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EGFR targeting PhosTACs as a dual inhibitory approach reveals differential downstream signaling Sci. Adv. (IF 13.6) Pub Date : 2024-03-27 Zhenyi Hu, Po-Han Chen, Wenxue Li, Mackenzie Krone, Sijin Zheng, Jacques Saarbach, Ines Urquizo Velasco, John Hines, Yansheng Liu, Craig M. Crews
We recently developed a heterobifunctional approach [phosphorylation targeting chimeras (PhosTACs)] to achieve the targeted protein dephosphorylation (TPDephos). Here, we envisioned combining the inhibitory effects of receptor tyrosine kinase inhibitors (RTKIs) and the active dephosphorylation by phosphatases to achieve dual inhibition of kinases. We report an example of tyrosine phosphatase–based
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The Sun’s differential rotation is controlled by high-latitude baroclinically unstable inertial modes Sci. Adv. (IF 13.6) Pub Date : 2024-03-27 Yuto Bekki, Robert H. Cameron, Laurent Gizon
Rapidly rotating fluids have a rotation profile that depends only on the distance from the rotation axis, in accordance with the Taylor-Proudman theorem. Although the Sun was expected to be such a body, helioseismology showed that the rotation rate in the convection zone is closer to constant on radii. It has been postulated that this deviation is due to the poles being warmer than the equator by a
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A case for a binary black hole system revealed via quasi-periodic outflows Sci. Adv. (IF 13.6) Pub Date : 2024-03-27 Dheeraj R. Pasham, Francesco Tombesi, Petra Suková, Michal Zajaček, Suvendu Rakshit, Eric Coughlin, Peter Kosec, Vladimír Karas, Megan Masterson, Andrew Mummery, Thomas W.-S. Holoien, Muryel Guolo, Jason Hinkle, Bart Ripperda, Vojtěch Witzany, Ben Shappee, Erin Kara, Assaf Horesh, Sjoert van Velzen, Itai Sfaradi, David Kaplan, Noam Burger, Tara Murphy, Ronald Remillard, James F. Steiner, Thomas Wevers
Binaries containing a compact object orbiting a supermassive black hole are thought to be precursors of gravitational wave events, but their identification has been extremely challenging. Here, we report quasi-periodic variability in x-ray absorption, which we interpret as quasi-periodic outflows (QPOuts) from a previously low-luminosity active galactic nucleus after an outburst, likely caused by a
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Atom-by-atom imaging of moiré transformations in 2D transition metal dichalcogenides Sci. Adv. (IF 13.6) Pub Date : 2024-03-27 Yichao Zhang, Ji-Hwan Baek, Chia-Hao Lee, Yeonjoon Jung, Seong Chul Hong, Gillian Nolan, Kenji Watanabe, Takashi Taniguchi, Gwan-Hyoung Lee, Pinshane Y. Huang
Understanding the atomic-scale mechanisms that govern the structure of interfaces is critical across materials systems but particularly so for two-dimensional (2D) moiré materials. Here, we image, atom-by-atom, the thermally induced structural evolution of twisted bilayer transition metal dichalcogenides using in situ transmission electron microscopy. We observe low-temperature, local conversion of
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CRIF1 deficiency induces FOXP3LOW inflammatory non-suppressive regulatory T cells, thereby promoting antitumor immunity Sci. Adv. (IF 13.6) Pub Date : 2024-03-27 Sangsin Lee, Seung Geun Song, Gwanghun Kim, Sehui Kim, Hyun Jung Yoo, Jaemoon Koh, Ye-Ji Kim, Jingwen Tian, Eunji Cho, Youn Soo Choi, Sunghoe Chang, Hyun Mu Shin, Kyeong Cheon Jung, Ji Hoon Kim, Tae Min Kim, Yoon Kyung Jeon, Hye Young Kim, Minho Shong, Ji Hyung Kim, Doo Hyun Chung
Recently identified human FOXP3lowCD45RA− inflammatory non-suppressive (INS) cells produce proinflammatory cytokines, exhibit reduced suppressiveness, and promote antitumor immunity unlike conventional regulatory T cells (Tregs). In spite of their implication in tumors, the mechanism for generation of FOXP3lowCD45RA− INS cells in vivo is unclear. We showed that the FOXP3lowCD45RA− cells in human tumors
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Lupus susceptibility gene Pbx1 controls the development, stability, and function of regulatory T cells via Rtkn2 expression Sci. Adv. (IF 13.6) Pub Date : 2024-03-27 Seung-Chul Choi, Yuk Pheel Park, Tracoyia Roach, Damian Jimenez, Amanda Fisher, Mojgan Zadeh, Longhuan Ma, Eric S. Sobel, Yong Ge, Mansour Mohamadzadeh, Laurence Morel
The maintenance of regulatory T (Treg) cells critically prevents autoimmunity. Pre–B cell leukemia transcription factor 1 (Pbx1) variants are associated with lupus susceptibility, particularly through the expression of a dominant negative isoform Pbx1-d in CD4+ T cells. Pbx1-d overexpression impaired Treg cell homeostasis and promoted inflammatory CD4+ T cells. Here, we showed a high expression of
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Select EZH2 inhibitors enhance viral mimicry effects of DNMT inhibition through a mechanism involving NFAT:AP-1 signaling Sci. Adv. (IF 13.6) Pub Date : 2024-03-27 Alison A. Chomiak, Rochelle L. Tiedemann, Yanqing Liu, Xiangqian Kong, Ying Cui, Ashley K. Wiseman, Kate E. Thurlow, Evan M. Cornett, Michael J. Topper, Stephen B. Baylin, Scott B. Rothbart
DNA methyltransferase inhibitor (DNMTi) efficacy in solid tumors is limited. Colon cancer cells exposed to DNMTi accumulate lysine-27 trimethylation on histone H3 (H3K27me3). We propose this Enhancer of Zeste Homolog 2 (EZH2)–dependent repressive modification limits DNMTi efficacy. Here, we show that low-dose DNMTi treatment sensitizes colon cancer cells to select EZH2 inhibitors (EZH2is). Integrative
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TisB protein is the single molecular determinant underlying multiple downstream effects of ofloxacin in Escherichia coli Sci. Adv. (IF 13.6) Pub Date : 2024-03-27 Julien Cayron, Thierry Oms, Tatjana Schlechtweg, Safia Zedek, Laurence Van Melderen
Bactericidal antibiotics can cause metabolic perturbations that contribute to antibiotic-induced lethality. The molecular mechanism underlying these downstream effects remains unknown. Here, we show that ofloxacin, a fluoroquinolone that poisons DNA gyrase, induces a cascade of metabolic changes that are dependent on an active SOS response. We identified the SOS-regulated TisB protein as the unique
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Learning the sound inventory of a complex vocal skill via an intrinsic reward Sci. Adv. (IF 13.6) Pub Date : 2024-03-27 Hazem Toutounji, Anja T. Zai, Ofer Tchernichovski, Richard H. R. Hahnloser, Dina Lipkind
Reinforcement learning (RL) is thought to underlie the acquisition of vocal skills like birdsong and speech, where sounding like one’s “tutor” is rewarding. However, what RL strategy generates the rich sound inventories for song or speech? We find that the standard actor-critic model of birdsong learning fails to explain juvenile zebra finches’ efficient learning of multiple syllables. However, when
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Iterative assay for transposase-accessible chromatin by sequencing to isolate functionally relevant neuronal subtypes Sci. Adv. (IF 13.6) Pub Date : 2024-03-27 Collin B. Merrill, Iris Titos, Miguel A. Pabon, Austin B. Montgomery, Aylin R. Rodan, Adrian Rothenfluh
The Drosophila brain contains tens of thousands of distinct cell types. Thousands of different transgenic lines reproducibly target specific neuron subsets, yet most still express in several cell types. Furthermore, most lines were developed without a priori knowledge of where the transgenes would be expressed. To aid in the development of cell type–specific tools for neuronal identification and manipulation
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Discovery and characterization of noncanonical E2-conjugating enzymes Sci. Adv. (IF 13.6) Pub Date : 2024-03-27 Syed Arif Abdul Rehman, Chiara Cazzaniga, Elena Di Nisio, Odetta Antico, Axel Knebel, Clare Johnson, Alp T. Şahin, Peter E. G. F. Ibrahim, Frederic Lamoliatte, Rodolfo Negri, MK Miratul Muqit, Virginia De Cesare
E2-conjugating enzymes (E2s) play a central role in the enzymatic cascade that leads to the attachment of ubiquitin to a substrate. This process, termed ubiquitylation, is required to maintain cellular homeostasis and affects almost all cellular process. By interacting with multiple E3 ligases, E2s dictate the ubiquitylation landscape within the cell. Since its discovery, ubiquitylation has been regarded
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Multiple parallel cell lineages in the developing mammalian cerebral cortex Sci. Adv. (IF 13.6) Pub Date : 2024-03-27 Lucia Del-Valle-Anton, Salma Amin, Daniela Cimino, Florian Neuhaus, Elena Dvoretskova, Virginia Fernández, Yigit K. Babal, Cristina Garcia-Frigola, Anna Prieto-Colomina, Raquel Murcia-Ramón, Yuki Nomura, Adrián Cárdenas, Chao Feng, Juan Antonio Moreno-Bravo, Magdalena Götz, Christian Mayer, Víctor Borrell
Cortical neurogenesis follows a simple lineage: apical radial glia cells (RGCs) generate basal progenitors, and these produce neurons. How this occurs in species with expanded germinal zones and a folded cortex, such as human, remains unclear. We used single-cell RNA sequencing from individual cortical germinal zones in ferret and barcoded lineage tracking to determine the molecular diversity of progenitor
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Virtual formalin-fixed and paraffin-embedded staining of fresh brain tissue via stimulated Raman CycleGAN model Sci. Adv. (IF 13.6) Pub Date : 2024-03-27 Zhijie Liu, Lingchao Chen, Haixia Cheng, Jianpeng Ao, Ji Xiong, Xing Liu, Yaxin Chen, Ying Mao, Minbiao Ji
Intraoperative histology is essential for surgical guidance and decision-making. However, frozen-sectioned hematoxylin and eosin (H&E) staining suffers from degraded accuracy, whereas the gold-standard formalin-fixed and paraffin-embedded (FFPE) H&E is too lengthy for intraoperative use. Stimulated Raman scattering (SRS) microscopy has shown rapid histology of brain tissue with lipid/protein contrast
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Glutamine antagonist DRP-104 suppresses tumor growth and enhances response to checkpoint blockade in KEAP1 mutant lung cancer Sci. Adv. (IF 13.6) Pub Date : 2024-03-27 Ray Pillai, Sarah E. LeBoeuf, Yuan Hao, Connie New, Jenna L. E. Blum, Ali Rashidfarrokhi, Shih Ming Huang, Christian Bahamon, Warren L. Wu, Burcu Karadal-Ferrena, Alberto Herrera, Ellie Ivanova, Michael Cross, Jozef P. Bossowski, Hongyu Ding, Makiko Hayashi, Sahith Rajalingam, Triantafyllia Karakousi, Volkan I. Sayin, Kamal M. Khanna, Kwok-Kin Wong, Robert Wild, Aristotelis Tsirigos, John T. Poirier
Loss-of-function mutations in KEAP1 frequently occur in lung cancer and are associated with poor prognosis and resistance to standard of care treatment, highlighting the need for the development of targeted therapies. We previously showed that KEAP1 mutant tumors consume glutamine to support the metabolic rewiring associated with NRF2-dependent antioxidant production. Here, using preclinical patient-derived
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A different interpretation of the DIANA fMRI signal Sci. Adv. (IF 13.6) Pub Date : 2024-03-27 Valerie Doan Phi Van, Sajal Sen, Alan Jasanoff
Direct detection of neural activity by functional magnetic resonance imaging (fMRI) has been a longstanding goal in neuroscience. A recent study argued that it is possible to detect neuroelectrical potentials using a specialized fMRI scanning approach the authors termed “direct imaging of neuronal activity” (DIANA). We implemented DIANA in anesthetized rats and measured responses to somatosensory stimulation
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No replication of direct neuronal activity–related (DIANA) fMRI in anesthetized mice Sci. Adv. (IF 13.6) Pub Date : 2024-03-27 Sang-Han Choi, Geun Ho Im, Sangcheon Choi, Xin Yu, Peter A. Bandettini, Ravi S. Menon, Seong-Gi Kim
Direct imaging of neuronal activity (DIANA) by functional magnetic resonance imaging (fMRI) could be a revolutionary approach for advancing systems neuroscience research. To independently replicate this observation, we performed fMRI experiments in anesthetized mice. The blood oxygenation level–dependent (BOLD) response to whisker stimulation was reliably detected in the primary barrel cortex before
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Surgical tumor–derived nanoplatform targets tumor-associated macrophage for personalized postsurgical cancer immunotherapy Sci. Adv. (IF 13.6) Pub Date : 2024-03-27 Gongxi Qiao, Shenglin Li, Xumin Pan, Ping Xie, Ruixi Peng, Xiangrong Huang, Mengyun He, Jianhui Jiang, Xia Chu
Directly activating CD8+ T cells within the tumor through antigen-presenting cells (APCs) hold promise for tumor elimination. However, M2-like tumor-associated macrophages (TAMs), the most abundant APCs in tumors, hinder CD8+ T cell activation due to inefficient antigen cross-presentation. Here, we demonstrated a personalized nanotherapeutic platform using surgical tumor–derived galactose ligand–modified
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Activation of endogenous retroviruses and induction of viral mimicry by MEK1/2 inhibition in pancreatic cancer Sci. Adv. (IF 13.6) Pub Date : 2024-03-27 Alice Cortesi, Francesco Gandolfi, Fabiana Arco, Pierluigi Di Chiaro, Emanuele Valli, Sara Polletti, Roberta Noberini, Francesco Gualdrini, Sergio Attanasio, Francesca Citron, I-lin Ho, Rutvi Shah, Er-Yen Yen, Mara Cetty Spinella, Simona Ronzoni, Simona Rodighiero, Nico Mitro, Tiziana Bonaldi, Serena Ghisletti, Silvia Monticelli, Andrea Viale, Giuseppe Riccardo Diaferia, Gioacchino Natoli
While pancreatic ductal adenocarcinomas (PDACs) are addicted to KRAS-activating mutations, inhibitors of downstream KRAS effectors, such as the MEK1/2 kinase inhibitor trametinib, are devoid of therapeutic effects. However, the extensive rewiring of regulatory circuits driven by the attenuation of the KRAS pathway may induce vulnerabilities of therapeutic relevance. An in-depth molecular analysis of
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Bond-length dependence of attosecond ionization delays in O2 arising from electron correlation to a shape resonance Sci. Adv. (IF 13.6) Pub Date : 2024-03-27 Daniel Hammerland, Thomas Berglitsch, Pengju Zhang, Tran Trung Luu, Kiyoshi Ueda, Robert R. Lucchese, Hans Jakob Wörner
We experimentally and theoretically demonstrate that electron correlation can cause the bond-length sensitivity of a shape resonance to induce an unexpected vibrational state–dependent ionization delay in a nonresonant channel. This discovery was enabled by a high-resolution attosecond-interferometry experiment based on a 400-nm driving and dressing wavelength. The short-wavelength driver results in
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Generation of entangled waveguided photon pairs by free electrons Sci. Adv. (IF 13.6) Pub Date : 2024-03-22 Theis P. Rasmussen, Álvaro Rodríguez Echarri, Joel D. Cox, F. Javier García de Abajo
Entangled photons are a key resource in quantum technologies. While intense laser light propagating in nonlinear crystals is conventionally used to generate entangled photons, such schemes have low efficiency due to the weak nonlinear response of known materials and losses associated with in/out photon coupling. Here, we show how to generate entangled polariton pairs directly within optical waveguides
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TisB protein is the single molecular determinant underlying multiple downstream effects of ofloxacin in Escherichia coli Sci. Adv. (IF 13.6) Pub Date : 2024-03-27 Julien Cayron, Thierry Oms, Tatjana Schlechtweg, Safia Zedek, Laurence Van Melderen
Bactericidal antibiotics can cause metabolic perturbations that contribute to antibiotic-induced lethality. The molecular mechanism underlying these downstream effects remains unknown. Here, we show that ofloxacin, a fluoroquinolone that poisons DNA gyrase, induces a cascade of metabolic changes that are dependent on an active SOS response. We identified the SOS-regulated TisB protein as the unique
-
Learning the sound inventory of a complex vocal skill via an intrinsic reward Sci. Adv. (IF 13.6) Pub Date : 2024-03-27 Hazem Toutounji, Anja T. Zai, Ofer Tchernichovski, Richard H. R. Hahnloser, Dina Lipkind
Reinforcement learning (RL) is thought to underlie the acquisition of vocal skills like birdsong and speech, where sounding like one’s “tutor” is rewarding. However, what RL strategy generates the rich sound inventories for song or speech? We find that the standard actor-critic model of birdsong learning fails to explain juvenile zebra finches’ efficient learning of multiple syllables. However, when
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Cardiac tissue model of immune-induced dysfunction reveals the role of free mitochondrial DNA and the therapeutic effects of exosomes Sci. Adv. (IF 13.6) Pub Date : 2024-03-27 Rick Xing Ze Lu, Naimeh Rafatian, Yimu Zhao, Karl T. Wagner, Erika L. Beroncal, Bo Li, Carol Lee, Jingan Chen, Eryn Churcher, Daniel Vosoughi, Chuan Liu, Ying Wang, Andrew Baker, Uriel Trahtemberg, Bowen Li, Agostino Pierro, Ana C. Andreazza, Claudia C. dos Santos, Milica Radisic
Despite tremendous progress in the development of mature heart-on-a-chip models, human cell–based models of myocardial inflammation are lacking. Here, we bioengineered a vascularized heart-on-a-chip with circulating immune cells to model severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–induced acute myocarditis. We observed hallmarks of coronavirus disease (COVID-19)–induced myocardial
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A different interpretation of the DIANA fMRI signal Sci. Adv. (IF 13.6) Pub Date : 2024-03-27 Valerie Doan Phi Van, Sajal Sen, Alan Jasanoff
Direct detection of neural activity by functional magnetic resonance imaging (fMRI) has been a longstanding goal in neuroscience. A recent study argued that it is possible to detect neuroelectrical potentials using a specialized fMRI scanning approach the authors termed “direct imaging of neuronal activity” (DIANA). We implemented DIANA in anesthetized rats and measured responses to somatosensory stimulation
-
Glutamine antagonist DRP-104 suppresses tumor growth and enhances response to checkpoint blockade in KEAP1 mutant lung cancer Sci. Adv. (IF 13.6) Pub Date : 2024-03-27 Ray Pillai, Sarah E. LeBoeuf, Yuan Hao, Connie New, Jenna L. E. Blum, Ali Rashidfarrokhi, Shih Ming Huang, Christian Bahamon, Warren L. Wu, Burcu Karadal-Ferrena, Alberto Herrera, Ellie Ivanova, Michael Cross, Jozef P. Bossowski, Hongyu Ding, Makiko Hayashi, Sahith Rajalingam, Triantafyllia Karakousi, Volkan I. Sayin, Kamal M. Khanna, Kwok-Kin Wong, Robert Wild, Aristotelis Tsirigos, John T. Poirier
Loss-of-function mutations in KEAP1 frequently occur in lung cancer and are associated with poor prognosis and resistance to standard of care treatment, highlighting the need for the development of targeted therapies. We previously showed that KEAP1 mutant tumors consume glutamine to support the metabolic rewiring associated with NRF2-dependent antioxidant production. Here, using preclinical patient-derived
-
Bond-length dependence of attosecond ionization delays in O 2 arising from electron correlation to a shape resonance Sci. Adv. (IF 13.6) Pub Date : 2024-03-27 Daniel Hammerland, Thomas Berglitsch, Pengju Zhang, Tran Trung Luu, Kiyoshi Ueda, Robert R. Lucchese, Hans Jakob Wörner
We experimentally and theoretically demonstrate that electron correlation can cause the bond-length sensitivity of a shape resonance to induce an unexpected vibrational state–dependent ionization delay in a nonresonant channel. This discovery was enabled by a high-resolution attosecond-interferometry experiment based on a 400-nm driving and dressing wavelength. The short-wavelength driver results in
-
Different components of cognitive-behavioral therapy affect specific cognitive mechanisms Sci. Adv. (IF 13.6) Pub Date : 2024-03-27 Agnes Norbury, Tobias U. Hauser, Stephen M. Fleming, Raymond J. Dolan, Quentin J. M. Huys
Psychological therapies are among the most effective treatments for common mental health problems—however, we still know relatively little about how exactly they improve symptoms. Here, we demonstrate the power of combining theory with computational methods to parse effects of different components of cognitive-behavioral therapies onto underlying mechanisms. Specifically, we present data from a series
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Virtual formalin-fixed and paraffin-embedded staining of fresh brain tissue via stimulated Raman CycleGAN model Sci. Adv. (IF 13.6) Pub Date : 2024-03-27 Zhijie Liu, Lingchao Chen, Haixia Cheng, Jianpeng Ao, Ji Xiong, Xing Liu, Yaxin Chen, Ying Mao, Minbiao Ji
Intraoperative histology is essential for surgical guidance and decision-making. However, frozen-sectioned hematoxylin and eosin (H&E) staining suffers from degraded accuracy, whereas the gold-standard formalin-fixed and paraffin-embedded (FFPE) H&E is too lengthy for intraoperative use. Stimulated Raman scattering (SRS) microscopy has shown rapid histology of brain tissue with lipid/protein contrast
-
Activation of endogenous retroviruses and induction of viral mimicry by MEK1/2 inhibition in pancreatic cancer Sci. Adv. (IF 13.6) Pub Date : 2024-03-27 Alice Cortesi, Francesco Gandolfi, Fabiana Arco, Pierluigi Di Chiaro, Emanuele Valli, Sara Polletti, Roberta Noberini, Francesco Gualdrini, Sergio Attanasio, Francesca Citron, I-lin Ho, Rutvi Shah, Er-Yen Yen, Mara Cetty Spinella, Simona Ronzoni, Simona Rodighiero, Nico Mitro, Tiziana Bonaldi, Serena Ghisletti, Silvia Monticelli, Andrea Viale, Giuseppe Riccardo Diaferia, Gioacchino Natoli
While pancreatic ductal adenocarcinomas (PDACs) are addicted to KRAS-activating mutations, inhibitors of downstream KRAS effectors, such as the MEK1/2 kinase inhibitor trametinib, are devoid of therapeutic effects. However, the extensive rewiring of regulatory circuits driven by the attenuation of the KRAS pathway may induce vulnerabilities of therapeutic relevance. An in-depth molecular analysis of
-
Surgical tumor–derived nanoplatform targets tumor-associated macrophage for personalized postsurgical cancer immunotherapy Sci. Adv. (IF 13.6) Pub Date : 2024-03-27 Gongxi Qiao, Shenglin Li, Xumin Pan, Ping Xie, Ruixi Peng, Xiangrong Huang, Mengyun He, Jianhui Jiang, Xia Chu
Directly activating CD8 + T cells within the tumor through antigen-presenting cells (APCs) hold promise for tumor elimination. However, M2-like tumor-associated macrophages (TAMs), the most abundant APCs in tumors, hinder CD8 + T cell activation due to inefficient antigen cross-presentation. Here, we demonstrated a personalized nanotherapeutic platform using surgical tumor–derived galactose ligand–modified
-
CRIF1 deficiency induces FOXP3 LOW inflammatory non-suppressive regulatory T cells, thereby promoting antitumor immunity Sci. Adv. (IF 13.6) Pub Date : 2024-03-27 Sangsin Lee, Seung Geun Song, Gwanghun Kim, Sehui Kim, Hyun Jung Yoo, Jaemoon Koh, Ye-Ji Kim, Jingwen Tian, Eunji Cho, Youn Soo Choi, Sunghoe Chang, Hyun Mu Shin, Kyeong Cheon Jung, Ji Hoon Kim, Tae Min Kim, Yoon Kyung Jeon, Hye Young Kim, Minho Shong, Ji Hyung Kim, Doo Hyun Chung
Recently identified human FOXP3 low CD45RA − inflammatory non-suppressive (INS) cells produce proinflammatory cytokines, exhibit reduced suppressiveness, and promote antitumor immunity unlike conventional regulatory T cells (T regs ). In spite of their implication in tumors, the mechanism for generation of FOXP3 low CD45RA − INS cells in vivo is unclear. We showed that the FOXP3 low CD45RA − cells
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Sensitive detection of multiple blood biomarkers via immunomagnetic exosomal PCR for the diagnosis of Alzheimer’s disease Sci. Adv. (IF 13.6) Pub Date : 2024-03-27 Shun Hu, Liding Zhang, Ying Su, Xiaohan Liang, Jie Yang, Qingming Luo, Haiming Luo
Blood exosomes are emerging as potential biomarkers for diagnosing brain diseases such as Alzheimer’s disease (AD). There is currently a lack of an ultrasensitive technology for identifying core AD biomarkers in blood exosomes to optimize the utility of biomarkers in clinical practice. Here, an immunomagnetic exosomal polymerase chain reaction (iMEP) platform was developed using DNA-conjugated antibodies
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Compounding effects in flood drivers challenge estimates of extreme river floods Sci. Adv. (IF 13.6) Pub Date : 2024-03-27 Shijie Jiang, Larisa Tarasova, Guo Yu, Jakob Zscheischler
Estimating river flood risks under climate change is challenging, largely due to the interacting and combined influences of various flood-generating drivers. However, a more detailed quantitative analysis of such compounding effects and the implications of their interplay remains underexplored on a large scale. Here, we use explainable machine learning to disentangle compounding effects between drivers
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The Sun’s differential rotation is controlled by high-latitude baroclinically unstable inertial modes Sci. Adv. (IF 13.6) Pub Date : 2024-03-27 Yuto Bekki, Robert H. Cameron, Laurent Gizon
Rapidly rotating fluids have a rotation profile that depends only on the distance from the rotation axis, in accordance with the Taylor-Proudman theorem. Although the Sun was expected to be such a body, helioseismology showed that the rotation rate in the convection zone is closer to constant on radii. It has been postulated that this deviation is due to the poles being warmer than the equator by a
-
Atom-by-atom imaging of moiré transformations in 2D transition metal dichalcogenides Sci. Adv. (IF 13.6) Pub Date : 2024-03-27 Yichao Zhang, Ji-Hwan Baek, Chia-Hao Lee, Yeonjoon Jung, Seong Chul Hong, Gillian Nolan, Kenji Watanabe, Takashi Taniguchi, Gwan-Hyoung Lee, Pinshane Y. Huang
Understanding the atomic-scale mechanisms that govern the structure of interfaces is critical across materials systems but particularly so for two-dimensional (2D) moiré materials. Here, we image, atom-by-atom, the thermally induced structural evolution of twisted bilayer transition metal dichalcogenides using in situ transmission electron microscopy. We observe low-temperature, local conversion of
-
Discovery and characterization of noncanonical E2-conjugating enzymes Sci. Adv. (IF 13.6) Pub Date : 2024-03-27 Syed Arif Abdul Rehman, Chiara Cazzaniga, Elena Di Nisio, Odetta Antico, Axel Knebel, Clare Johnson, Alp T. Şahin, Peter E. G. F. Ibrahim, Frederic Lamoliatte, Rodolfo Negri, MK Miratul Muqit, Virginia De Cesare
E2-conjugating enzymes (E2s) play a central role in the enzymatic cascade that leads to the attachment of ubiquitin to a substrate. This process, termed ubiquitylation, is required to maintain cellular homeostasis and affects almost all cellular process. By interacting with multiple E3 ligases, E2s dictate the ubiquitylation landscape within the cell. Since its discovery, ubiquitylation has been regarded
-
Iterative assay for transposase-accessible chromatin by sequencing to isolate functionally relevant neuronal subtypes Sci. Adv. (IF 13.6) Pub Date : 2024-03-27 Collin B. Merrill, Iris Titos, Miguel A. Pabon, Austin B. Montgomery, Aylin R. Rodan, Adrian Rothenfluh
The Drosophila brain contains tens of thousands of distinct cell types. Thousands of different transgenic lines reproducibly target specific neuron subsets, yet most still express in several cell types. Furthermore, most lines were developed without a priori knowledge of where the transgenes would be expressed. To aid in the development of cell type–specific tools for neuronal identification and manipulation
-
Lupus susceptibility gene Pbx1 controls the development, stability, and function of regulatory T cells via Rtkn2 expression Sci. Adv. (IF 13.6) Pub Date : 2024-03-27 Seung-Chul Choi, Yuk Pheel Park, Tracoyia Roach, Damian Jimenez, Amanda Fisher, Mojgan Zadeh, Longhuan Ma, Eric S. Sobel, Yong Ge, Mansour Mohamadzadeh, Laurence Morel
The maintenance of regulatory T (T reg ) cells critically prevents autoimmunity. Pre–B cell leukemia transcription factor 1 ( Pbx1 ) variants are associated with lupus susceptibility, particularly through the expression of a dominant negative isoform Pbx1-d in CD4 + T cells. Pbx1-d overexpression impaired T reg cell homeostasis and promoted inflammatory CD4 + T cells. Here, we showed a high expression
-
A case for a binary black hole system revealed via quasi-periodic outflows Sci. Adv. (IF 13.6) Pub Date : 2024-03-27 Dheeraj R. Pasham, Francesco Tombesi, Petra Suková, Michal Zajaček, Suvendu Rakshit, Eric Coughlin, Peter Kosec, Vladimír Karas, Megan Masterson, Andrew Mummery, Thomas W.-S. Holoien, Muryel Guolo, Jason Hinkle, Bart Ripperda, Vojtěch Witzany, Ben Shappee, Erin Kara, Assaf Horesh, Sjoert van Velzen, Itai Sfaradi, David Kaplan, Noam Burger, Tara Murphy, Ronald Remillard, James F. Steiner, Thomas Wevers
Binaries containing a compact object orbiting a supermassive black hole are thought to be precursors of gravitational wave events, but their identification has been extremely challenging. Here, we report quasi-periodic variability in x-ray absorption, which we interpret as quasi-periodic outflows (QPOuts) from a previously low-luminosity active galactic nucleus after an outburst, likely caused by a
-
Select EZH2 inhibitors enhance viral mimicry effects of DNMT inhibition through a mechanism involving NFAT:AP-1 signaling Sci. Adv. (IF 13.6) Pub Date : 2024-03-27 Alison A. Chomiak, Rochelle L. Tiedemann, Yanqing Liu, Xiangqian Kong, Ying Cui, Ashley K. Wiseman, Kate E. Thurlow, Evan M. Cornett, Michael J. Topper, Stephen B. Baylin, Scott B. Rothbart
DNA methyltransferase inhibitor (DNMTi) efficacy in solid tumors is limited. Colon cancer cells exposed to DNMTi accumulate lysine-27 trimethylation on histone H3 (H3K27me3). We propose this Enhancer of Zeste Homolog 2 (EZH2)–dependent repressive modification limits DNMTi efficacy. Here, we show that low-dose DNMTi treatment sensitizes colon cancer cells to select EZH2 inhibitors (EZH2is). Integrative
-
EGFR targeting PhosTACs as a dual inhibitory approach reveals differential downstream signaling Sci. Adv. (IF 13.6) Pub Date : 2024-03-27 Zhenyi Hu, Po-Han Chen, Wenxue Li, Mackenzie Krone, Sijin Zheng, Jacques Saarbach, Ines Urquizo Velasco, John Hines, Yansheng Liu, Craig M. Crews
We recently developed a heterobifunctional approach [phosphorylation targeting chimeras (PhosTACs)] to achieve the targeted protein dephosphorylation (TPDephos). Here, we envisioned combining the inhibitory effects of receptor tyrosine kinase inhibitors (RTKIs) and the active dephosphorylation by phosphatases to achieve dual inhibition of kinases. We report an example of tyrosine phosphatase–based
-
Food matters: Dietary shifts increase the feasibility of 1.5°C pathways in line with the Paris Agreement Sci. Adv. (IF 13.6) Pub Date : 2024-03-27 Florian Humpenöder, Alexander Popp, Leon Merfort, Gunnar Luderer, Isabelle Weindl, Benjamin Leon Bodirsky, Miodrag Stevanović, David Klein, Renato Rodrigues, Nico Bauer, Jan Philipp Dietrich, Hermann Lotze-Campen, Johan Rockström
A transition to healthy diets such as the EAT-Lancet Planetary Health Diet could considerably reduce greenhouse gas (GHG) emissions. However, the specific contributions of dietary shifts for the feasibility of 1.5°C pathways remain unclear. Here, we use the open-source integrated assessment modeling (IAM) framework REMIND-MAgPIE to compare 1.5°C pathways with and without dietary shifts. We find that
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Multiple parallel cell lineages in the developing mammalian cerebral cortex Sci. Adv. (IF 13.6) Pub Date : 2024-03-27 Lucia Del-Valle-Anton, Salma Amin, Daniela Cimino, Florian Neuhaus, Elena Dvoretskova, Virginia Fernández, Yigit K. Babal, Cristina Garcia-Frigola, Anna Prieto-Colomina, Raquel Murcia-Ramón, Yuki Nomura, Adrián Cárdenas, Chao Feng, Juan Antonio Moreno-Bravo, Magdalena Götz, Christian Mayer, Víctor Borrell
Cortical neurogenesis follows a simple lineage: apical radial glia cells (RGCs) generate basal progenitors, and these produce neurons. How this occurs in species with expanded germinal zones and a folded cortex, such as human, remains unclear. We used single-cell RNA sequencing from individual cortical germinal zones in ferret and barcoded lineage tracking to determine the molecular diversity of progenitor
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No replication of direct neuronal activity–related (DIANA) fMRI in anesthetized mice Sci. Adv. (IF 13.6) Pub Date : 2024-03-27 Sang-Han Choi, Geun Ho Im, Sangcheon Choi, Xin Yu, Peter A. Bandettini, Ravi S. Menon, Seong-Gi Kim
Direct imaging of neuronal activity (DIANA) by functional magnetic resonance imaging (fMRI) could be a revolutionary approach for advancing systems neuroscience research. To independently replicate this observation, we performed fMRI experiments in anesthetized mice. The blood oxygenation level–dependent (BOLD) response to whisker stimulation was reliably detected in the primary barrel cortex before
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Glutamine antagonists may KEAP lung cancer in check Sci. Adv. (IF 13.6) Pub Date : 2024-03-27 Eliot B. Blatt, Ralph J. DeBerardinis
The glutamine antagonist DRP-104 blocks purine synthesis and combines with checkpoint inhibitors to promote antitumor immunity in KEAP1/NRF2-mutant lung cancers.
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Changes in an enzyme ensemble during catalysis observed by high-resolution XFEL crystallography Sci. Adv. (IF 13.6) Pub Date : 2024-03-27 Nathan Smith, Medhanjali Dasgupta, David C. Wych, Cole Dolamore, Raymond G. Sierra, Stella Lisova, Darya Marchany-Rivera, Aina E. Cohen, Sébastien Boutet, Mark S. Hunter, Christopher Kupitz, Frédéric Poitevin, Frank R. Moss, David W. Mittan-Moreau, Aaron S. Brewster, Nicholas K. Sauter, Iris D. Young, Alexander M. Wolff, Virendra K. Tiwari, Nivesh Kumar, David B. Berkowitz, Ryan G. Hadt, Michael C
Enzymes populate ensembles of structures necessary for catalysis that are difficult to experimentally characterize. We use time-resolved mix-and-inject serial crystallography at an x-ray free electron laser to observe catalysis in a designed mutant isocyanide hydratase (ICH) enzyme that enhances sampling of important minor conformations. The active site exists in a mixture of conformations, and formation
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Aligned carbon nanotube–based electronics on glass wafer Sci. Adv. (IF 13.6) Pub Date : 2024-03-22 Xiaohan Cheng, Zipeng Pan, Chenwei Fan, Zhichen Wu, Li Ding, Lian-mao Peng
Carbon nanotubes (CNTs), due to excellent electronic properties, are emerging as a promising semiconductor for diverse electronic applications with superiority over silicon. However, until now, the supposed superiority of CNTs by “head-to-head” comparison within a well-defined voltage range remains unrealized. Here, we report aligned CNT (ACNT)–based electronics on a glass wafer and successfully develop
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Incipient carbonate melting drives metal and sulfur mobilization in the mantle Sci. Adv. (IF 13.6) Pub Date : 2024-03-22 Isra S. Ezad, Martin Saunders, Svyatoslav S. Shcheka, Marco L. Fiorentini, Lauren R. Gorojovsky, Michael W. Förster, Stephen F. Foley
We present results from high-pressure, high-temperature experiments that generate incipient carbonate melts at mantle conditions (~90 kilometers depth and temperatures between 750° and 1050°C). We show that these primitive carbonate melts can sequester sulfur in its oxidized form of sulfate, as well as base and precious metals from mantle lithologies of peridotite and pyroxenite. It is proposed that
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Isotopic biographies reveal horse rearing and trading networks in medieval London Sci. Adv. (IF 13.6) Pub Date : 2024-03-22 Alexander J. E. Pryor, Carly Ameen, Robert Liddiard, Gary Baker, Katherine S. Kanne, J. Andy Milton, Christopher D. Standish, Bastian Hambach, Ludovic Orlando, Lorelei Chauvey, Stephanie Schiavinato, Laure Calvière-Tonasso, Gaetan Tressières, Stefanie Wagner, John Southon, Beth Shapiro, Alan Pipe, Oliver H. Creighton, Alan K. Outram
This paper reports a high-resolution isotopic study of medieval horse mobility, revealing their origins and in-life mobility both regionally and internationally. The animals were found in an unusual horse cemetery site found within the City of Westminster, London, England. Enamel strontium, oxygen, and carbon isotope analysis of 15 individuals provides information about likely place of birth, diet
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Chemosensory detection of polyamine metabolites guides C. elegans to nutritive microbes Sci. Adv. (IF 13.6) Pub Date : 2024-03-22 Benjamin Brissette, Lia Ficaro, Chenguang Li, Drew R. Jones, Sharad Ramanathan, Niels Ringstad
Much is known about molecular mechanisms by which animals detect pathogenic microbes, but how animals sense beneficial microbes remains poorly understood. The roundworm Caenorhabditis elegans is a microbivore that must distinguish nutritive microbes from pathogens. We characterized a neural circuit used by C. elegans to rapidly discriminate between nutritive bacteria and pathogens. Distinct sensory
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Iterative nanoparticle bioengineering enabled by x-ray fluorescence imaging Sci. Adv. (IF 13.6) Pub Date : 2024-03-22 Giovanni M. Saladino, Bertha Brodin, Ronak Kakadiya, Muhammet S. Toprak, Hans M. Hertz
Nanoparticles (NPs) are currently developed for drug delivery and molecular imaging. However, they often get intercepted before reaching their target, leading to low targeting efficacy and signal-to-noise ratio. They tend to accumulate in organs like lungs, liver, kidneys, and spleen. The remedy is to iteratively engineer NP surface properties and administration strategies, presently a time-consuming
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Physical science research needed to evaluate the viability and risks of marine cloud brightening Sci. Adv. (IF 13.6) Pub Date : 2024-03-20 Graham Feingold, Virendra P. Ghate, Lynn M. Russell, Peter Blossey, Will Cantrell, Matthew W. Christensen, Michael S. Diamond, Andrew Gettelman, Franziska Glassmeier, Edward Gryspeerdt, James Haywood, Fabian Hoffmann, Colleen M. Kaul, Matthew Lebsock, Allison C. McComiskey, Daniel T. McCoy, Yi Ming, Johannes Mülmenstädt, Anna Possner, Prasanth Prabhakaran, Patricia K. Quinn, K. Sebastian Schmidt, Raymond
Marine cloud brightening (MCB) is the deliberate injection of aerosol particles into shallow marine clouds to increase their reflection of solar radiation and reduce the amount of energy absorbed by the climate system. From the physical science perspective, the consensus of a broad international group of scientists is that the viability of MCB will ultimately depend on whether observations and models
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Emergence of co-tuning in inhibitory neurons as a network phenomenon mediated by randomness, correlations, and homeostatic plasticity Sci. Adv. (IF 13.6) Pub Date : 2024-03-20 Fereshteh Lagzi, Adrienne L. Fairhall
Cortical excitatory neurons show clear tuning to stimulus features, but the tuning properties of inhibitory interneurons are ambiguous. While inhibitory neurons have been considered to be largely untuned, some studies show that some parvalbumin-expressing (PV) neurons do show feature selectivity and participate in co-tuned subnetworks with pyramidal neurons. In this study, we first use mean-field theory
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Childhood cancer mutagenesis caused by transposase-derived PGBD5 Sci. Adv. (IF 13.6) Pub Date : 2024-03-22 Makiko Yamada, Ross R. Keller, Rodrigo Lopez Gutierrez, Daniel Cameron, Hiromichi Suzuki, Reeti Sanghrajka, Jake Vaynshteyn, Jeffrey Gerwin, Francesco Maura, William Hooper, Minita Shah, Nicolas Robine, Phillip Demarest, N. Sumru Bayin, Luz Jubierre Zapater, Casie Reed, Steven Hébert, Ignas Masilionis, Ronan Chaligne, Nicholas D. Socci, Michael D. Taylor, Claudia L. Kleinman, Alexandra L. Joyner, G
Genomic rearrangements are a hallmark of most childhood tumors, including medulloblastoma, one of the most common brain tumors in children, but their causes remain largely unknown. Here, we show that PiggyBac transposable element derived 5 (Pgbd5) promotes tumor development in multiple developmentally accurate mouse models of Sonic Hedgehog (SHH) medulloblastoma. Most Pgbd5-deficient mice do not develop
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Modeling the inner part of the jet in M87: Confronting jet morphology with theory Sci. Adv. (IF 13.6) Pub Date : 2024-03-22 Hai Yang, Feng Yuan, Hui Li, Yosuke Mizuno, Fan Guo, Rusen Lu, Luis C. Ho, Xi Lin, Andrzej A. Zdziarski, Jieshuang Wang
The formation of jets in black hole accretion systems is a long-standing problem. It has been proposed that a jet can be formed by extracting the rotation energy of the black hole (“BZ-jet”) or the accretion flow (“disk-jet”). While both models can produce collimated relativistic outflows, neither has successfully explained the observed jet morphology. By using general relativistic magnetohydrodynamic
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Stochastic neuro-fuzzy system implemented in memristor crossbar arrays Sci. Adv. (IF 13.6) Pub Date : 2024-03-22 Tuo Shi, Hui Zhang, Shiyu Cui, Jinchang Liu, Zixi Gu, Zhanfeng Wang, Xiaobing Yan, Qi Liu
Neuro-symbolic artificial intelligence has garnered considerable attention amid increasing industry demands for high-performance neural networks that are interpretable and adaptable to previously unknown problem domains with minimal reconfiguration. However, implementing neuro-symbolic hardware is challenging due to the complexity in symbolic knowledge representation and calculation. We experimentally
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Non–steady state thermometry with optical diffraction tomography Sci. Adv. (IF 13.6) Pub Date : 2024-03-22 Adarsh B. Vasista, Bernard Ciraulo, Falko Schmidt, Jaime Ortega Arroyo, Romain Quidant
Label-free thermometry is a pivotal tool for many disciplines. However, most current approaches are only suitable for planar heat sources in steady state, thereby restricting the range of systems that can be reliably studied. Here, we introduce pump probe–based optical diffraction tomography (ODT) as a method to map temperature precisely and accurately in three dimensions (3D) at the single-particle
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Bone-inspired stress-gaining elastomer enabled by dynamic molecular locking Sci. Adv. (IF 13.6) Pub Date : 2024-03-22 Yang Wang, Qingbao Guan, Yue Guo, Lijie Sun, Rasoul Esmaeely Neisiany, Xuran Guo, Hongfei Huang, Lei Yang, Zhengwei You
The limited capacity of typical materials to resist stress loading, which affects their mechanical performance, is one of the most formidable challenges in materials science. Here, we propose a bone-inspired stress-gaining concept of converting typically destructive stress into a favorable factor to substantially enhance the mechanical properties of elastomers. The concept was realized by a molecular
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Complementary integration of organic electrochemical transistors for front-end amplifier circuits of flexible neural implants Sci. Adv. (IF 13.6) Pub Date : 2024-03-22 Ilke Uguz, David Ohayon, Sinan Yilmaz, Sophie Griggs, Rajendar Sheelamanthula, Jason D. Fabbri, Iain McCulloch, Sahika Inal, Kenneth L. Shepard
The ability to amplify, translate, and process small ionic potential fluctuations of neural processes directly at the recording site is essential to improve the performance of neural implants. Organic front-end analog electronics are ideal for this application, allowing for minimally invasive amplifiers owing to their tissue-like mechanical properties. Here, we demonstrate fully organic complementary
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Critical fluctuations in a confined driven-dissipative quantum condensate Sci. Adv. (IF 13.6) Pub Date : 2024-03-22 Hassan Alnatah, Paolo Comaron, Shouvik Mukherjee, Jonathan Beaumariage, Loren N. Pfeiffer, Ken West, Kirk Baldwin, Marzena Szymańska, David W. Snoke
Phase fluctuations determine the low-energy properties of quantum condensates. However, at the condensation threshold, both density and phase fluctuations are relevant. While strong emphasis has been given to the investigation of phase fluctuations, which dominate the physics of the quantum system away from the critical point, number fluctuations have been much less explored even in thermal equilibrium