续化学合成提供了基本见解。
{"title":"Electrochemical conversion of oxalic acid to glycolic acid via oxygen vacancy–mediated tandem catalysis","authors":"Min Li, Fantao Kong, Hao Zhuo, Wenshu Luo, Xiangzhi Cui, Jianlin Shi","doi":"10.1126/sciadv.aeb1911","DOIUrl":"https://doi.org/10.1126/sciadv.aeb1911","url":null,"abstract":"The electrochemical conversion of oxalic acid (OX) to glycolic acid (GC) offers a sustainable route for biomass valorization yet suffers from inefficient proton-coupled electron transfer and competitive hydrogen evolution. We report an oxygen vacancy (O <jats:sub>V</jats:sub> )–mediated atomic interface strategy to construct Fe <jats:sup>δ-</jats:sup> -O <jats:sub>V</jats:sub> -Ti <jats:sup>3+</jats:sup> dual-active sites in TiO <jats:sub>2</jats:sub> , enabling tandem activation of H <jats:sup>+</jats:sup> and C═O bond through a (2e <jats:sup>−</jats:sup> + 2e <jats:sup>−</jats:sup> ) relay mechanism. The Fe-TiO <jats:sub>X</jats:sub> /titanium paper electrocatalyst achieves a faradaic efficiency of 74.3% with >60% GC selectivity at industrially relevant current densities (~100 milliamperes per square centimeter), stable for ~60 hours, which is a record high in electrochemical conversion of OX to GC. In situ spectroscopy and density functional theory calculations reveal that the Fe <jats:sup>δ-</jats:sup> sites dynamically stabilize H* intermediates while inhibiting H <jats:sub>2</jats:sub> formation, while Ti <jats:sup>3+</jats:sup> sites form a σ─π coordination bond with the carbonyl oxygen in OX, lowering the energy barrier of the rate-determining step. This work provides a paradigm for designing a dual site in electrochemical tandem reactions, offering fundamental insights in sustainable chemical synthesis.","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"40 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2026-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146222954","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}
Fanconi anemia (FA) is characterized by bone marrow failure, congenital abnormalities, and cancer predisposition. Mutations in RAD51 paralogs have been identified in FA-like disorders and cancers. Although the role of RAD51 paralogs is well established in homologous recombination (HR)–mediated DNA repair, little is known about their role during replication stress responses. Here, we report that the RAD51C-XRCC3 (CX3) complex of RAD51 paralogs participates in the FA pathway of R-loop tolerance mechanism. CX3 complex suppresses R-loops, transcription-replication collisions (TRCs), and associated genome instability under physiological and replication stress conditions. Mechanistically, the CX3 complex physically interacts with FANCM and facilitates its recruitment to the R-loop sites to promote its resolution. Notably, cells expressing the RAD51C R258H pathological mutant exhibit defective interaction with FANCM and display inefficient R-loop processing. The CX3 complex–mediated R-loop resolution is independent of its fork maintenance function. Collectively, we demonstrate a previously unidentified role of the CX3 complex in preventing R-loop–induced genome instability by regulating FANCM-mediated R-loop resolution.
{"title":"RAD51C-XRCC3 complex regulates FANCM-mediated R-loop resolution to safeguard genome integrity","authors":"Satyaranjan Sahoo, Tarun Nagraj, Debanjali Bhattacharya, Nupur Nagar, Kumar Somyajit, Krishna Mohan Poluri, Ganesh Nagaraju","doi":"","DOIUrl":"","url":null,"abstract":"<div >Fanconi anemia (FA) is characterized by bone marrow failure, congenital abnormalities, and cancer predisposition. Mutations in <i>RAD51</i> paralogs have been identified in FA-like disorders and cancers. Although the role of RAD51 paralogs is well established in homologous recombination (HR)–mediated DNA repair, little is known about their role during replication stress responses. Here, we report that the RAD51C-XRCC3 (CX3) complex of RAD51 paralogs participates in the FA pathway of R-loop tolerance mechanism. CX3 complex suppresses R-loops, transcription-replication collisions (TRCs), and associated genome instability under physiological and replication stress conditions. Mechanistically, the CX3 complex physically interacts with FANCM and facilitates its recruitment to the R-loop sites to promote its resolution. Notably, cells expressing the RAD51C R258H pathological mutant exhibit defective interaction with FANCM and display inefficient R-loop processing. The CX3 complex–mediated R-loop resolution is independent of its fork maintenance function. Collectively, we demonstrate a previously unidentified role of the CX3 complex in preventing R-loop–induced genome instability by regulating FANCM-mediated R-loop resolution.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 8","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146224581","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}
Youngji Joh, Sang-Wook Yeh, Thomas L. Delworth, Zachary M. Labe, Andrew T. Wittenberg, William F. Cooke, Jiale Lou, Young-Gyu Park
Decadal synchronization between the Gulf Stream and Kuroshio currents has recently been reported. Given the large-scale coupled variability of western boundary currents and extensions (WBCEs), further investigation into its seasonality, predictability, and potential future changes is needed. Observations and high-resolution climate simulations reveal distinctive covariance between North Pacific and North Atlantic WBCE sea surface temperatures during boreal summer, possibly linked to preceding Arctic sea-ice variability. Model simulations suggest that cold-season Greenland and Barents Sea ice loss enhances anomalous planetary-scale atmospheric waves and meridional jet shifts, contributing to summertime WBCE temperature anomalies. Although we show that summer WBCE covariability arises from intrinsic variability, future climate projections and targeted model experiments imply that this internal coupled variability may be modulated by radiatively forced changes. Our findings suggest that summer WBCE covariability has increased in the historical record but may weaken in response to future reductions in Arctic sea ice under higher radiative forcing.
{"title":"Evolving synchronization of the Gulf Stream and Kuroshio-Oyashio Extension in a changing climate","authors":"Youngji Joh, Sang-Wook Yeh, Thomas L. Delworth, Zachary M. Labe, Andrew T. Wittenberg, William F. Cooke, Jiale Lou, Young-Gyu Park","doi":"","DOIUrl":"","url":null,"abstract":"<div >Decadal synchronization between the Gulf Stream and Kuroshio currents has recently been reported. Given the large-scale coupled variability of western boundary currents and extensions (WBCEs), further investigation into its seasonality, predictability, and potential future changes is needed. Observations and high-resolution climate simulations reveal distinctive covariance between North Pacific and North Atlantic WBCE sea surface temperatures during boreal summer, possibly linked to preceding Arctic sea-ice variability. Model simulations suggest that cold-season Greenland and Barents Sea ice loss enhances anomalous planetary-scale atmospheric waves and meridional jet shifts, contributing to summertime WBCE temperature anomalies. Although we show that summer WBCE covariability arises from intrinsic variability, future climate projections and targeted model experiments imply that this internal coupled variability may be modulated by radiatively forced changes. Our findings suggest that summer WBCE covariability has increased in the historical record but may weaken in response to future reductions in Arctic sea ice under higher radiative forcing.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 8","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146224602","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}
Fanconi anemia (FA) is characterized by bone marrow failure, congenital abnormalities, and cancer predisposition. Mutations in RAD51 paralogs have been identified in FA-like disorders and cancers. Although the role of RAD51 paralogs is well established in homologous recombination (HR)–mediated DNA repair, little is known about their role during replication stress responses. Here, we report that the RAD51C-XRCC3 (CX3) complex of RAD51 paralogs participates in the FA pathway of R-loop tolerance mechanism. CX3 complex suppresses R-loops, transcription-replication collisions (TRCs), and associated genome instability under physiological and replication stress conditions. Mechanistically, the CX3 complex physically interacts with FANCM and facilitates its recruitment to the R-loop sites to promote its resolution. Notably, cells expressing the RAD51C R258H pathological mutant exhibit defective interaction with FANCM and display inefficient R-loop processing. The CX3 complex–mediated R-loop resolution is independent of its fork maintenance function. Collectively, we demonstrate a previously unidentified role of the CX3 complex in preventing R-loop–induced genome instability by regulating FANCM-mediated R-loop resolution.
{"title":"RAD51C-XRCC3 complex regulates FANCM-mediated R-loop resolution to safeguard genome integrity","authors":"Satyaranjan Sahoo, Tarun Nagraj, Debanjali Bhattacharya, Nupur Nagar, Kumar Somyajit, Krishna Mohan Poluri, Ganesh Nagaraju","doi":"10.1126/sciadv.aea5932","DOIUrl":"https://doi.org/10.1126/sciadv.aea5932","url":null,"abstract":"Fanconi anemia (FA) is characterized by bone marrow failure, congenital abnormalities, and cancer predisposition. Mutations in <jats:italic toggle=\"yes\">RAD51</jats:italic> paralogs have been identified in FA-like disorders and cancers. Although the role of RAD51 paralogs is well established in homologous recombination (HR)–mediated DNA repair, little is known about their role during replication stress responses. Here, we report that the RAD51C-XRCC3 (CX3) complex of RAD51 paralogs participates in the FA pathway of R-loop tolerance mechanism. CX3 complex suppresses R-loops, transcription-replication collisions (TRCs), and associated genome instability under physiological and replication stress conditions. Mechanistically, the CX3 complex physically interacts with FANCM and facilitates its recruitment to the R-loop sites to promote its resolution. Notably, cells expressing the RAD51C R258H pathological mutant exhibit defective interaction with FANCM and display inefficient R-loop processing. The CX3 complex–mediated R-loop resolution is independent of its fork maintenance function. Collectively, we demonstrate a previously unidentified role of the CX3 complex in preventing R-loop–induced genome instability by regulating FANCM-mediated R-loop resolution.","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"235 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2026-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146222920","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}
Christopher Douville, Jeeun Parksong, Marco Dal Molin, Sarah Graham, Patricia T. Greipp, Ryan Knudson, Samuel Curtis, Yuxuan Wang, Lisa Dobbyn, Maria Popoli, Janine Ptak, Natalie Silliman, Katharine Romans, Christine A. Iacobuzio-Donahue, Alvin P. Makoohon-Moore, Anne Marie Lennon, Michael Goggins, Ralph H. Hruban, Ashley Kiemen, Chetan Bettegowda, Kenneth W. Kinzler, Nickolas Papadopoulos, Laura D. Wood, Bert Vogelstein
We searched for oncogenes activated by copy number increases using whole-genome sequencing data of 535 pancreatic ductal adenocarcinomas (PDACs). We found that gains of 1q were the second most common gain, occurring in 213 (39.8%) of PDACs. Single-cell analysis via fluorescence in situ hybridization on 33 cancers confirmed these results. A portion of 1q, rather than the entire 1q arm, was gained in 75 (14.0%) PDACs, allowing us to pinpoint two ~3-megabase regions of 1q that were nearly always gained. These two regions contained NCSTN and PSEN2 , genes that code two subunits of the γ-secretase complex. Evaluation of 267 precancerous lesions revealed that extra copies of NCSTN and PSEN2 were common (49%) in noninvasive neoplasms (high-grade pancreatic intraepithelial neoplasms), which are at relatively high risk for progression to PDACs, but uncommon (6%) in low-grade pancreatic intraepithelial neoplasia lesions, which have low malignant potential. We hypothesize that γ-secretase genes are genetically activated oncogenes in the early phases of pancreatic neoplasia.
{"title":"Evidence that extra copies of chromosome 1q play a role in the early phases of pancreatic neoplasia","authors":"Christopher Douville, Jeeun Parksong, Marco Dal Molin, Sarah Graham, Patricia T. Greipp, Ryan Knudson, Samuel Curtis, Yuxuan Wang, Lisa Dobbyn, Maria Popoli, Janine Ptak, Natalie Silliman, Katharine Romans, Christine A. Iacobuzio-Donahue, Alvin P. Makoohon-Moore, Anne Marie Lennon, Michael Goggins, Ralph H. Hruban, Ashley Kiemen, Chetan Bettegowda, Kenneth W. Kinzler, Nickolas Papadopoulos, Laura D. Wood, Bert Vogelstein","doi":"10.1126/sciadv.adx7501","DOIUrl":"https://doi.org/10.1126/sciadv.adx7501","url":null,"abstract":"We searched for oncogenes activated by copy number increases using whole-genome sequencing data of 535 pancreatic ductal adenocarcinomas (PDACs). We found that gains of 1q were the second most common gain, occurring in 213 (39.8%) of PDACs. Single-cell analysis via fluorescence in situ hybridization on 33 cancers confirmed these results. A portion of 1q, rather than the entire 1q arm, was gained in 75 (14.0%) PDACs, allowing us to pinpoint two ~3-megabase regions of 1q that were nearly always gained. These two regions contained <jats:italic toggle=\"yes\">NCSTN</jats:italic> and <jats:italic toggle=\"yes\">PSEN2</jats:italic> , genes that code two subunits of the γ-secretase complex. Evaluation of 267 precancerous lesions revealed that extra copies of <jats:italic toggle=\"yes\">NCSTN</jats:italic> and <jats:italic toggle=\"yes\">PSEN2</jats:italic> were common (49%) in noninvasive neoplasms (high-grade pancreatic intraepithelial neoplasms), which are at relatively high risk for progression to PDACs, but uncommon (6%) in low-grade pancreatic intraepithelial neoplasia lesions, which have low malignant potential. We hypothesize that γ-secretase genes are genetically activated oncogenes in the early phases of pancreatic neoplasia.","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"66 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2026-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146222947","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}
Youngji Joh, Sang-Wook Yeh, Thomas L. Delworth, Zachary M. Labe, Andrew T. Wittenberg, William F. Cooke, Jiale Lou, Young-Gyu Park
Decadal synchronization between the Gulf Stream and Kuroshio currents has recently been reported. Given the large-scale coupled variability of western boundary currents and extensions (WBCEs), further investigation into its seasonality, predictability, and potential future changes is needed. Observations and high-resolution climate simulations reveal distinctive covariance between North Pacific and North Atlantic WBCE sea surface temperatures during boreal summer, possibly linked to preceding Arctic sea-ice variability. Model simulations suggest that cold-season Greenland and Barents Sea ice loss enhances anomalous planetary-scale atmospheric waves and meridional jet shifts, contributing to summertime WBCE temperature anomalies. Although we show that summer WBCE covariability arises from intrinsic variability, future climate projections and targeted model experiments imply that this internal coupled variability may be modulated by radiatively forced changes. Our findings suggest that summer WBCE covariability has increased in the historical record but may weaken in response to future reductions in Arctic sea ice under higher radiative forcing.
{"title":"Evolving synchronization of the Gulf Stream and Kuroshio-Oyashio Extension in a changing climate","authors":"Youngji Joh, Sang-Wook Yeh, Thomas L. Delworth, Zachary M. Labe, Andrew T. Wittenberg, William F. Cooke, Jiale Lou, Young-Gyu Park","doi":"10.1126/sciadv.adx6366","DOIUrl":"https://doi.org/10.1126/sciadv.adx6366","url":null,"abstract":"Decadal synchronization between the Gulf Stream and Kuroshio currents has recently been reported. Given the large-scale coupled variability of western boundary currents and extensions (WBCEs), further investigation into its seasonality, predictability, and potential future changes is needed. Observations and high-resolution climate simulations reveal distinctive covariance between North Pacific and North Atlantic WBCE sea surface temperatures during boreal summer, possibly linked to preceding Arctic sea-ice variability. Model simulations suggest that cold-season Greenland and Barents Sea ice loss enhances anomalous planetary-scale atmospheric waves and meridional jet shifts, contributing to summertime WBCE temperature anomalies. Although we show that summer WBCE covariability arises from intrinsic variability, future climate projections and targeted model experiments imply that this internal coupled variability may be modulated by radiatively forced changes. Our findings suggest that summer WBCE covariability has increased in the historical record but may weaken in response to future reductions in Arctic sea ice under higher radiative forcing.","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"96 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2026-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146222922","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}
Nitric oxide synthase (NOS) is a widely studied multidomain redox enzyme that produces the key signaling molecule and cytotoxic agent nitric oxide (NO) for functions that range from mammalian vasodilation to prokaryotic antibiotic resistance. NOS enzymes from metazoans and cyanobacteria rely on dynamic associations of their oxygenase and coupled diflavin reductase domains that have largely evaded detailed structural characterization. Cryo–electron microscopy studies of a representative dimeric six-domain Synechococcus NOS reveal the architecture of the full-length enzyme, which contains an unusual regulatory C2 domain, and additional nitric oxide dioxygenase (NOD) and pseudoglobin modules. Five distinct structural states depict how pterin binding couples to tight and loose oxygenase conformations and how the Ca 2+ -sensitive C2 domain moves over 85 angstroms to alternatively regulate either the NOS or NOD heme center. The extended carboxyl-terminal tail and its dynamic interactions highlight an added layer of regulation required by multidomain NOSs compared to other diflavin reductases.
{"title":"Structure and dynamics of a multidomain nitric oxide synthase regulated by a C2 domain","authors":"Dhruva Nair, Brian R. Crane","doi":"10.1126/sciadv.aeb4529","DOIUrl":"https://doi.org/10.1126/sciadv.aeb4529","url":null,"abstract":"Nitric oxide synthase (NOS) is a widely studied multidomain redox enzyme that produces the key signaling molecule and cytotoxic agent nitric oxide (NO) for functions that range from mammalian vasodilation to prokaryotic antibiotic resistance. NOS enzymes from metazoans and cyanobacteria rely on dynamic associations of their oxygenase and coupled diflavin reductase domains that have largely evaded detailed structural characterization. Cryo–electron microscopy studies of a representative dimeric six-domain <jats:italic toggle=\"yes\">Synechococcus</jats:italic> NOS reveal the architecture of the full-length enzyme, which contains an unusual regulatory C2 domain, and additional nitric oxide dioxygenase (NOD) and pseudoglobin modules. Five distinct structural states depict how pterin binding couples to tight and loose oxygenase conformations and how the Ca <jats:sup>2+</jats:sup> -sensitive C2 domain moves over 85 angstroms to alternatively regulate either the NOS or NOD heme center. The extended carboxyl-terminal tail and its dynamic interactions highlight an added layer of regulation required by multidomain NOSs compared to other diflavin reductases.","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"20 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2026-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146222959","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}
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