TY  - JOUR
AB  - Recognition of exogenous RNA by Toll-like receptors (TLRs) is central to pathogen defense. Using two distinct binding pockets, TLR7 and TLR8 recognize RNA degradation products generated by endolysosomal nucleases. RNA modifications present in endogenous RNA prevent TLR activation; notably, pseudouridine-containing RNA lacks immunostimulatory activity. Indeed, this property has been critical to the successful implementation of mRNA technology for medical purposes. However, the molecular mechanism for this immune evasion has remained elusive. Here, we report that RNase T2 and PLD exonucleases do not adequately process pseudouridine-containing RNA to generate TLR-agonistic ligands. As a second safety mechanism, TLR8 neglects pseudouridine as a ligand for its first binding pocket and TLR7 neglects pseudouridine-containing RNA as a ligand for its second pocket. Interestingly, the medically used N1-methylpseudouridine also evades RNase T2, PLD3, and PLD4 processing but is able to directly activate TLR8. Taken together, our findings provide a molecular basis for self-avoidance by RNA-sensing TLRs.
AU  - Berouti, M.*
AU  - Wagner, M.*
AU  - Greulich, W.*
AU  - Piseddu, I.*
AU  - Gärtig, J.*
AU  - Hansbauer, L.*
AU  - Müller-Hermes, C.
AU  - Heiss, M.*
AU  - Pichler, A.*
AU  - Tölke, A.J.*
AU  - Witte, G.*
AU  - Hopfner, K.P.*
AU  - Anz, D.*
AU  - Sattler, M.
AU  - Carell, T.*
AU  - Hornung, V.*
C1  - 75050
C2  - 57754
TI  - Pseudouridine RNA avoids immune detection through impaired endolysosomal processing and TLR engagement.
JO  - Cell
PY  - 2025
SN  - 0092-8674
ER  - 

TY  - JOUR
AB  - Advanced gene editing methods have accelerated biomedical discovery and hold great therapeutic promise, but safe and efficient delivery of gene editors remains challenging. In this study, we present a virus-like particle (VLP) system featuring nucleocytosolic shuttling vehicles that retrieve pre-assembled Cas-effectors via aptamer-tagged guide RNAs. This approach ensures preferential loading of fully assembled editor ribonucleoproteins (RNPs) and enhances the efficacy of prime editing, base editing, trans-activators, and nuclease activity coupled to homology-directed repair in multiple immortalized, primary, stem cell, and stem-cell-derived cell types. We also achieve additional protection of inherently unstable prime editing guide RNAs (pegRNAs) by shielding the 3'-exposed end with Csy4/Cas6f, further enhancing editing performance. Furthermore, we identify a minimal set of packaging and budding modules that can serve as a platform for bottom-up engineering of enveloped delivery vehicles. Notably, our system demonstrates superior per-VLP editing efficiency in primary T lymphocytes and two mouse models of inherited retinal disease, highlighting its therapeutic potential.
AU  - Geilenkeuser, J.
AU  - Armbrust, N.
AU  - Steinmaßl, E.
AU  - Du, S.W.*
AU  - Schmidt, S.
AU  - Binder, E.M.H.
AU  - Li, Y.
AU  - Warsing, N.W.
AU  - Wendel, S.V.
AU  - von der Linde, F.
AU  - Schiele, E.M.
AU  - Niu, X.
AU  - Stroppel, L.
AU  - Berezin, O.
AU  - Santl, T.
AU  - Orschmann, T.
AU  - Nelson, K.
AU  - Gruber, C.
AU  - Palczewska, G.*
AU  - Menezes, C.R.*
AU  - Risaliti, E.*
AU  - Engfer, Z.J.*
AU  - Koleci, N.*
AU  - Schmidts, A.*
AU  - Geerlof, A.
AU  - Palczewski, K.*
AU  - Westmeyer, G.G.
AU  - Truong, D.J.J.
C1  - 74059
C2  - 57319
CY  - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
TI  - Engineered nucleocytosolic vehicles for loading of programmable editors.
JO  - Cell
VL  - 188
IS  - 10
PB  - Cell Press
PY  - 2025
SN  - 0092-8674
ER  - 

TY  - JOUR
AB  - In cancer cachexia, the presence of a tumor triggers systemic metabolic disruption that leads to involuntary body weight loss and accelerated mortality in affected patients. Here, we conducted transcriptomic and epigenomic profiling of the liver in various weight-stable cancer and cancer cachexia models. An integrative multilevel analysis approach identified a distinct gene expression signature that included hepatocyte-secreted factors and the circadian clock component REV-ERBα as key modulator of hepatic transcriptional reprogramming in cancer cachexia. Notably, hepatocyte-specific genetic reconstitution of REV-ERBα in cachexia ameliorated peripheral tissue wasting. This improvement was associated with decreased levels of specific cachexia-controlled hepatocyte-secreted factors. These hepatokines promoted catabolism in multiple cell types and were elevated in cachectic cancer patients. Our findings reveal a mechanism by which the liver contributes to peripheral tissue wasting in cancer cachexia, offering perspectives for future therapeutic interventions.
AU  - Kaltenecker, D.
AU  - Schmidt, S.F.
AU  - Weber, P.
AU  - Loft, A.
AU  - Morigny, P.
AU  - Machado, J.
AU  - Geppert, J.
AU  - Saul, K.B.*
AU  - Benedikt-Kühnast, P.
AU  - Molocea, C.-E.
AU  - Scott, R.*
AU  - Haase, K.*
AU  - Martignoni, M.E.*
AU  - Alfaro, A.J.
AU  - Chow, K.K.
AU  - Simoes Fernandez, E.
AU  - Pinhata Otoch, J.*
AU  - Lima, J.D.C.C.*
AU  - Swanton, C.*
AU  - Spielmann, N.
AU  - Hrabě de Angelis, M.
AU  - Elsner, M.
AU  - Ertürk, A.
AU  - Dyar, K.A.
AU  - Rohm, M.
AU  - Prokopchuk, O.*
AU  - Jamal-Hanjani, M.*
AU  - Seelaender, M.*
AU  - Backs, J.*
AU  - Herzig, S.
AU  - Berriel Diaz, M.
C1  - 75223
C2  - 57864
CY  - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
SP  - 4549-4566.e22
TI  - Functional liver genomics identifies hepatokines promoting wasting in cancer cachexia.
JO  - Cell
VL  - 188
IS  - 17
PB  - Cell Press
PY  - 2025
SN  - 0092-8674
ER  - 

TY  - JOUR
AB  - Transcriptional activation of the embryonic genome (EGA) is a major developmental landmark enabling the embryo to become independent from maternal control. The magnitude and control of transcriptional reprogramming during this event across mammals remains poorly understood. Here, we developed Smart-seq+5' for high sensitivity, full-length transcript coverage and simultaneous capture of 5' transcript information from single cells and single embryos. Using Smart-seq+5', we profiled 34 developmental stages in 5 mammalian species and provide an extensive characterization of the transcriptional repertoire of early development before, during, and after EGA. We demonstrate widespread transposable element (TE)-driven transcription across species, including, remarkably, of DNA transposons. We identify 19,657 TE-driven genic transcripts, suggesting extensive TE co-option in early development over evolutionary timescales. TEs display similar expression dynamics across species and species-specific patterns, suggesting shared and divergent regulation. Our work provides a powerful resource for understanding transcriptional regulation of mammalian development.
AU  - Oomen, M.E.
AU  - Rodriguez-Terrones, D.
AU  - Kurome, M.*
AU  - Zakhartchenko, V.*
AU  - Mottes, L.
AU  - Simmet, K.*
AU  - Noll, C.
AU  - Nakatani, T.
AU  - Mourra-Díaz, D.M.
AU  - Aksoy, I.*
AU  - Savatier, P.*
AU  - Goke, J.*
AU  - Wolf, E.*
AU  - Kaessmann, H.*
AU  - Torres-Padilla, M.E.
C1  - 73141
C2  - 56866
SP  - 1156-1174.e20
TI  - An atlas of transcription initiation reveals regulatory principles of gene and transposable element expression in early mammalian development.
JO  - Cell
VL  - 188
IS  - 4
PY  - 2025
SN  - 0092-8674
ER  - 

TY  - JOUR
AB  - The folding of the genome in the 3D nuclear space is fundamental for regulating all DNA-related processes. The association of the genome with the nuclear lamina into lamina-associated domains (LADs) represents the earliest feature of nuclear organization during development. Here, we performed a gain-of-function screen in mouse embryos to obtain mechanistic insights. We find that perturbations impacting histone H3 modifications, heterochromatin, and histone content are crucial for the establishment of nuclear architecture in zygotes and/or 2-cell-stage embryos. Notably, some perturbations exerted differential effects on zygotes versus 2-cell-stage embryos. Moreover, embryos with disrupted LADs can rebuild nuclear architecture at the 2-cell stage, indicating that the initial establishment of LADs in zygotes might be dispensable for early development. Our findings provide valuable insights into the functional interplay between chromatin and structural components of the nucleus that guide genome-lamina interactions during the earliest developmental stages.
AU  - Pal, M.
AU  - Schauer, T.
AU  - Burton, A.
AU  - Nakatani, T.
AU  - Pecori, F.
AU  - Hernández-Giménez, A.*
AU  - Nadelson, I.
AU  - Marti-Renom, M.A.*
AU  - Torres-Padilla, M.E.
C1  - 74203
C2  - 57101
TI  - The establishment of nuclear organization in mouse embryos is orchestrated by multiple epigenetic pathways.
JO  - Cell
VL  - 188
PY  - 2025
SN  - 0092-8674
ER  - 

TY  - JOUR
AB  - In a human cell, DNA is packed with histones, RNA, and chromatin-associated proteins, forming a cohesive gel. At any given moment, only a subset of the proteome has physical access to the DNA and organizes its structure, transcription, replication, repair, and other essential molecular functions. We have developed a "zero-distance" photo-crosslinking approach to quantify proteins in direct contact with DNA in living cells. Collecting DNA interactomes from human breast cancer cells, we present an atlas of over one thousand proteins with physical access to DNA and hundreds of peptide-nucleotide crosslinks pinpointing protein-DNA interfaces with single-amino-acid resolution. Quantitative comparisons of DNA interactomes from differentially treated cells recapitulate the recruitment of key transcription factors as well as DNA repair proteins and uncover fast-acting restrictors of chromatin accessibility on a timescale of minutes. This opens a direct way to explore genomic regulation in a hypothesis-free manner, applicable to many organisms and systems.
AU  - Trendel, J.*
AU  - Trendel, S.*
AU  - Sha, S.*
AU  - Greulich, F.*
AU  - Goll, S.*
AU  - Wudy, S.I.*
AU  - Kleigrewe, K.*
AU  - Kubicek, S.*
AU  - Uhlenhaut, N.H.
AU  - Kuster, B.*
C1  - 74795
C2  - 57579
CY  - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
SP  - 4424-4440
TI  - The human proteome with direct physical access to DNA.
JO  - Cell
VL  - 188
IS  - 16
PB  - Cell Press
PY  - 2025
SN  - 0092-8674
ER  - 

TY  - JOUR
AB  - Ferroptosis is a form of cell death due to iron-induced lipid peroxidation. Ferroptosis suppressor protein 1 (FSP1) protects against this death by generating antioxidants, which requires nicotinamide adenine dinucleotide, reduced form (NADH) as a cofactor. We initially uncover that NADH exists at significant levels on cellular membranes and then find that this form of NADH is generated by aldehyde dehydrogenase 7A1 (ALDH7A1) to support FSP1 activity. ALDH7A1 activity also acts directly to decrease lipid peroxidation by consuming reactive aldehydes. Furthermore, ALDH7A1 promotes the membrane recruitment of FSP1, which is instigated by ferroptotic stress activating AMP-activated protein kinase (AMPK) to promote the membrane localization of ALDH7A1 that stabilizes FSP1 on membranes. These findings advance a fundamental understanding of NADH by revealing a previously unappreciated pool on cellular membranes, with the elucidation of its function providing a major understanding of how FSP1 acts and how an aldehyde dehydrogenase protects against ferroptosis.
AU  - Yang, J.S.*
AU  - Morris, A.J.*
AU  - Kamizaki, K.*
AU  - Chen, J.*
AU  - Stark, J.*
AU  - Oldham, W.M.*
AU  - Nakamura, T.
AU  - Mishima, E.
AU  - Loscalzo, J.*
AU  - Minami, Y.*
AU  - Conrad, M.
AU  - Henry, W.S.*
AU  - Hsu, V.W.*
C1  - 74130
C2  - 57335
CY  - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
SP  - 2569-2585.e20
TI  - ALDH7A1 protects against ferroptosis by generating membrane NADH and regulating FSP1.
JO  - Cell
VL  - 188
IS  - 10
PB  - Cell Press
PY  - 2025
SN  - 0092-8674
ER  - 

TY  - JOUR
AB  - In this issue of Cell, Han et al. find that tumor cells metastasizing to the bone marrow hijack macrophages to seize iron from red blood cells. This metabolic plunder thereby fuels tumor progression while contributing to anemia.
AU  - Zheng, J.
AU  - Conrad, M.
C1  - 75938
C2  - 58206
SP  - 6107-6108
TI  - Iron raider: Tumors in the bone marrow.
JO  - Cell
VL  - 188
IS  - 22
PY  - 2025
SN  - 0092-8674
ER  - 

TY  - JOUR
AB  - Cells are essential to understanding health and disease, yet traditional models fall short of modeling and simulating their function and behavior. Advances in AI and omics offer groundbreaking opportunities to create an AI virtual cell (AIVC), a multi-scale, multi-modal large-neural-network-based model that can represent and simulate the behavior of molecules, cells, and tissues across diverse states. This Perspective provides a vision on their design and how collaborative efforts to build AIVCs will transform biological research by allowing high-fidelity simulations, accelerating discoveries, and guiding experimental studies, offering new opportunities for understanding cellular functions and fostering interdisciplinary collaborations in open science.
AU  - Bunne, C.*
AU  - Roohani, Y.*
AU  - Rosen, Y.*
AU  - Gupta, A.*
AU  - Zhang, X.*
AU  - Roed, M.*
AU  - Alexandrov, T.*
AU  - AlQuraishi, M.*
AU  - Brennan, P.*
AU  - Burkhardt, D.B.*
AU  - Califano, A.*
AU  - Cool, J.*
AU  - Dernburg, A.F.*
AU  - Ewing, K.*
AU  - Fox, E.B.*
AU  - Haury, M.*
AU  - Herr, A.E.*
AU  - Horvitz, E.*
AU  - Hsu, P.D.*
AU  - Jain, V.*
AU  - Johnson, G.R.*
AU  - Kalil, T.*
AU  - Kelley, D.R.*
AU  - Kelley, S.O.*
AU  - Kreshuk, A.*
AU  - Mitchison, T.*
AU  - Otte, S.*
AU  - Shendure, J.*
AU  - Sofroniew, N.J.*
AU  - Theis, F.J.
AU  - Theodoris, C.V.*
AU  - Upadhyayula, S.*
AU  - Valer, M.*
AU  - Wang, B.*
AU  - Xing, E.*
AU  - Yeung-Levy, S.*
AU  - Zitnik, M.*
AU  - Karaletsos, T.*
AU  - Regev, A.*
AU  - Lundberg, E.*
AU  - Leskovec, J.*
AU  - Quake, S.R.*
C1  - 72764
C2  - 56734
CY  - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
SP  - 7045-7063
TI  - How to build the virtual cell with artificial intelligence: Priorities and opportunities.
JO  - Cell
VL  - 187
IS  - 25
PB  - Cell Press
PY  - 2024
SN  - 0092-8674
ER  - 

TY  - JOUR
AB  - Deciphering the cell-state transitions underlying immune adaptation across time is fundamental for advancing biology. Empirical in vivo genomic technologies that capture cellular dynamics are currently lacking. We present Zman-seq, a single-cell technology recording transcriptomic dynamics across time by introducing time stamps into circulating immune cells, tracking them in tissues for days. Applying Zman-seq resolved cell-state and molecular trajectories of the dysfunctional immune microenvironment in glioblastoma. Within 24 hours of tumor infiltration, cytotoxic natural killer cells transitioned to a dysfunctional program regulated by TGFB1 signaling. Infiltrating monocytes differentiated into immunosuppressive macrophages, characterized by the upregulation of suppressive myeloid checkpoints Trem2, Il18bp, and Arg1, over 36 to 48 hours. Treatment with an antagonistic anti-TREM2 antibody reshaped the tumor microenvironment by redirecting the monocyte trajectory toward pro-inflammatory macrophages. Zman-seq is a broadly applicable technology, enabling empirical measurements of differentiation trajectories, which can enhance the development of more efficacious immunotherapies.
AU  - Kirschenbaum, D.*
AU  - Xie, K.*
AU  - Ingelfinger, F.*
AU  - Katzenelenbogen, Y.*
AU  - Abadie, K.*
AU  - Look, T.*
AU  - Sheban, F.*
AU  - Phan, T.S.*
AU  - Li, B.*
AU  - Zwicky, P.*
AU  - Yofe, I.*
AU  - David, E.*
AU  - Mazuz, K.*
AU  - Hou, J.*
AU  - Chen, Y.*
AU  - Shaim, H.*
AU  - Shanley, M.*
AU  - Becker, S.
AU  - Qian, J.*
AU  - Colonna, M.*
AU  - Ginhoux, F.*
AU  - Rezvani, K.*
AU  - Theis, F.J.
AU  - Yosef, N.*
AU  - Weiss, T.*
AU  - Weiner, A.*
AU  - Amit, I.*
C1  - 69043
C2  - 53825
CY  - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
SP  - 149-165.e23
TI  - Time-resolved single-cell transcriptomics defines immune trajectories in glioblastoma.
JO  - Cell
VL  - 187
IS  - 1
PB  - Cell Press
PY  - 2024
SN  - 0092-8674
ER  - 

TY  - JOUR
AB  - For more than a century, physicians have searched for ways to pharmacologically reduce excess body fat. The tide has finally turned with recent advances in biochemically engineered agonists for the receptor of glucagon-like peptide-1 (GLP-1) and their use in GLP-1-based polyagonists. These polyagonists reduce body weight through complementary pharmacology by incorporating the receptors for glucagon and/or the glucose-dependent insulinotropic polypeptide (GIP). In their most advanced forms, gut-hormone polyagonists achieve an unprecedented weight reduction of up to ∼20%–30%, offering a pharmacological alternative to bariatric surgery. Along with favorable effects on glycemia, fatty liver, and kidney disease, they also offer beneficial effects on the cardiovascular system and adipose tissue. These new interventions, therefore, hold great promise for the future of anti-obesity medications.
AU  - Kusminski, C.M.*
AU  - Perez-Tilve, D.*
AU  - Müller, T.D.
AU  - DiMarchi, R.D.*
AU  - Tschöp, M.H.
AU  - Scherer, P.E.*
C1  - 71248
C2  - 55958
SP  - 3829-3853
TI  - Transforming obesity: The advancement of multi-receptor drugs.
JO  - Cell
VL  - 187
IS  - 15
PY  - 2024
SN  - 0092-8674
ER  - 

TY  - JOUR
AB  - As the number of single-cell datasets continues to grow rapidly, workflows that map new data to well-curated reference atlases offer enormous promise for the biological community. In this perspective, we discuss key computational challenges and opportunities for single-cell reference-mapping algorithms. We discuss how mapping algorithms will enable the integration of diverse datasets across disease states, molecular modalities, genetic perturbations, and diverse species and will eventually replace manual and laborious unsupervised clustering pipelines.
AU  - Lotfollahi, M.
AU  - Hao, Y.*
AU  - Theis, F.J.
AU  - Satija, R.*
C1  - 70652
C2  - 55698
CY  - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
SP  - 2343-2358
TI  - The future of rapid and automated single-cell data analysis using reference mapping.
JO  - Cell
VL  - 187
IS  - 10
PB  - Cell Press
PY  - 2024
SN  - 0092-8674
ER  - 

TY  - JOUR
AB  - Pyrenoids are subcompartments of algal chloroplasts that increase the efficiency of Rubisco-driven CO2 fixation. Diatoms fix up to 20% of global CO2, but their pyrenoids remain poorly characterized. Here, we used in vivo photo-crosslinking to identify pyrenoid shell (PyShell) proteins, which we localized to the pyrenoid periphery of model pennate and centric diatoms, Phaeodactylum tricornutum and Thalassiosira pseudonana. In situ cryo-electron tomography revealed that pyrenoids of both diatom species are encased in a lattice-like protein sheath. Single-particle cryo-EM yielded a 2.4-Å-resolution structure of an in vitro TpPyShell1 lattice, which showed how protein subunits interlock. T. pseudonana TpPyShell1/2 knockout mutants had no PyShell sheath, altered pyrenoid morphology, and a high-CO2 requiring phenotype, with reduced photosynthetic efficiency and impaired growth under standard atmospheric conditions. The structure and function of the diatom PyShell provide a molecular view of how CO2 is assimilated in the ocean, a critical ecosystem undergoing rapid change.
AU  - Shimakawa, G.*
AU  - Demulder, M.*
AU  - Flori, S.*
AU  - Kawamoto, A.*
AU  - Tsuji, Y.*
AU  - Nawaly, H.*
AU  - Tanaka, A.*
AU  - Tohda, R.*
AU  - Ota, T.*
AU  - Matsui, H.*
AU  - Morishima, N.*
AU  - Okubo, R.*
AU  - Wietrzynski, W.*
AU  - Lamm, L.
AU  - Righetto, R.*
AU  - Uwizeye, C.*
AU  - Gallet, B.*
AU  - Jouneau, P.H.*
AU  - Gerle, C.*
AU  - Kurisu, G.*
AU  - Finazzi, G.*
AU  - Engel, B.D.*
AU  - Matsuda, Y.*
C1  - 71894
C2  - 56482
CY  - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
SP  - 5919-5934
TI  - Diatom pyrenoids are encased in a protein shell that enables efficient CO2 fixation.
JO  - Cell
VL  - 187
IS  - 21
PB  - Cell Press
PY  - 2024
SN  - 0092-8674
ER  - 

TY  - JOUR
AB  - The medical burden of stroke extends beyond the brain injury itself and is largely determined by chronic comorbidities that develop secondarily. We hypothesized that these comorbidities might share a common immunological cause, yet chronic effects post-stroke on systemic immunity are underexplored. Here, we identify myeloid innate immune memory as a cause of remote organ dysfunction after stroke. Single-cell sequencing revealed persistent pro-inflammatory changes in monocytes/macrophages in multiple organs up to 3 months after brain injury, notably in the heart, leading to cardiac fibrosis and dysfunction in both mice and stroke patients. IL-1β was identified as a key driver of epigenetic changes in innate immune memory. These changes could be transplanted to naive mice, inducing cardiac dysfunction. By neutralizing post-stroke IL-1β or blocking pro-inflammatory monocyte trafficking with a CCR2/5 inhibitor, we prevented post-stroke cardiac dysfunction. Such immune-targeted therapies could potentially prevent various IL-1β-mediated comorbidities, offering a framework for secondary prevention immunotherapy.
AU  - Simats, A.*
AU  - Zhang, S.*
AU  - Messerer, D.*
AU  - Chong, F.
AU  - Beşkardeş, S.
AU  - Chivukula, A.S.*
AU  - Cao, J.*
AU  - Besson-Girard, S.*
AU  - Montellano, F.A.*
AU  - Morbach, C.*
AU  - Carofiglio, O.*
AU  - Ricci, A.*
AU  - Roth, S.*
AU  - Llovera, G.*
AU  - Singh, R.*
AU  - Chen, Y.*
AU  - Filser, S.*
AU  - Plesnila, N.*
AU  - Braun, C.*
AU  - Spitzer, H.*
AU  - Gokce, O.*
AU  - Dichgans, M.*
AU  - Heuschmann, P.U.*
AU  - Hatakeyama, K.*
AU  - Beltrán, E.*
AU  - Clauss, S.*
AU  - Bonev, B.
AU  - Schulz, C.*
AU  - Liesz, A.*
C1  - 71283
C2  - 56011
CY  - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
SP  - 4637-4655.e26
TI  - Innate immune memory after brain injury drives inflammatory cardiac dysfunction.
JO  - Cell
VL  - 187
IS  - 17
PB  - Cell Press
PY  - 2024
SN  - 0092-8674
ER  - 

TY  - JOUR
AB  - To understand biological processes, it is necessary to reveal the molecular heterogeneity of cells by gaining access to the location and interaction of all biomolecules. Significant advances were achieved by super-resolution microscopy, but such methods are still far from reaching the multiplexing capacity of proteomics. Here, we introduce secondary label-based unlimited multiplexed DNA-PAINT (SUM-PAINT), a high-throughput imaging method that is capable of achieving virtually unlimited multiplexing at better than 15 nm resolution. Using SUM-PAINT, we generated 30-plex single-molecule resolved datasets in neurons and adapted omics-inspired analysis for data exploration. This allowed us to reveal the complexity of synaptic heterogeneity, leading to the discovery of a distinct synapse type. We not only provide a resource for researchers, but also an integrated acquisition and analysis workflow for comprehensive spatial proteomics at single-protein resolution.
AU  - Unterauer, E.M.*
AU  - Shetab Boushehri, S.
AU  - Jevdokimenko, K.*
AU  - Masullo, L.A.*
AU  - Ganji, M.*
AU  - Sograte-Idrissi, S.*
AU  - Kowalewski, R.*
AU  - Strauss, S.*
AU  - Reinhardt, S.C.M.*
AU  - Perovic, A.*
AU  - Marr, C.
AU  - Opazo, F.*
AU  - Fornasiero, E.F.*
AU  - Jungmann, R.*
C1  - 70372
C2  - 55394
CY  - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
SP  - 1785-1800.e16
TI  - Spatial proteomics in neurons at single-protein resolution.
JO  - Cell
VL  - 187
IS  - 7
PB  - Cell Press
PY  - 2024
SN  - 0092-8674
ER  - 

TY  - JOUR
AB  - Inflammation-induced neurodegeneration is a defining feature of multiple sclerosis (MS), yet the underlying mechanisms remain unclear. By dissecting the neuronal inflammatory stress response, we discovered that neurons in MS and its mouse model induce the stimulator of interferon genes (STING). However, activation of neuronal STING requires its detachment from the stromal interaction molecule 1 (STIM1), a process triggered by glutamate excitotoxicity. This detachment initiates non-canonical STING signaling, which leads to autophagic degradation of glutathione peroxidase 4 (GPX4), essential for neuronal redox homeostasis and thereby inducing ferroptosis. Both genetic and pharmacological interventions that target STING in neurons protect against inflammation-induced neurodegeneration. Our findings position STING as a central regulator of the detrimental neuronal inflammatory stress response, integrating inflammation with glutamate signaling to cause neuronal cell death, and present it as a tractable target for treating neurodegeneration in MS.
AU  - Woo, M.S.*
AU  - Mayer, C.*
AU  - Binkle-Ladisch, L.*
AU  - Sonner, J.K.*
AU  - Rosenkranz, S.C.*
AU  - Shaposhnykov, A.*
AU  - Rothammer, N.*
AU  - Tsvilovskyy, V.*
AU  - Lorenz, S.
AU  - Raich, L.*
AU  - Bal, L.C.*
AU  - Vieira, V.*
AU  - Wagner, I.*
AU  - Bauer, S.*
AU  - Glatzel, M.*
AU  - Conrad, M.
AU  - Merkler, D.*
AU  - Freichel, M.*
AU  - Friese, M.A.*
C1  - 70844
C2  - 55762
CY  - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
SP  - 4043-4060.e30
TI  - STING orchestrates the neuronal inflammatory stress response in multiple sclerosis.
JO  - Cell
VL  - 187
IS  - 15
PB  - Cell Press
PY  - 2024
SN  - 0092-8674
ER  - 

TY  - JOUR
AB  - The bone marrow in the skull is important for shaping immune responses in the brain and meninges, but its molecular makeup among bones and relevance in human diseases remain unclear. Here, we show that the mouse skull has the most distinct transcriptomic profile compared with other bones in states of health and injury, characterized by a late-stage neutrophil phenotype. In humans, proteome analysis reveals that the skull marrow is the most distinct, with differentially expressed neutrophil-related pathways and a unique synaptic protein signature. 3D imaging demonstrates the structural and cellular details of human skull-meninges connections (SMCs) compared with veins. Last, using translocator protein positron emission tomography (TSPO-PET) imaging, we show that the skull bone marrow reflects inflammatory brain responses with a disease-specific spatial distribution in patients with various neurological disorders. The unique molecular profile and anatomical and functional connections of the skull show its potential as a site for diagnosing, monitoring, and treating brain diseases.
AU  - Kolabas, Z.I.
AU  - Kuemmerle, L.
AU  - Perneczky, R.*
AU  - Förstera, B.
AU  - Ulukaya, S.
AU  - Ali, M.
AU  - Kapoor, S.
AU  - Bartos, L.M.*
AU  - Büttner, M.
AU  - Caliskan, Ö.S.
AU  - Rong, Z.
AU  - Mai, H.
AU  - Höher, L.
AU  - Jeridi, D.
AU  - Molbay, M.
AU  - Khalin, I.*
AU  - Deligiannis, I.K.
AU  - Negwer, M.
AU  - Roberts, K.*
AU  - Simats, A.*
AU  - Carofiglio, O.*
AU  - Todorov, M.I.
AU  - Horvath, I.
AU  - Öztürk, F.
AU  - Hummel, S.*
AU  - Biechele, G.*
AU  - Zatcepin, A.*
AU  - Unterrainer, M.*
AU  - Gnörich, J.*
AU  - Roodselaar, J.*
AU  - Shrouder, J.*
AU  - Khosravani, P.*
AU  - Tast, B.*
AU  - Richter, L.*
AU  - Díaz-Marugán, L.*
AU  - Kaltenecker, D.
AU  - Lux, L.
AU  - Chen, Y.*
AU  - Zhao, S.
AU  - Rauchmann, B.S.*
AU  - Sterr, M.
AU  - Kunze, I.
AU  - Stanic Aguilera, K.N.
AU  - Kan, V.W.Y.*
AU  - Besson-Girard, S.*
AU  - Katzdobler, S.*
AU  - Palleis, C.*
AU  - Schädler, J.*
AU  - Paetzold, J.C.
AU  - Liebscher, S.*
AU  - Hauser, A.E.*
AU  - Gokce, O.*
AU  - Lickert, H.
AU  - Steinke, H.*
AU  - Benakis, C.*
AU  - Braun, C.*
AU  - Martinez Jimenez, C.P.
AU  - Buerger, K.*
AU  - Albert, N.L.*
AU  - Höglinger, G.*
AU  - Levin, J.*
AU  - Haass, C.*
AU  - Kopczak, A.*
AU  - Dichgans, M.*
AU  - Havla, J.*
AU  - Kümpfel, T.*
AU  - Kerschensteiner, M.*
AU  - Schifferer, M.*
AU  - Simons, M.*
AU  - Liesz, A.*
AU  - Krahmer, N.
AU  - Bayraktar, O.A.*
AU  - Franzmeier, N.*
AU  - Plesnila, N.*
AU  - Erener, S.
AU  - Puelles, V.G.*
AU  - Delbridge, C.*
AU  - Bhatia, H.S.
AU  - Hellal, F.
AU  - Elsner, M.
AU  - Bechmann, I.*
AU  - Ondruschka, B.*
AU  - Brendel, M.*
AU  - Theis, F.J.
AU  - Ertürk, A.
C1  - 68009
C2  - 54487
CY  - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
SP  - 3706-3725.e29
TI  - Distinct molecular profiles of skull bone marrow in health and neurological disorders.
JO  - Cell
VL  - 186
IS  - 17
PB  - Cell Press
PY  - 2023
SN  - 0092-8674
ER  - 

TY  - JOUR
AB  - Regulation of viral RNA biogenesis is fundamental to productive SARS-CoV-2 infection. To characterize host RNA-binding proteins (RBPs) involved in this process, we biochemically identified proteins bound to genomic and subgenomic SARS-CoV-2 RNAs. We find that the host protein SND1 binds the 5' end of negative-sense viral RNA and is required for SARS-CoV-2 RNA synthesis. SND1-depleted cells form smaller replication organelles and display diminished virus growth kinetics. We discover that NSP9, a viral RBP and direct SND1 interaction partner, is covalently linked to the 5' ends of positive- and negative-sense RNAs produced during infection. These linkages occur at replication-transcription initiation sites, consistent with NSP9 priming viral RNA synthesis. Mechanistically, SND1 remodels NSP9 occupancy and alters the covalent linkage of NSP9 to initiating nucleotides in viral RNA. Our findings implicate NSP9 in the initiation of SARS-CoV-2 RNA synthesis and unravel an unsuspected role of a cellular protein in orchestrating viral RNA production.
AU  - Schmidt, N.*
AU  - Ganskih, S.*
AU  - Wei, Y.*
AU  - Gabel, A.*
AU  - Zielinski, S.*
AU  - Keshishian, H.*
AU  - Lareau, C.A.*
AU  - Zimmermann, L.*
AU  - Makroczyova, J.*
AU  - Pearce, C.*
AU  - Krey, K.*
AU  - Hennig, T.*
AU  - Stegmaier, S.*
AU  - Moyon, L.
AU  - Horlacher, M.
AU  - Werner, S.*
AU  - Aydin, J.*
AU  - Olguin-Nava, M.*
AU  - Potabattula, R.*
AU  - Kibe, A.*
AU  - Dölken, L.*
AU  - Smyth, R.P.*
AU  - Caliskan, N.*
AU  - Marsico, A.
AU  - Krempl, C.*
AU  - Bodem, J.*
AU  - Pichlmair, A.*
AU  - Carr, S.A.*
AU  - Chlanda, P.*
AU  - Erhard, F.*
AU  - Munschauer, M.*
C1  - 68631
C2  - 54807
CY  - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
SP  - 4834-4850.e23
TI  - SND1 binds SARS-CoV-2 negative-sense RNA and promotes viral RNA synthesis through NSP9.
JO  - Cell
VL  - 186
IS  - 22
PB  - Cell Press
PY  - 2023
SN  - 0092-8674
ER  - 

TY  - JOUR
AB  - Spatial molecular profiling of complex tissues is essential to investigate cellular function in physiological and pathological states. However, methods for molecular analysis of large biological specimens imaged in 3D are lacking. Here, we present DISCO-MS, a technology that combines whole-organ/whole-organism clearing and imaging, deep-learning-based image analysis, robotic tissue extraction, and ultra-high-sensitivity mass spectrometry. DISCO-MS yielded proteome data indistinguishable from uncleared samples in both rodent and human tissues. We used DISCO-MS to investigate microglia activation along axonal tracts after brain injury and characterized early- and late-stage individual amyloid-beta plaques in a mouse model of Alzheimer's disease. DISCO-bot robotic sample extraction enabled us to study the regional heterogeneity of immune cells in intact mouse bodies and aortic plaques in a complete human heart. DISCO-MS enables unbiased proteome analysis of preclinical and clinical tissues after unbiased imaging of entire specimens in 3D, identifying diagnostic and therapeutic opportunities for complex diseases. Video abstract: [Figure presented]
AU  - Bhatia, H.S.
AU  - Brunner, A.D.*
AU  - Öztürk, F.
AU  - Kapoor, S.
AU  - Rong, Z.
AU  - Mai, H.
AU  - Thielert, M.*
AU  - Ali, M.
AU  - Al-Maskari, R.*
AU  - Paetzold, J.C.
AU  - Kofler, F.
AU  - Todorov, M.I.
AU  - Molbay, M.
AU  - Kolabas, Z.I.
AU  - Negwer, M.
AU  - Höher, L.
AU  - Steinke, H.*
AU  - Dima, A.*
AU  - Gupta, B.
AU  - Kaltenecker, D.
AU  - Caliskan, Ö.S.
AU  - Brandt, D.
AU  - Krahmer, N.
AU  - Müller, S.*
AU  - Lichtenthaler, S.F.*
AU  - Hellal, F.
AU  - Bechmann, I.*
AU  - Menze, B.*
AU  - Theis, F.J.
AU  - Mann, M.*
AU  - Ertürk, A.
C1  - 67071
C2  - 53441
CY  - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
SP  - 5040-5058.e19
TI  - Spatial proteomics in three-dimensional intact specimens.
JO  - Cell
VL  - 185
IS  - 26
PB  - Cell Press
PY  - 2022
SN  - 0092-8674
ER  - 

TY  - JOUR
AB  - The centromere represents a single region in most eukaryotic chromosomes. However, several plant and animal lineages assemble holocentromeres along the entire chromosome length. Here, we compare genome organization and evolution as a function of centromere type by assembling chromosome-scale holocentric genomes with repeat-based holocentromeres from three beak-sedge (Rhynchospora pubera, R. breviuscula, and R. tenuis) and their closest monocentric relative, Juncus effusus. We demonstrate that transition to holocentricity affected 3D genome architecture by redefining genomic compartments, while distributing centromere function to thousands of repeat-based centromere units genome-wide. We uncover a complex genome organization in R. pubera that hides its unexpected octoploidy and describe a marked reduction in chromosome number for R. tenuis, which has only two chromosomes. We show that chromosome fusions, facilitated by repeat-based holocentromeres, promoted karyotype evolution and diploidization. Our study thus sheds light on several important aspects of genome architecture and evolution influenced by centromere organization.
AU  - Hofstatter, P.G.*
AU  - Thangavel, G.*
AU  - Lux, T.
AU  - Neumann, P.*
AU  - Vondrak, T.*
AU  - Novak, P.*
AU  - Zhang, M.*
AU  - Costa, L.T.*
AU  - Castellani, M.*
AU  - Scott, A.*
AU  - Toegelová, H.*
AU  - Fuchs, J.*
AU  - Mata-Sucre, Y.*
AU  - Dias, Y.*
AU  - Vanzela, A.L.L.*
AU  - Huettel, B.*
AU  - Almeida, C.C.S.*
AU  - Šimková, H.*
AU  - Souza, G.*
AU  - Pedrosa-Harand, A.*
AU  - Macas, J.*
AU  - Mayer, K.F.X.
AU  - Houben, A.*
AU  - Marques, A.R.*
C1  - 65851
C2  - 52819
SP  - 3153-3168.e18
TI  - Repeat-based holocentromeres influence genome architecture and karyotype evolution.
JO  - Cell
VL  - 185
IS  - 17
PY  - 2022
SN  - 0092-8674
ER  - 

TY  - JOUR
AU  - Jakobsson, J.*
AU  - Vincendeau, M.
C1  - 64143
C2  - 51806
CY  - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
SP  - 400-400.e1
TI  - SnapShot: Human endogenous retroviruses.
JO  - Cell
VL  - 185
IS  - 2
PB  - Cell Press
PY  - 2022
SN  - 0092-8674
ER  - 

TY  - JOUR
AB  - Technological advances in a variety of scientific disciplines are being applied in the life sciences leading to an increase in the number scientists who see themselves or are classed as being multidisciplinary. Although their diverse skills are celebrated and needed to understand the immense complexity of life, being a multidisciplinary researcher can pose unique challenges. We asked multidisciplinary researchers and the director of an institute that fosters multidisciplinary research for their thoughts on what they see as the challenges or obstacles that multidisciplinary scientists can often face.
AU  - Wang, S.*
AU  - Marr, L.C.*
AU  - Contreras, L.M.*
AU  - Theis, F.J.
AU  - Nurse, P.*
C1  - 67583
C2  - 53554
SP  - 2623-2625
TI  - The challenges in finding your home as a multidisciplinary scientist.
JO  - Cell
VL  - 185
IS  - 15
PY  - 2022
SN  - 0092-8674
ER  - 

TY  - JOUR
AB  - Osteoarthritis affects over 300 million people worldwide. Here, we conduct a genome-wide association study meta-analysis across 826,690 individuals (177,517 with osteoarthritis) and identify 100 independently associated risk variants across 11 osteoarthritis phenotypes, 52 of which have not been associated with the disease before. We report thumb and spine osteoarthritis risk variants and identify differences in genetic effects between weight-bearing and non-weight-bearing joints. We identify sex-specific and early age-at-onset osteoarthritis risk loci. We integrate functional genomics data from primary patient tissues (including articular cartilage, subchondral bone, and osteophytic cartilage) and identify high-confidence effector genes. We provide evidence for genetic correlation with phenotypes related to pain, the main disease symptom, and identify likely causal genes linked to neuronal processes. Our results provide insights into key molecular players in disease processes and highlight attractive drug targets to accelerate translation.
AU  - Boer, C.G.*
AU  - Hatzikotoulas, K.
AU  - Southam, L.
AU  - Stefansdottir, L.*
AU  - Zhang, Y.*
AU  - Coutinho de Almeida, R.*
AU  - Wu, T.T.*
AU  - Zheng, J.*
AU  - Hartley, A.*
AU  - Teder-Laving, M.*
AU  - Skogholt, A.H.*
AU  - Terao, C.*
AU  - Zengini, E.*
AU  - Alexiadis, G.*
AU  - Barysenska, A.
AU  - Bjornsdottir, G.*
AU  - Gabrielsen, M.E.*
AU  - Gilly, A.
AU  - Ingvarsson, T.*
AU  - Johnsen, M.B.*
AU  - Jonsson, H.*
AU  - Kloppenburg, M.*
AU  - Luetge, A.*
AU  - Lund, S.H.*
AU  - Mägi, R.*
AU  - Mangino, M.*
AU  - Nelissen, R.R.G.H.H.*
AU  - Shivakumar, M.*
AU  - Steinberg, J.
AU  - Takuwa, H.*
AU  - Thomas, L.F.*
AU  - Tuerlings, M.*
AU  - arcOGEN Consortium*
AU  - HUNT All-In Pain*
AU  - ARGO Consortium*
AU  - Regeneron Genetics Center*
AU  - Babis, G.C.*
AU  - Cheung, J.P.Y.*
AU  - Kang, J.H.*
AU  - Kraft, P.*
AU  - Lietman, S.A.*
AU  - Samartzis, D.*
AU  - Slagboom, P.E.*
AU  - Stefansson, K.*
AU  - Thorsteinsdottir, U.*
AU  - Tobias, J.H.*
AU  - Uitterlinden, A.G.*
AU  - Winsvold, B.*
AU  - Zwart, J.A.*
AU  - Davey Smith, G.*
AU  - Sham, P.C.*
AU  - Thorleifsson, G.*
AU  - Gaunt, T.R.*
AU  - Morris, A.P.*
AU  - Valdes, A.M.*
AU  - Tsezou, A.*
AU  - Cheah, K.S.E.*
AU  - Ikegawa, S.*
AU  - Hveem, K.*
AU  - Esko, T.*
AU  - Wilkinson, J.M.*
AU  - Meulenbelt, I.*
AU  - Lee, M.T.M.*
AU  - van Meurs, J.B.J.*
AU  - Styrkarsdottir, U.*
AU  - Zeggini, E.
C1  - 62864
C2  - 51117
CY  - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
SP  - 4784-4818.e17
TI  - Deciphering osteoarthritis genetics across 826,690 individuals from 9 populations.
JO  - Cell
VL  - 184
IS  - 18
PB  - Cell Press
PY  - 2021
SN  - 0092-8674
ER  - 

TY  - JOUR
AB  - Neural stem cells (NSCs) in the adult brain transit from the quiescent state to proliferation to produce new neurons. The mechanisms regulating this transition in freely behaving animals are, however, poorly understood. We customized in vivo imaging protocols to follow NSCs for several days up to months, observing their activation kinetics in freely behaving mice. Strikingly, NSC division is more frequent during daylight and is inhibited by darkness-induced melatonin signaling. The inhibition of melatonin receptors affected intracellular Ca2+ dynamics and promoted NSC activation. We further discovered a Ca2+ signature of quiescent versus activated NSCs and showed that several microenvironmental signals converge on intracellular Ca2+ pathways to regulate NSC quiescence and activation. In vivo NSC-specific optogenetic modulation of Ca2+ fluxes to mimic quiescent-state-like Ca2+ dynamics in freely behaving mice blocked NSC activation and maintained their quiescence, pointing to the regulatory mechanisms mediating NSC activation in freely behaving animals.
AU  - Gengatharan, A.*
AU  - Malvaut, S.*
AU  - Marymonchyk, A.*
AU  - Ghareghani, M.*
AU  - Snapyan, M.*
AU  - Fischer-Sternjak, J.
AU  - Ninkovic, J.
AU  - Götz, M.
AU  - Saghatelyan, A.*
C1  - 61064
C2  - 49688
CY  - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
SP  - 709-722.e13
TI  - Adult neural stem cell activation in mice is regulated by the day/night cycle and intracellular calcium dynamics.
JO  - Cell
VL  - 184
IS  - 3
PB  - Cell Press
PY  - 2021
SN  - 0092-8674
ER  - 

TY  - JOUR
AB  - Vesicle-inducing protein in plastids 1 (VIPP1) is essential for the biogenesis and maintenance of thylakoid membranes, which transform light into life. However, it is unknown how VIPP1 performs its vital membrane-remodeling functions. Here, we use cryo-electron microscopy to determine structures of cyanobacterial VIPP1 rings, revealing how VIPP1 monomers flex and interweave to form basket-like assemblies of different symmetries. Three VIPP1 monomers together coordinate a non-canonical nucleotide binding pocket on one end of the ring. Inside the ring's lumen, amphipathic helices from each monomer align to form large hydrophobic columns, enabling VIPP1 to bind and curve membranes. In vivo mutations in these hydrophobic surfaces cause extreme thylakoid swelling under high light, indicating an essential role of VIPP1 lipid binding in resisting stress-induced damage. Using cryo-correlative light and electron microscopy (cryo-CLEM), we observe oligomeric VIPP1 coats encapsulating membrane tubules within the Chlamydomonas chloroplast. Our work provides a structural foundation for understanding how VIPP1 directs thylakoid biogenesis and maintenance.
AU  - Gupta, T.K.*
AU  - Klumpe, S.*
AU  - Gries, K.*
AU  - Heinz, S.*
AU  - Wietrzynski, W.
AU  - Ohnishi, N.*
AU  - Niemeyer, J.*
AU  - Spaniol, B.*
AU  - Schaffer, M.*
AU  - Rast, A.*
AU  - Ostermeier, M.*
AU  - Strauss, M.*
AU  - Plitzko, J.M.*
AU  - Baumeister, W.*
AU  - Rudack, T.*
AU  - Sakamoto, W.*
AU  - Nickelsen, J.*
AU  - Schuller, J.M.*
AU  - Schroda, M.*
AU  - Engel, B.D.
C1  - 62379
C2  - 50703
CY  - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
SP  - 3643-3659.e23
TI  - Structural basis for VIPP1 oligomerization and maintenance of thylakoid membrane integrity.
JO  - Cell
VL  - 184
IS  - 14
PB  - Cell Press
PY  - 2021
SN  - 0092-8674
ER  - 

TY  - JOUR
AB  - Environmental insults impair human health around the world. Contaminated air, water, soil, food, and occupational and household settings expose humans of all ages to a plethora of chemicals and environmental stressors. We propose eight hallmarks of environmental insults that jointly underpin the damaging impact of environmental exposures during the lifespan. Specifically, they include oxidative stress and inflammation, genomic alterations and mutations, epigenetic alterations, mitochondrial dysfunction, endocrine disruption, altered intercellular communication, altered microbiome communities, and impaired nervous system function. They provide a framework to understand why complex mixtures of environmental exposures induce severe health effects even at relatively modest concentrations.
AU  - Peters, A.
AU  - Nawrot, T.S.*
AU  - Baccarelli, A.A.*
C1  - 61454
C2  - 50120
CY  - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
SP  - 1455-1468
TI  - Hallmarks of environmental insults.
JO  - Cell
VL  - 184
IS  - 6
PB  - Cell Press
PY  - 2021
SN  - 0092-8674
ER  - 

TY  - JOUR
AB  - COVID-19-induced “acute respiratory distress syndrome” (ARDS) is associated with prolonged respiratory failure and high mortality, but the mechanistic basis of lung injury remains incompletely understood. Here, we analyze pulmonary immune responses and lung pathology in two cohorts of patients with COVID-19 ARDS using functional single-cell genomics, immunohistology, and electron microscopy. We describe an accumulation of CD163-expressing monocyte-derived macrophages that acquired a profibrotic transcriptional phenotype during COVID-19 ARDS. Gene set enrichment and computational data integration revealed a significant similarity between COVID-19-associated macrophages and profibrotic macrophage populations identified in idiopathic pulmonary fibrosis. COVID-19 ARDS was associated with clinical, radiographic, histopathological, and ultrastructural hallmarks of pulmonary fibrosis. Exposure of human monocytes to SARS-CoV-2, but not influenza A virus or viral RNA analogs, was sufficient to induce a similar profibrotic phenotype in vitro. In conclusion, we demonstrate that SARS-CoV-2 triggers profibrotic macrophage responses and pronounced fibroproliferative ARDS.
AU  - Wendisch, D.*
AU  - Dietrich, O.*
AU  - Mari, T.*
AU  - von Stillfried, S.*
AU  - Ibarra Del Rio, I.A.
AU  - Mittermaier, M.*
AU  - Mache, C.*
AU  - Chua, R.L.*
AU  - Knöll, R.*
AU  - Timm, S.*
AU  - Brumhard, S.*
AU  - Krammer, T.*
AU  - Zauber, H.*
AU  - Hiller, A.L.*
AU  - Pascual-Reguant, A.*
AU  - Mothes, R.*
AU  - Bülow, R.D.*
AU  - Schulze, J.*
AU  - Leipold, A.M.*
AU  - Djudjaj, S.*
AU  - Erhard, F.*
AU  - Geffers, R.*
AU  - Pott, F.*
AU  - Kazmierski, J.*
AU  - Radke, J.*
AU  - Pergantis, P.*
AU  - Baßler, K.*
AU  - Conrad, C.*
AU  - Aschenbrenner, A.C.*
AU  - Sawitzki, B.*
AU  - Landthaler, M.*
AU  - Wyler, E.*
AU  - Horst, D.*
AU  - Hippenstiel, S.*
AU  - Hocke, A.C.*
AU  - Heppner, F.L.*
AU  - Uhrig, A.*
AU  - Garcia, C.*
AU  - Machleidt, F.*
AU  - Herold, S.*
AU  - Elezkurtaj, S.*
AU  - Thibeault, C.*
AU  - Witzenrath, M.*
AU  - Cochain, C.*
AU  - Suttorp, N.*
AU  - Drosten, C.*
AU  - Goffinet, C.*
AU  - Kurth, F.*
AU  - Schultze, J.L.*
AU  - Radbruch, H.*
AU  - Ochs, M.*
AU  - Eils, R.*
AU  - Müller-Redetzky, H.*
AU  - Hauser, A.E.*
AU  - Luecken, M.
AU  - Theis, F.J.
AU  - Wolff, T.*
AU  - Boor, P.*
AU  - Selbach, M.*
AU  - Saliba, A.E.*
AU  - Sander, L.E.*
C1  - 63845
C2  - 51774
CY  - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
SP  - 6243-6261.e27
TI  - SARS-CoV-2 infection triggers profibrotic macrophage responses and lung fibrosis.
JO  - Cell
VL  - 184
IS  - 26
PB  - Cell Press
PY  - 2021
SN  - 0092-8674
ER  - 

TY  - JOUR
AB  - Ferroptosis is a regulated form of cell death that occurs when phospholipids with polyunsaturated fatty acyl tails are oxidized in an iron-dependent manner. Research in recent years has uncovered complex cellular networks that induce and suppress lethal lipid peroxidation. This SnapShot provides an overview of ferroptosis-related pathways, including relevant biomolecules and small-molecule modulators regulating them.
AU  - Hadian, K.
AU  - Stockwell, B.R.*
C1  - 59251
C2  - 48694
CY  - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
SP  - 1188-1188.e1
TI  - SnapShot: Ferroptosis.
JO  - Cell
VL  - 181
IS  - 5
PB  - Cell Press
PY  - 2020
SN  - 0092-8674
ER  - 

TY  - JOUR
AB  - Researchers around the globe have been mounting, accelerating, and redeploying efforts across disciplines and organizations to tackle the SARS-CoV-2 outbreak. However, humankind continues to be afflicted by numerous other devastating diseases in increasing numbers. Here, we outline considerations and opportunities toward striking a good balance between maintaining and redefining research priorities.
AU  - Zeggini, E.
AU  - Baumann, M.*
AU  - Götz, M.
AU  - Herzig, S.
AU  - Hrabě de Angelis, M.
AU  - Tschöp, M.H.
C1  - 59130
C2  - 48571
CY  - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
SP  - 1189-1193
TI  - Biomedical research goes viral: Dangers and opportunities.
JO  - Cell
VL  - 181
IS  - 6
PB  - Cell Press
PY  - 2020
SN  - 0092-8674
ER  - 

TY  - JOUR
AB  - Optical tissue transparency permits scalable cellular and molecular 
      investigation of complex tissues in 3D. Adult human organs are 
      particularly challenging to render transparent because of the 
      accumulation of dense and sturdy molecules in decades-aged tissues. To 
      overcome these challenges, we developed SHANEL, a method based on a new 
      tissue permeabilization approach to clear and label stiff human organs. 
      We used SHANEL to render the intact adult human brain and kidney 
      transparent and perform 3D histology with antibodies and dyes in 
      centimeters-depth. Thereby, we revealed structural details of the intact
       human eye, human thyroid, human kidney, and transgenic pig pancreas at 
      the cellular resolution. Furthermore, we developed a deep learning 
      pipeline to analyze millions of cells in cleared human brain tissues 
      within hours with standard lab computers. Overall, SHANEL is a robust 
      and unbiased technology to chart the cellular and molecular architecture
       of large intact mammalian organs.
AU  - Zhao, S.
AU  - Todorov, M.I.
AU  - Cai, R.
AU  - Ai-Maskari, R.*
AU  - Steinke, H.*
AU  - Kemter, E.*
AU  - Mai, H.
AU  - Rong, Z.
AU  - Warmer, M.
AU  - Stanic Aguilera, K.N.
AU  - Schoppe, O.*
AU  - Paetzold, J.C.*
AU  - Gesierich, B.*
AU  - Wong, M.N.*
AU  - Huber, T.B.*
AU  - Duering, M.*
AU  - Bruns, O.T.
AU  - Menze, B.*
AU  - Lipfert, J.*
AU  - Puelles, V.G.*
AU  - Wolf, E.*
AU  - Bechmann, I.*
AU  - Ertürk, A.
C1  - 58893
C2  - 48419
SP  - 796-812
TI  - Cellular and molecular probing of intact human organs.
JO  - Cell
VL  - 180
IS  - 4
PY  - 2020
SN  - 0092-8674
ER  - 

TY  - JOUR
AB  - There is pressing urgency to understand the pathogenesis of the severe acute respiratory syndrome coronavirus clade 2 (SARS-CoV-2), which causes the disease COVID-19. SARS-CoV-2 spike (S) protein binds angiotensin-converting enzyme 2 (ACE2), and in concert with host proteases, principally transmembrane serine protease 2 (TMPRSS2), promotes cellular entry. The cell subsets targeted by SARS-CoV-2 in host tissues and the factors that regulate ACE2 expression remain unknown. Here, we leverage human, non-human primate, and mouse single-cell RNA-sequencing (scRNA-seq) datasets across health and disease to uncover putative targets of SARS-CoV-2 among tissue-resident cell subsets. We identify ACE2 and TMPRSS2 co-expressing cells within lung type II pneumocytes, ileal absorptive enterocytes, and nasal goblet secretory cells. Strikingly, we discovered that ACE2 is a human interferon-stimulated gene (ISG) in vitro using airway epithelial cells and extend our findings to in vivo viral infections. Our data suggest that SARS-CoV-2 could exploit species-specific interferon-driven upregulation of ACE2, a tissue-protective mediator during lung injury, to enhance infection.
AU  - Ziegler, C.G.K.*
AU  - Allon, S.J.*
AU  - Nyquist, S.K.*
AU  - Mbano, I.M.*
AU  - Miao, V.N.*
AU  - Tzouanas, C.N.*
AU  - Cao, Y.*
AU  - Yousif, A.S.*
AU  - Bals, J.*
AU  - Hauser, B.M.*
AU  - Feldman, J.*
AU  - Muus, C.*
AU  - Wadsworth, M.H.*
AU  - Kazer, S.W.*
AU  - Hughes, T.K.*
AU  - Doran, B.*
AU  - Gatter, G.J.*
AU  - Vukovic, M.*
AU  - Taliaferro, F.*
AU  - Mead, B.E.*
AU  - Guo, Z.*
AU  - Wang, J.P.*
AU  - Gras, D.*
AU  - Plaisant, M.*
AU  - Ansari, M.
AU  - Angelidis, I.
AU  - Adler, H.
AU  - Sucre, J.M.S.*
AU  - Taylor, C.J.*
AU  - Lin, B.*
AU  - Waghray, A.*
AU  - Mitsialis, V.*
AU  - Dwyer, D.F.*
AU  - Buchheit, K.M.*
AU  - Boyce, J.A.*
AU  - Barrett, N.A.*
AU  - Laidlaw, T.M.*
AU  - Carroll, S.L.*
AU  - Colonna, L.*
AU  - Tkachev, V.*
AU  - Peterson, C.W.*
AU  - Yu, A.*
AU  - Zheng, H.B.*
AU  - Gideon, H.P.*
AU  - Winchell, C.G.*
AU  - Lin, P.L.*
AU  - Bingle, C.D.*
AU  - Snapper, S.B.*
AU  - Kropski, J.A.*
AU  - Theis, F.J.
AU  - Schiller, H. B.
AU  - Zaragosi, L.E.*
AU  - Barbry, P.*
AU  - Leslie, A.*
AU  - Kiem, H.P.*
AU  - Flynn, J.L.*
AU  - Fortune, S.M.*
AU  - Berger, B.*
AU  - Finberg, R.W.*
AU  - Kean, L.S.*
AU  - Garber, M.*
AU  - Schmidt, A.G.*
AU  - Lingwood, D.*
AU  - Shalek, A.K.*
AU  - Ordovas-Montanes, J.*
C1  - 59153
C2  - 48597
CY  - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
SP  - 1016-1035
TI  - SARS-CoV-2 receptor ACE2 is an interferon-stimulated gene in human airway epithelial cells and is detected in specific cell subsets across tissues.
JO  - Cell
VL  - 181
IS  - 5
PB  - Cell Press
PY  - 2020
SN  - 0092-8674
ER  - 

TY  - JOUR
AB  - Maintaining proteostasis in eukaryotic protein folding involves cooperation of distinct chaperone systems. To understand how the essential ring-shaped chaperonin TRiC/CCT cooperates with the chaperone prefoldin/GIMc (PFD), we integrate cryoelectron microscopy (cryo-EM), crosslinking-masss-pectrometry and biochemical and cellular approaches to elucidate the structural and functional interplay between TRiC/CCT and PFD. We find these hetero-oligomeric chaperones associate in a defined architecture, through a conserved interface of electrostatic contacts that serves as a pivot point for a TRiC-PFD conformational cycle. PFD alternates between an open "latched" conformation and a closed "engaged" conformation that aligns the PFD-TRiC substrate binding chambers. PFD can act after TRiC bound its substrates to enhance the rate and yield of the folding reaction, suppressing non-productive reaction cycles. Disrupting the TRiC-PFD interaction in vivo is strongly deleterious, leading to accumulation of amyloid aggregates. The supra-chaperone assembly formed by PFD and TRiC is essential to prevent toxic conformations and ensure effective cellular proteostasis.
AU  - Gestaut, D.*
AU  - Roh, S.H.*
AU  - Ma, B.*
AU  - Pintilie, G.*
AU  - Joachimiak, L.A.*
AU  - Leitner, A.*
AU  - Walzthoeni, T.
AU  - Aebersold, R.*
AU  - Chiu, H.*
AU  - Frydman, J.*
C1  - 55822
C2  - 46594
CY  - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
SP  - 751-765.e15
TI  - The chaperonin TRiC/CCT associates with prefoldin through a conserved electrostatic interface essential for cellular proteostasis.
JO  - Cell
VL  - 177
IS  - 3
PB  - Cell Press
PY  - 2019
SN  - 0092-8674
ER  - 

TY  - JOUR
AB  - Genomic studies in African populations provide unique opportunities to understand disease etiology, human diversity, and population history. In the largest study of its kind, comprising genome-wide data from 6,400 individuals and whole-genome sequences from 1,978 individuals from rural Uganda, we find evidence of geographically correlated fine-scale population substructure. Historically, the ancestry of modern Ugandans was best represented by a mixture of ancient East African pastoralists. We demonstrate the value of the largest sequence panel from Africa to date as an imputation resource. Examining 34 cardiometabolic traits, we show systematic differences in trait heritability between European and African populations, probably reflecting the differential impact of genes and environment. In a multi-trait pan-African GWAS of up to 14,126 individuals, we identify novel loci associated with anthropometric, hematological, lipid, and glycemic traits. We find that several functionally important signals are driven by Africa-specific variants, highlighting the value of studying diverse populations across the region.
AU  - Gurdasani, D.*
AU  - Carstensen, T.*
AU  - Fatumo, S.*
AU  - Chen, G.*
AU  - Franklin, C.S.*
AU  - Prado-Martinez, J.*
AU  - Bouman, H.*
AU  - Abascal, F.*
AU  - Haber, M.*
AU  - Tachmazidou, I.*
AU  - Mathieson, I.*
AU  - Ekoru, K.*
AU  - DeGorter, M.K.*
AU  - Nsubuga, R.N.*
AU  - Finan, C.*
AU  - Wheeler, E.*
AU  - Chen, L.*
AU  - Cooper, D.N.*
AU  - Schiffels, S.*
AU  - Chen, Y.*
AU  - Ritchie, G.R.S.*
AU  - Pollard, M.O.*
AU  - Fortune, M.D.*
AU  - Mentzer, A.J.*
AU  - Garrison, E.*
AU  - Bergström, A.*
AU  - Hatzikotoulas, K.*
AU  - Adeyemo, A.*
AU  - Doumatey, A.*
AU  - Elding, H.*
AU  - Wain, L.V.*
AU  - Ehret, G.*
AU  - Auer, P.L.*
AU  - Kooperberg, C.L.*
AU  - Reiner, A.P.*
AU  - Franceschini, N.*
AU  - Maher, D.P.*
AU  - Montgomery, S.B.*
AU  - Kadie, C.*
AU  - Widmer, C.*
AU  - Xue, Y.*
AU  - Seeley, J.*
AU  - Asiki, G.*
AU  - Kamali, A.*
AU  - Young, E.H.*
AU  - Pomilla, C.*
AU  - Soranzo, N.*
AU  - Zeggini, E.
AU  - Pirie, F.*
AU  - Morris, A.P.*
AU  - Heckerman, D.*
AU  - Tyler-Smith, C.*
AU  - Motala, A.*
AU  - Rotimi, C.*
AU  - Kaleebu, P.*
AU  - Barroso, I.*
AU  - Sandhu, M.S.*
C1  - 57250
C2  - 47642
CY  - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
SP  - 984-1002.e36
TI  - Uganda Genome Resource enables insights into population history and genomic discovery in Africa.
JO  - Cell
VL  - 179
IS  - 4
PB  - Cell Press
PY  - 2019
SN  - 0092-8674
ER  - 

TY  - JOUR
AB  - Reliable detection of disseminated tumor cells and of the biodistribution of tumor-targeting therapeutic antibodies within the entire body has long been needed to better understand and treat cancer metastasis. Here, we developed an integrated pipeline for automated quantification of cancer metastases and therapeutic antibody targeting, named DeepMACT. First, we enhanced the fluorescent signal of cancer cells more than 100-fold by applying the vDISCO method to image metastasis in transparent mice. Second, we developed deep learning algorithms for automated quantification of metastases with an accuracy matching human expert manual annotation. Deep learning-based quantification in 5 different metastatic cancer models including breast, lung, and pancreatic cancer with distinct organotropisms allowed us to systematically analyze features such as size, shape, spatial distribution, and the degree to which metastases are targeted by a therapeutic monoclonal antibody in entire mice. DeepMACT can thus considerably improve the discovery of effective antibody-based therapeutics at the preclinical stage.
AU  - Pan, C.
AU  - Schoppe, O.*
AU  - Parra-Damas, A.*
AU  - Cai, R.
AU  - Todorov, M.I.
AU  - Gondi, G.
AU  - von Neubeck, B.
AU  - Böğürcü-Seidel, N.*
AU  - Seidel, S.*
AU  - Sleiman, K.*
AU  - Veltkamp, C.*
AU  - Förstera, B.
AU  - Mai, H.
AU  - Rong, Z.
AU  - Trompak, O.*
AU  - Ghasemigharagoz, A.*
AU  - Reimer, M.A.*
AU  - Cuesta, A.M.*
AU  - Coronel, J.*
AU  - Jeremias, I.
AU  - Saur, D.*
AU  - Acker-Palmer, A.*
AU  - Acker, T.*
AU  - Garvalov, B.K.*
AU  - Menze, B.*
AU  - Zeidler, R.
AU  - Ertürk, A.
C1  - 57649
C2  - 47844
CY  - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
SP  - 1661-1676
TI  - Deep learning reveals cancer metastasis and therapeutic antibody targeting in entire body.
JO  - Cell
VL  - 179
IS  - 7
PB  - Cell Press
PY  - 2019
SN  - 0092-8674
ER  - 

TY  - JOUR
AB  - Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.
AU  - Cross-Disorder Group of the Psychiatric Genomics Consortium (Wichmann, H.-E.)
C1  - 58120
C2  - 48045
SP  - 1469-1482.e11
TI  - Genomic relationships, novel loci, and pleiotropic mechanisms across eight psychiatric disorders.
JO  - Cell
VL  - 179
IS  - 7
PY  - 2019
SN  - 0092-8674
ER  - 

TY  - JOUR
AB  - Cerebral cortex size differs dramatically between reptiles, birds, and mammals, owing to developmental differences in neuron production. In mammals, signaling pathways regulating neurogenesis have been identified, but genetic differences behind their evolution across amniotes remain unknown. We show that direct neurogenesis from radial glia cells, with limited neuron production, dominates the avian, reptilian, and mammalian paleocortex, whereas in the evolutionarily recent mammalian neocortex, most neurogenesis is indirect via basal progenitors. Gain- and loss-of-function experiments in mouse, chick, and snake embryos and in human cerebral organoids demonstrate that high Slit/Robo and low Dll1 signaling, via Jag1 and Jag2, are necessary and sufficient to drive direct neurogenesis. Attenuating Robo signaling and enhancing Dll1 in snakes and birds recapitulates the formation of basal progenitors and promotes indirect neurogenesis. Our study identifies modulation in activity levels of conserved signaling pathways as a primary mechanism driving the expansion and increased complexity of the mammalian neocortex during amniote evolution.
AU  - Cárdenas, A.*
AU  - Villalba, A.*
AU  - de Juan Romero, C.*
AU  - Picó, E.*
AU  - Kyrousi, C.*
AU  - Tzika, A.C.*
AU  - Tessier-Lavigne, M.*
AU  - Ma, L.*
AU  - Drukker, M.
AU  - Cappello, S.*
AU  - Borrell, V.*
C1  - 53702
C2  - 44970
CY  - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
SP  - 590-606.e21
TI  - Evolution of cortical neurogenesis in amniotes controlled by robo signaling levels.
JO  - Cell
VL  - 174
IS  - 3
PB  - Cell Press
PY  - 2018
SN  - 0092-8674
ER  - 

TY  - JOUR
AB  - Metabolic diseases are often characterized by circadian misalignment in different tissues, yet how altered coordination and communication among tissue clocks relate to specific pathogenic mechanisms remains largely unknown. Applying an integrated systems biology approach, we performed 24-hr metabolomics profiling of eight mouse tissues simultaneously. We present a temporal and spatial atlas of circadian metabolism in the context of systemic energy balance and under chronic nutrient stress (high-fat diet [HFD]). Comparative analysis reveals how the repertoires of tissue metabolism are linked and gated to specific temporal windows and how this highly specialized communication and coherence among tissue clocks is rewired by nutrient challenge. Overall, we illustrate how dynamic metabolic relationships can be reconstructed across time and space and how integration of circadian metabolomics data from multiple tissues can improve our understanding of health and disease.
AU  - Dyar, K.A.
AU  - Lutter, D.
AU  - Artati, A.
AU  - Ceglia, N.J.*
AU  - Liu, Y.*
AU  - Armenta, D.*
AU  - Jastroch, M.
AU  - Schneider, S.*
AU  - de Mateo, S.*
AU  - Cervantes, M.*
AU  - Abbondante, S.*
AU  - Tognini, P.*
AU  - Orozco-Solis, R.*
AU  - Kinouchi, K.*
AU  - Wang, C.*
AU  - Swerdloff, R.*
AU  - Nadeef, S.*
AU  - Masri, S.*
AU  - Magistretti, P.*
AU  - Orlando, V.*
AU  - Borrelli, E.*
AU  - Uhlenhaut, N.H.
AU  - Baldi, P.*
AU  - Adamski, J.
AU  - Tschöp, M.H.
AU  - Eckel-Mahan, K.L.*
AU  - Sassone-Corsi, P.*
C1  - 54245
C2  - 45323
CY  - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
SP  - 1571-1585.e11
TI  - Atlas of circadian metabolism reveals system-wide coordination and communication between clocks.
JO  - Cell
VL  - 174
IS  - 6
PB  - Cell Press
PY  - 2018
SN  - 0092-8674
ER  - 

TY  - JOUR
AB  - Purpose of Review Advances in technology have expanded telemedicine opportunities covering medical practice, research, and education. This is of particular importance in movement disorders (MDs), where the combination of disease progression, mobility limitations, and the sparse distribution of MD specialists increase the difficulty to access. In this review, we discuss the prospects, challenges, and strategies for telemedicine in MDs.Recent Findings Telemedicine for MDs has been mainly evaluated in Parkinson's disease (PD) and compared to in-office care is cost-effective with similar clinical care, despite the barriers to engagement. However, particular groups including pediatric patients, rare MDs, and the use of telemedicine in underserved areas need further research.Summary Interdisciplinary telemedicine and tele-education for MDs are feasible, provide similar care, and reduce travel costs and travel time compared to in-person visits. These benefits have been mainly demonstrated for PD but serve as a model for further validation in other movement disorders.
AU  - Hofweber, M.*
AU  - Hutten, S.*
AU  - Bourgeois, B.*
AU  - Spreitzer, E.*
AU  - Niedner-Boblenz, A.
AU  - Schifferer, M.*
AU  - Ruepp, M.D.*
AU  - Simons, M.*
AU  - Niessing, D.
AU  - Madl, T.*
AU  - Dormann, D.*
C1  - 53436
C2  - 44855
CY  - 233 Spring St, New York, Ny 10013 Usa
SP  - 706-719.e13
TI  - Phase separation of FUS is suppressed by its nuclear import receptor and arginine methylation.
JO  - Cell
VL  - 173
IS  - 3
PB  - Springer
PY  - 2018
SN  - 0092-8674
ER  - 

TY  - JOUR
AB  - Selenoproteins are rare proteins among all kingdoms of life containing the 21 st amino acid, selenocysteine. Selenocysteine resembles cysteine, differing only by the substitution of selenium for sulfur. Yet the actual advantage of selenolate- versus thiolate-based catalysis has remained enigmatic, as most of the known selenoproteins also exist as cysteine-containing homologs. Here, we demonstrate that selenolate-based catalysis of the essential mammalian selenoprotein GPX4 is unexpectedly dispensable for normal embryogenesis. Yet the survival of a specific type of interneurons emerges to exclusively depend on selenocysteine-containing GPX4, thereby preventing fatal epileptic seizures. Mechanistically, selenocysteine utilization by GPX4 confers exquisite resistance to irreversible overoxidation as cells expressing a cysteine variant are highly sensitive toward peroxide-induced ferroptosis. Remarkably, concomitant deletion of all selenoproteins in Gpx4 cys/cys cells revealed that selenoproteins are dispensable for cell viability provided partial GPX4 activity is retained. Conclusively, 200 years after its discovery, a specific and indispensable role for selenium is provided. The trace element selenium protects a critical population of interneurons from ferroptotic cell death.
AU  - Ingold, I.
AU  - Berndt, C.*
AU  - Schmitt, S.*
AU  - Doll, S.
AU  - Poschmann, G.*
AU  - Buday, K.
AU  - Roveri, A.*
AU  - Peng, X.*
AU  - Porto Freitas, F.
AU  - Seibt, T.*
AU  - Mehr, L.
AU  - Aichler, M.
AU  - Walch, A.K.
AU  - Lamp, D.
AU  - Jastroch, M.
AU  - Miyamoto, S.*
AU  - Wurst, W.
AU  - Ursini, F.*
AU  - Arnér, E.S.J.*
AU  - Fradejas-Villar, N.*
AU  - Schweizer, U.*
AU  - Zischka, H.
AU  - Friedmann Angeli, J.P.F.
AU  - Conrad, M.
C1  - 52658
C2  - 44114
CY  - Cambridge
SP  - 409–422.e21
TI  - Selenium utilization by GPX4 is required to prevent hydroperoxide-induced ferroptosis.
JO  - Cell
VL  - 172
IS  - 3
PB  - Cell Press
PY  - 2018
SN  - 0092-8674
ER  - 

TY  - JOUR
AB  - The molecular mediator and functional significance of meal-assosiated brown fat (BAT) thermogenesis remains elusive. Here, we identified the gut hormone secretin as a non-synmpathetic BAT activator mediating prandial thermogenesis, which consequentially induces satiation, thereby establishing a gut-secretin-BAT-brain axis in mammals with a physiological role of prandial thermogenesis in the control of satiation. Mechanistically, meal-associated rise in circulating secretin activates BAT thermogenesis by stimulating lipolysis upon binding to secretin receptors in brown adipocytes, is sensed in the brain and promotes satiation. Chronic infusion of a modified human secretin transiently elevates energy expenditure in diet-induced obese mice. Clinical trials with human subjects showed that thermogenesis after a single-meal ingestion correlated with postprandial secretin levels and that secretin infusions increased glucose uptake in BAT. Collectively, our findings highlight the largely unappreciated function of BAT in the control of satiation and qualify BAT as an even more attractive target for treating obesity.
AU  - Li, Y.*
AU  - Schnabl, K.*
AU  - Gabler, S.M.*
AU  - Willershäuser, M.*
AU  - Reber, J.
AU  - Karlas, A.
AU  - Laurila, S.*
AU  - Lahesmaa, M.*
AU  - U Din, M.*
AU  - Bast-Habersbrunner, A.*
AU  - Virtanen, K.A.*
AU  - Fromme, T.*
AU  - Bolze, F.*
AU  - O'Farrell, L.S.*
AU  - Alsina-Fernandez, J.*
AU  - Coskun, T.*
AU  - Ntziachristos, V.
AU  - Nuutila, P.*
AU  - Klingenspor, M.*
C1  - 54778
C2  - 45842
CY  - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
SP  - 1561-1574
TI  - Secretin-activated brown fat mediates prandial thermogenesis to induce satiation.
JO  - Cell
VL  - 175
IS  - 6
PB  - Cell Press
PY  - 2018
SN  - 0092-8674
ER  - 

TY  - JOUR
AB  - Trained innate immunity fosters a sustained favorable response of myeloid cells to a secondary challenge, despite their short lifespan in circulation. We thus hypothesized that trained immunity acts via modulation of hematopoietic stem and progenitor cells (HSPCs). Administration of beta-glucan (prototypical trained-immunity-inducing agonist) to mice induced expansion of progenitors of the myeloid lineage, which was associated with elevated signaling by innate immune mediators, such as IL-1 beta and granulocyte-macrophage colony-stimulating factor (GM-CSF), and with adaptations in glucose metabolism and cholesterol biosynthesis. The trained-immunity-related increase in myelopoiesis resulted in a beneficial response to secondary LPS challenge and protection from chemotherapy-induced myelosuppression in mice. Therefore, modulation of myeloid progenitors in the bone marrow is an integral component of trained immunity, which to date, was considered to involve functional changes of mature myeloid cells in the periphery.
AU  - Mitroulis, I.*
AU  - Ruppova, K.*
AU  - Wang, B.*
AU  - Chen, L.S.*
AU  - Grzybek, M.
AU  - Grinenko, T.*
AU  - Eugster, A.*
AU  - Troullinaki, M.*
AU  - Palladini, A.
AU  - Kourtzelis, I.*
AU  - Chatzigeorgiou, A.*
AU  - Schlitzer, A.*
AU  - Beyer, M.*
AU  - Joosten, L.A.B.*
AU  - Isermann, B.*
AU  - Lesche, M.*
AU  - Petzold, A.*
AU  - Simons, K.*
AU  - Henry, I.*
AU  - Dahl, A.*
AU  - Schultze, J.L.*
AU  - Wielockx, B.*
AU  - Zamboni, N.*
AU  - Mirtschink, P.*
AU  - Coskun, Ü.
AU  - Hajishengallis, G.*
AU  - Netea, M.G.*
AU  - Chavakis, T.*
C1  - 52718
C2  - 44296
CY  - Cambridge
SP  - 147-161.e12
TI  - Modulation of myelopoiesis progenitors is an integral component of trained immunity.
JO  - Cell
VL  - 172
IS  - 1-2
PB  - Cell Press
PY  - 2018
SN  - 0092-8674
ER  - 

TY  - JOUR
AB  - Land plants evolved from charophytic algae, among which Charophyceae possess the most complex body plans. We present the genome of Chara braunii; comparison of the genome to those of land plants identified evolutionary novelties for plant terrestrialization and land plant heritage genes. C. braunii employs unique xylan synthases for cell wall biosynthesis, a phragmoplast (cell separation) mechanism similar to that of land plants, and many phytohormones. C. braunii plastids are controlled via land-plant-like retrograde signaling, and transcriptional regulation is more elaborate than in other algae. The morphological complexity of this organism may result from expanded gene families, with three cases of particular note: genes effecting tolerance to reactive oxygen species (ROS), LysM receptor-like kinases, and transcription factors (TFs). Transcriptomic analysis of sexual reproductive structures reveals intricate control by TFs, activity of the ROS gene network, and the ancestral use of plant-like storage and stress protection proteins in the zygote.
AU  - Nishiyama, T.*
AU  - Sakayama, H.*
AU  - de Vries, J.*
AU  - Buschmann, H.*
AU  - Saint-Marcoux, D.*
AU  - Ullrich, K.K.*
AU  - Haas, F.B.*
AU  - Vanderstraeten, L.*
AU  - Becker, D.*
AU  - Lang, D.
AU  - Vosolsobě, S.*
AU  - Rombauts, S.*
AU  - Wilhelmsson, P.K.I.*
AU  - Janitza, P.*
AU  - Kern, R.*
AU  - Heyl, A.*
AU  - Rümpler, F.*
AU  - Villalobos, L.I.A.C.*
AU  - Clay, J.M.*
AU  - Skokan, R.*
AU  - Toyoda, A.*
AU  - Suzuki, Y.*
AU  - Kagoshima, H.*
AU  - Schijlen, E.*
AU  - Tajeshwar, N.*
AU  - Catarino, B.*
AU  - Hetherington, A.J.*
AU  - Saltykova, A.*
AU  - Bonnot, C.*
AU  - Breuninger, H.*
AU  - Symeonidi, A.*
AU  - Radhakrishnan, G.V.*
AU  - Van Nieuwerburgh, F.*
AU  - Deforce, D.*
AU  - Chang, C.*
AU  - Karol, K.G.*
AU  - Hedrich, R.*
AU  - Ulvskov, P.*
AU  - Glöckner, G.*
AU  - Delwiche, C.F.*
AU  - Petrášek, J.*
AU  - van de Peer, Y.*
AU  - Friml, J.*
AU  - Beilby, M.*
AU  - Dolan, L.*
AU  - Kohara, Y.*
AU  - Sugano, S.*
AU  - Fujiyama, A.*
AU  - Delaux, P.M.*
AU  - Quint, M.*
AU  - Theißen, G.*
AU  - Hagemann, M.*
AU  - Harholt, J.*
AU  - Dunand, C.*
AU  - Zachgo, S.*
AU  - Langdale, J.*
AU  - Maumus, F.*
AU  - Van Der Straeten, D.*
AU  - Gould, S.B.*
AU  - Rensing, S.A.*
C1  - 53909
C2  - 45128
SP  - 448-464.e24
TI  - The Chara Genome: Secondary complexity and implications for plant terrestrialization.
JO  - Cell
VL  - 174
IS  - 2
PY  - 2018
SN  - 0092-8674
ER  - 

TY  - JOUR
AB  - Because human energy metabolism evolved to favor adiposity over leanness, the availability of palatable, easily attainable, and calorically dense foods has led to unprecedented levels of obesity and its associated metabolic co-morbidities that appear resistant to traditional lifestyle interventions. However, recent progress identifying the molecular signaling pathways through which the brain and the gastrointestinal system communicate to govern energy homeostasis, combined with emerging insights on the molecular mechanisms underlying successful bariatric surgery, gives reason to be optimistic that novel precision medicines that mimic, enhance, and/or modulate gut-brain signaling can have unprecedented potential for stopping the obesity and type 2 diabetes pandemics.
AU  - Clemmensen, C.
AU  - Müller, T.D.
AU  - Woods, S.C.*
AU  - Berthoud, H.R.*
AU  - Seeley, R.J.*
AU  - Tschöp, M.H.
C1  - 50638
C2  - 42656
CY  - Cambridge
SP  - 758-774
TI  - Gut-brain cross-talk in metabolic control.
JO  - Cell
VL  - 168
IS  - 5
PB  - Cell Press
PY  - 2017
SN  - 0092-8674
ER  - 

TY  - JOUR
AB  - Ferroptosis is a form of regulated cell death characterized by the iron-dependent accumulation of lipid hydroperoxides to lethal levels. Emerging evidence suggests that ferroptosis represents an ancient vulnerability caused by the incorporation of polyunsaturated fatty acids into cellular membranes, and cells have developed complex systems that exploit and defend against this vulnerability in different contexts. The sensitivity to ferroptosis is tightly linked to numerous biological processes, including amino acid, iron, and polyunsaturated fatty acid metabolism, and the biosynthesis of glutathione, phospholipids, NADPH, and coenzyme Q10. Ferroptosis has been implicated in the pathological cell death associated with degenerative diseases (i.e., Alzheimer's, Huntington's, and Parkinson's diseases), carcinogenesis, stroke, intracerebral hemorrhage, traumatic brain injury, ischemia-reperfusion injury, and kidney degeneration in mammals and is also implicated in heat stress in plants. Ferroptosis may also have a tumor-suppressor function that could be harnessed for cancer therapy. This Primer reviews the mechanisms underlying ferroptosis, highlights connections to other areas of biology and medicine, and recommends tools and guidelines for studying this emerging form of regulated cell death.
AU  - Stockwell, B.R.*
AU  - Friedmann Angeli, J.P.F.
AU  - Bayir, H.*
AU  - Bush, A.I.*
AU  - Conrad, M.
AU  - Dixon, S.J.*
AU  - Fulda, S.*
AU  - Gascón, S.
AU  - Hatzios, S.K.*
AU  - Kagan, V.E.*
AU  - Noel, K.*
AU  - Jiang, X.*
AU  - Linkermann, A.*
AU  - Murphy, M.E.*
AU  - Overholtzer, M.*
AU  - Oyagi, A.*
AU  - Pagnussat, G.C.*
AU  - Park, J.*
AU  - Ran, Q.*
AU  - Rosenfeld, C.S.*
AU  - Salnikow, K.*
AU  - Tang, D.*
AU  - Torti, F.M.*
AU  - Torti, S.V.*
AU  - Toyokuni, S.*
AU  - Woerpel, K.A.*
AU  - Zhang, D.D.*
C1  - 52052
C2  - 43691
SP  - 273-285
TI  - Ferroptosis: A regulated cell death nexus linking metabolism, redox biology, and disease.
JO  - Cell
VL  - 171
IS  - 2
PY  - 2017
SN  - 0092-8674
ER  - 

TY  - JOUR
AB  - More than one-half billion people are obese, and despite progress in genetic research, much of the heritability of obesity remains enigmatic. Here, we identify a Trim28-dependent network capable of triggering obesity in a non-Mendelian, "on/off" manner. Trim28(+/D9) mutant mice exhibit a bi-modal body-weight distribution, with isogenic animals randomly emerging as either normal or obese and few intermediates. We find that the obese-"on" state is characterized by reduced expression of an imprinted gene network including Nnat, Peg3, Cdkn1c, and Plagl1 and that independent targeting of these alleles recapitulates the stochastic bi-stable disease phenotype. Adipose tissue transcriptome analyses in children indicate that humans too cluster into distinct sub-populations, stratifying according to Trim28 expression, transcriptome organization, and obesity-associated imprinted gene dysregulation. These data provide evidence of discrete polyphenism in mouse and man and thus carry important implications for complex trait genetics, evolution, and medicine.
AU  - Dalgaard, K.*
AU  - Landgraf, K.*
AU  - Heyne, S.*
AU  - Lempradl, A.*
AU  - Longinotto, J.*
AU  - Gossens, K.*
AU  - Ruf, M.*
AU  - Orthofer, M.*
AU  - Strogantsev, R.*
AU  - Selvaraj, M.*
AU  - Lu, T.T.*
AU  - Casas, E.*
AU  - Teperino, R.
AU  - Surani, M.A.*
AU  - Zvetkova, I.*
AU  - Rimmington, D.
AU  - Tung, Y.C.L.*
AU  - Lam, B.*
AU  - Larder, R.*
AU  - Yeo, G.S.H.*
AU  - O'Rahilly, S.*
AU  - Vavouri, T.*
AU  - Whitelaw, E.*
AU  - Penninger, J.M.*
AU  - Jenuwein, T.*
AU  - Cheung, C.*
AU  - Ferguson-Smith, A.C.*
AU  - Coll, A.P.*
AU  - Koerner, A.*
AU  - Pospisilik, J.A.*
C1  - 47903
C2  - 41621
CY  - Cambridge
SP  - 353-364
TI  - Trim28 haploinsufficiency triggers bi-stable epigenetic obesity.
JO  - Cell
VL  - 164
IS  - 3
PB  - Cell Press
PY  - 2016
SN  - 0092-8674
ER  - 

TY  - JOUR
AB  - Glucagon and thyroid hormone (T3) exhibit therapeutic potential for metabolic disease but also exhibit undesired effects. We achieved synergistic effects of these two hormones and mitigation of their adverse effects by engineering chemical conjugates enabling delivery of both activities within one precisely targeted molecule. Coordinated glucagon and T3 actions synergize to correct hyperlipidemia, steatohepatitis, atherosclerosis, glucose intolerance, and obesity in metabolically compromised mice. We demonstrate that each hormonal constituent mutually enriches cellular processes in hepatocytes and adipocytes via enhanced hepatic cholesterol metabolism and white fat browning. Synchronized signaling driven by glucagon and T3 reciprocally minimizes the inherent harmful effects of each hormone. Liver-directed T3 action offsets the diabetogenic liability of glucagon, and glucagon-mediated delivery spares the cardiovascular system from adverse T3 action. Our findings support the therapeutic utility of integrating these hormones into a single molecular entity that offers unique potential for treatment of obesity, type 2 diabetes, and cardiovascular disease.
AU  - Finan, B.
AU  - Clemmensen, C.
AU  - Zhu, Z.*
AU  - Stemmer, K.
AU  - Gauthier, K.*
AU  - Müller, L.
AU  - de Angelis, M.
AU  - Moreth, K.
AU  - Neff, F.
AU  - Perez-Tilve, D.*
AU  - Fischer, K.
AU  - Lutter, D.
AU  - Sánchez-Garrido, M.A.
AU  - Liu, P.*
AU  - Tuckermann, J.P.*
AU  - Malehmir, M.*
AU  - Healy, M.E.*
AU  - Weber, A.*
AU  - Heikenwälder, M.*
AU  - Jastroch, M.
AU  - Kleinert, M.
AU  - Jall, S.
AU  - Brandt, S.
AU  - Flamant, F.*
AU  - Schramm, K.-W.
AU  - Biebermann, H.*
AU  - Döring, Y.*
AU  - Weber, C.*
AU  - Habegger, K.M.*
AU  - Keuper, M.
AU  - Gelfanov, V.*
AU  - Liu, F.*
AU  - Köhrle, J.*
AU  - Rozman, J.
AU  - Fuchs, H.
AU  - Gailus-Durner, V.
AU  - Hrabě de Angelis, M.
AU  - Hofmann, S.M.
AU  - Yang, B.*
AU  - Tschöp, M.H.
AU  - DiMarchi, R.*
AU  - Müller, T.D.
C1  - 49702
C2  - 40741
CY  - Cambridge
SP  - 843-857.e14
TI  - Chemical hybridization of glucagon and thyroid hormone optimizes therapeutic Impact for metabolic disease.
JO  - Cell
VL  - 167
IS  - 3
PB  - Cell Press
PY  - 2016
SN  - 0092-8674
ER  - 

TY  - JOUR
AB  - We report that astrocytic insulin signaling co-regulates hypothalamic glucose sensing and systemic glucose metabolism. Postnatal ablation of insulin receptors (IRs) in glial fibrillary acidic protein (GFAP)-expressing cells affects hypothalamic astrocyte morphology, mitochondrial function, and circuit connectivity. Accordingly, astrocytic IR ablation reduces glucose-induced activation of hypothalamic pro-opio-melanocortin (POMC) neurons and impairs physiological responses to changes in glucose availability. Hypothalamus-specific knockout of astrocytic IRs, as well as postnatal ablation by targeting glutamate aspartate transporter (GLAST)-expressing cells, replicates such alterations. A normal response to altering directly CNS glucose levels in mice lacking astrocytic IRs indicates a role in glucose transport across the blood-brain barrier (BBB). This was confirmed in vivo in GFAP-IR KO mice by using positron emission tomography and glucose monitoring in cerebral spinal fluid. We conclude that insulin signaling in hypothalamic astrocytes co-controls CNS glucose sensing and systemic glucose metabolism via regulation of glucose uptake across the BBB.
AU  - García-Cáceres, C.
AU  - Quarta, C.
AU  - Varela, L.*
AU  - Gao, Y.
AU  - Gruber, T.
AU  - Legutko, B.
AU  - Jastroch, M.
AU  - Johansson, P.A.
AU  - Ninkovic, J.
AU  - Yi, C.-X.
AU  - Le Thuc, O.
AU  - Szigeti-Buck, K.*
AU  - Cai, W.*
AU  - Meyer, C.W.
AU  - Pfluger, P.T.
AU  - Fernandez, A.M.*
AU  - Luquet, S.*
AU  - Woods, S.C.*
AU  - Torres-Alemán, I.*
AU  - Kahn, C.R.*
AU  - Götz, M.
AU  - Horvath, T.L.*
AU  - Tschöp, M.H.
C1  - 49265
C2  - 41767
CY  - Cambridge
SP  - 867-880
TI  - Astrocytic insulin signaling couples brain glucose uptake with nutrient availability.
JO  - Cell
VL  - 166
IS  - 4
PB  - Cell Press
PY  - 2016
SN  - 0092-8674
ER  - 

TY  - JOUR
AB  - Heritable epigenetic mechanisms might contribute to the worldwide increase in the prevalence of obesity. Dalgaard et al. identify an epigenetic molecular switch that controls body weight control. The discovery suggests the existence of mammalian polyphenism in energy metabolism and might have implications for strategies to limit the obesity epidemic.
AU  - Quarta, C.
AU  - Schneider, R.
AU  - Tschöp, M.H.
C1  - 47785
C2  - 39479
CY  - Cambridge
SP  - 341-342
TI  - Epigenetic ON/OFF switches for obesity.
JO  - Cell
VL  - 164
IS  - 3
PB  - Cell Press
PY  - 2016
SN  - 0092-8674
ER  - 

TY  - JOUR
AB  - Selection and domestication of plants with genes that prevent grains from shattering in cereals was essential for human civilization's transition to agriculture-based societies. In this issue, Pourkheirandish et al. show that domestication of barley required evolution of a molecular system distinct from other grains, such as rice and maize, and reveal that present-day cultivars derive from two ancient domestication centers.
AU  - Haberer, G.
AU  - Mayer, K.F.X.
C1  - 46448
C2  - 37539
CY  - Cambridge
SP  - 469-471
TI  - Barley: From brittle to stable harvest.
JO  - Cell
VL  - 162
IS  - 3
PB  - Cell Press
PY  - 2015
SN  - 0092-8674
ER  - 

TY  - JOUR
AB  - Genome-wide association studies have revealed numerous risk loci associated with diverse diseases. However, identification of disease-causing variants within association loci remains a major challenge. Divergence in gene expression due to cis-regulatory variants in noncoding regions is central to disease susceptibility. We show that integrative computational analysis of phylogenetic conservation with a complexity assessment of co-occurring transcription factor binding sites (TFBS) can identify cis-regulatory variants and elucidate their mechanistic role in disease. Analysis of established type 2 diabetes risk loci revealed a striking clustering of distinct homeobox TFBS. We identified the PRRX1 homeobox factor as a repressor of PPARG2 expression in adipose cells and demonstrate its adverse effect on lipid metabolism and systemic insulin sensitivity, dependent on the rs4684847 risk allele that triggers PRRX1 binding. Thus, cross-species conservation analysis at the level of co-occurring TFBS provides a valuable contribution to the translation of genetic association signals to disease-related molecular mechanisms.
AU  - Claussnitzer, M.
AU  - Dankel, S.N.*
AU  - Klocke, B.*
AU  - Grallert, H.
AU  - Glunk, V.
AU  - Berulava, T.*
AU  - Lee, H.K.
AU  - Oskolkov, N.*
AU  - Fadista, J.*
AU  - Ehlers, K.
AU  - Wahl, S.
AU  - Hoffmann, C.*
AU  - Qian, K.
AU  - Rönn, T.*
AU  - Riess, H.
AU  - Müller-Nurasyid, M.
AU  - Bretschneider, N.*
AU  - Schroeder, T.
AU  - Skurk, T.*
AU  - Horsthemke, B.*
AU  - DIAGRAM Consortium (Gieger, C.
AU  - Huth, C.
AU  - Klopp, N.
AU  - Meitinger, T.
AU  - Petersen, A.-K.
AU  - Thorand, B.
AU  - Wichmann, H.-E.)
AU  - Spieler, D.
AU  - Klingenspor, M.
AU  - Seifert, M.*
AU  - Kern, M.J.*
AU  - Mehjert, N.*
AU  - Dahlman, I.*
AU  - Hansson, O.*
AU  - Hauck, S.M.
AU  - Blüher, M.*
AU  - Arner, P.*
AU  - Groop, L.*
AU  - Illig, T.
AU  - Suhre, K.
AU  - Hsu, Y.H.*
AU  - Mellgren, G.*
AU  - Hauner, H.
AU  - Laumen, H.
C1  - 28980
C2  - 33594
SP  - 343-358
TI  - Leveraging cross-species transcription factor binding site patterns: From diabetes risk loci to disease mechanisms.
JO  - Cell
VL  - 156
IS  - 1-2
PB  - Cell Press
PY  - 2014
SN  - 0092-8674
ER  - 

TY  - JOUR
AB  - Protein folding in the cell relies on the orchestrated action of conserved families of molecular chaperones, the Hsp70 and Hsp90 systems. Hsp70 acts early and Hsp90 late in the folding path, yet the molecular basis of this timing is enigmatic, mainly because the substrate specificity of Hsp90 is poorly understood. Here, we obtained a structural model of Hsp90 in complex with its natural disease-associated substrate, the intrinsically disordered Tau protein. Hsp90 binds to a broad region in Tau that includes the aggregation-prone repeats. Complementarily, a 106-Å-long substrate-binding interface in Hsp90 enables many low-affinity contacts. This allows recognition of scattered hydrophobic residues in late folding intermediates that remain after early burial of the Hsp70 sites. Our model resolves the paradox of how Hsp90 specifically selects for late folding intermediates but also for some intrinsically disordered proteins-through the eyes of Hsp90 they look the same.
AU  - Karagöz, G.E.*
AU  - Duarte, A.M.*
AU  - Akoury, E.*
AU  - Ippel, H.*
AU  - Biernat, J.*
AU  - Morán Luengo, T.*
AU  - Radli, M.*
AU  - Didenko, T.*
AU  - Nordhues, B.A.*
AU  - Veprintsev, D.B.*
AU  - Dickey, C.A.*
AU  - Mandelkow, E.-M.*
AU  - Zweckstetter, M.*
AU  - Boelens, R.*
AU  - Madl, T.
AU  - Rüdiger, S.G.*
C1  - 30712
C2  - 33791
CY  - Cambridge
SP  - 963-974
TI  - Hsp90-tau complex reveals molecular basis for specificity in chaperone action.
JO  - Cell
VL  - 156
IS  - 5
PB  - Cell Press
PY  - 2014
SN  - 0092-8674
ER  - 

TY  - JOUR
AB  - Fatty acids are an important class of signaling molecules regulating key aspects of whole body metabolism and physiology. In this issue, Yore et al. report a group of branched fatty acid esters of hydroxy fatty acids that regulate insulin secretion and glucose uptake through the activation of GPR120.
AU  - Ussar, S.
AU  - Tschöp, M.H.
C1  - 32521
C2  - 35102
CY  - Cambridge
SP  - 238-240
TI  - [Br]eaking FAt.
JO  - Cell
VL  - 159
IS  - 2
PB  - Cell Press
PY  - 2014
SN  - 0092-8674
ER  - 

TY  - JOUR
AB  - The linear ubiquitin (Ub) chain assembly complex (LUBAC) is an E3 ligase that specifically assembles Met1-linked (also known as linear) Ub chains that regulate nuclear factor κB (NF-κB) signaling. Deubiquitinases (DUBs) are key regulators of Ub signaling, but a dedicated DUB for Met1 linkages has not been identified. Here, we reveal a previously unannotated human DUB, OTULIN (also known as FAM105B), which is exquisitely specific for Met1 linkages. Crystal structures of the OTULIN catalytic domain in complex with diubiquitin reveal Met1-specific Ub-binding sites and a mechanism of substrate-assisted catalysis in which the proximal Ub activates the catalytic triad of the protease. Mutation of Ub Glu16 inhibits OTULIN activity by reducing kcat 240-fold. OTULIN overexpression or knockdown affects NF-κB responses to LUBAC, TNFα, and poly(I:C) and sensitizes cells to TNFα-induced cell death. We show that OTULIN binds LUBAC and that overexpression of OTULIN prevents TNFα-induced NEMO association with ubiquitinated RIPK1. Our data suggest that OTULIN regulates Met1-polyUb signaling.
AU  - Keusekotten, K.*
AU  - Elliott, P.R.*
AU  - Glockner, L.
AU  - Fiil, B.K.*
AU  - Damgaard, R.B.*
AU  - Kulathu, Y.*
AU  - Wauer, T.*
AU  - Hospenthal, M.K.*
AU  - Gyrd-Hansen, M.*
AU  - Krappmann, D.
AU  - Hofmann, K.*
AU  - Komander, D.*
C1  - 24823
C2  - 31694
SP  - 1312-1326
TI  - OTULIN antagonizes LUBAC signaling by specifically hydrolyzing Met1-linked polyubiquitin.
JO  - Cell
VL  - 153
IS  - 6
PB  - Cell Press
PY  - 2013
SN  - 0092-8674
ER  - 

TY  - JOUR
AB  - Evolution of the mammalian brain encompassed a remarkable increase in size of the cerebral cortex, which includes tangential and radial expansion. However, the mechanisms underlying these key features are still largely unknown. Here, we identified the DNA-associated protein Trnp1 as a regulator of cerebral cortex expansion in both of these dimensions. Gain- and loss-of-function experiments in the mouse cerebral cortex in vivo demonstrate that high Trnp1 levels promote neural stem cell self-renewal and tangential expansion. In contrast, lower levels promote radial expansion, with a potent increase of the number of intermediate progenitors and basal radial glial cells leading to folding of the otherwise smooth murine cerebral cortex. Remarkably, TRNP1 expression levels exhibit regional differences in the cerebral cortex of human fetuses, anticipating radial or tangential expansion. Thus, the dynamic regulation of Trnp1 is critical to control tangential and radial expansion of the cerebral cortex in mammals.
AU  - Stahl, R.
AU  - Walcher, T.
AU  - de Juan Rumero, C.*
AU  - Pilz, G.-A.
AU  - Cappello, S.
AU  - Irmler, M.
AU  - Sanz-Aquela, J.M.*
AU  - Beckers, J.
AU  - Blum, R.*
AU  - Borrell, V.*
AU  - Götz, M.
C1  - 24228
C2  - 31347
SP  - 535-549
TI  - Trnp1 regulates expansion and folding of the mammalian cerebral cortex by control of radial glial fate.
JO  - Cell
VL  - 153
IS  - 3
PB  - Cell Press
PY  - 2013
SN  - 0092-8674
ER  - 

TY  - JOUR
AB  - Mammalian target of rapamycin complex 1 (mTORC1) controls growth and survival in response to metabolic cues. Oxidative stress affects mTORC1 via inhibitory and stimulatory inputs. Whereas downregulation of TSC1-TSC2 activates mTORC1 upon oxidative stress, the molecular mechanism of mTORC1 inhibition remains unknown. Here, we identify astrin as an essential negative mTORC1 regulator in the cellular stress response. Upon stress, astrin inhibits mTORC1 association and recruits the mTORC1 component raptor to stress granules (SGs), thereby preventing mTORC1-hyperactivation-induced apoptosis. In turn, balanced mTORC1 activity enables expression of stress factors. By identifying astrin as a direct molecular link between mTORC1, SG assembly, and the stress response, we establish a unifying model of mTORC1 inhibition and activation upon stress. Importantly, we show that in cancer cells, apoptosis suppression during stress depends on astrin. Being frequently upregulated in tumors, astrin is a potential clinically relevant target to sensitize tumors to apoptosis.
AU  - Thedieck, K.*
AU  - Holzwarth, B.*
AU  - Prentzell, M.T.*
AU  - Boehlke, C.*
AU  - Klasener, K.*
AU  - Ruf, S.*
AU  - Sonntag, A.G.*
AU  - Maerz, L.*
AU  - Grellscheid, S.N.*
AU  - Kremmer, E.
AU  - Nitschke, R.*
AU  - Kuehn, E.W.*
AU  - Jonker, J.W.*
AU  - Groen, A.K.*
AU  - Reth, M.*
AU  - Hall, M.N.*
AU  - Baumeister, R.*
C1  - 27248
C2  - 32588
SP  - 859-874
TI  - Inhibition of mTORC1 by astrin and stress granules prevents apoptosis in cancer cells.
JO  - Cell
VL  - 154
IS  - 4
PB  - Cell Press
PY  - 2013
SN  - 0092-8674
ER  - 

TY  - JOUR
AB  - The let-7 tumor suppressor microRNAs are known for their regulation of oncogenes, while the RNA-binding proteins Lin28a/b promote malignancy by inhibiting let-7 biogenesis. We have uncovered unexpected roles for the Lin28/let-7 pathway in regulating metabolism. When overexpressed in mice, both Lin28a and LIN28B promote an insulin-sensitized state that resists high-fat-diet induced diabetes. Conversely, muscle-specific loss of Lin28a or overexpression of let-7 results in insulin resistance and impaired glucose tolerance. These phenomena occur, in part, through the let-7-mediated repression of multiple components of the insulin-PI3K-mTOR pathway, including IGF1R, INSR, and IRS2. In addition, the mTOR inhibitor, rapamycin, abrogates Lin28a-mediated insulin sensitivity and enhanced glucose uptake. Moreover, let-7 targets are enriched for genes containing SNPs associated with type 2 diabetes and control of fasting glucose in human genome-wide association studies. These data establish the Lin28/let-7 pathway as a central regulator of mammalian glucose metabolism.
AU  - Zhu, H.*
AU  - Shyh-Chang, N.*
AU  - Segrè, A.V.*
AU  - Shinoda, G.*
AU  - Shah, S.P.*
AU  - Einhorn, W.S.*
AU  - Takeuchi, A.*
AU  - Engreitz, J.M.*
AU  - Hagan, J.P.*
AU  - Kharas, M.G.*
AU  - Urbach, A.*
AU  - Thornton, J.E.*
AU  - Triboulet, R.*
AU  - Gregory, R.I*
AU  - DIAGRAM Consortium (Huth, C.
AU  - Grallert, H.
AU  - Gieger, C.
AU  - Klopp, N.
AU  - Meitinger, T.
AU  - Petersen, A.-K.
AU  - Thorand, B.
AU  - Wichmann, H.-E.
AU  - Illig, T.)
AU  - MAGIC Investigators (Grallert, H.
AU  - Gieger, C.
AU  - Meisinger, C.
AU  - Thorand, B.
AU  - Wichmann, H.-E.
AU  - Illig, T.)
AU  - Altshuler, D.*
AU  - Daley, G.Q.*
C1  - 6764
C2  - 29243
SP  - 81-94
TI  - The Lin28/let-7 axis regulates glucose metabolism.
JO  - Cell
VL  - 147
IS  - 1
PB  - Cell Press
PY  - 2011
SN  - 0092-8674
ER  - 

TY  - JOUR
AB  - Heart diseases are the most common causes of morbidity and death in humans. Using cardiac-specific RNAi-silencing in Drosophila, we knocked down 7061 evolutionarily conserved genes under conditions of stress. We present a first global roadmap of pathways potentially playing conserved roles in the cardiovascular system. One critical pathway identified was the CCR4-Not complex implicated in transcriptional and posttranscriptional regulatory mechanisms. Silencing of CCR4-Not components in adult Drosophila resulted in myofibrillar disarray and dilated cardiomyopathy. Heterozygous not3 knockout mice showed spontaneous impairment of cardiac contractility and increased susceptibility to heart failure. These heart defects were reversed via inhibition of HDACs, suggesting a mechanistic link to epigenetic chromatin remodeling. In humans, we show that a common NOT3 SNP correlates with altered cardiac QT intervals, a known cause of potentially lethal ventricular tachyarrhythmias. Thus, our functional genome-wide screen in Drosophila can identify candidates that directly translate into conserved mammalian genes involved in heart function.
AU  - Neely, G.G.*
AU  - Kuba, K.*
AU  - Cammarato, A.*
AU  - Isobe, K.*
AU  - Amann, S.*
AU  - Zhang, L.Y.*
AU  - Murata, M.*
AU  - Elmen, L.*
AU  - Gupta, V.*
AU  - Arora, S.*
AU  - Sarangi, R.*
AU  - Dan, D.*
AU  - Fujisawa, S.*
AU  - Usami, T.*
AU  - Xia, C.P.*
AU  - Keene, A.C.*
AU  - Alayari, N.N.*
AU  - Yamakawa, H.*
AU  - Elling, U.*
AU  - Berger, C.*
AU  - Novatchkova, M.*
AU  - Koglgruber, R.*
AU  - Fukuda, K.*
AU  - Nishina, H.*
AU  - Isobe, M.*
AU  - Pospisilik, J.A.*
AU  - Imai, Y.*
AU  - Pfeufer, A.
AU  - Hicks, A.A.*
AU  - Pramstaller, P.P.*
AU  - Subramaniam, S.*
AU  - Kimura, A.*
AU  - Ocorr, K.*
AU  - Bodmer, R.*
AU  - Penninger, J.M.*
C1  - 5926
C2  - 27498
SP  - 142-153
TI  - A global in vivo Drosophila RNAi screen identifies NOT3 as a conserved regulator of heart function.
JO  - Cell
VL  - 141
IS  - 1
PB  - Elsevier
PY  - 2010
SN  - 0092-8674
ER  - 

TY  - JOUR
AB  - We report that eight heterozygous missense mutations in TUBB3, encoding the neuron-specific beta-tubulin isotype III, result in a spectrum of human nervous system disorders that we now call the TUBB3 syndromes. Each mutation causes the ocular motility disorder CFEOM3, whereas some also result in intellectual and behavioral impairments, facial paralysis, and/or later-onset axonal sensorimotor polyneuropathy. Neuroimaging reveals a spectrum of abnormalities including hypoplasia of oculomotor nerves and dysgenesis of the corpus callosum, anterior commissure, and corticospinal tracts. A knock-in disease mouse model reveals axon guidance defects without evidence of cortical cell migration abnormalities. We show that the disease-associated mutations can impair tubulin heterodimer formation in vitro, although folded mutant heterodimers can still polymerize into microtubules. Modeling each mutation in yeast tubulin demonstrates that all alter dynamic instability whereas a subset disrupts the interaction of microtubules with kinesin motors. These findings demonstrate that normal TUBB3 is required for axon guidance and maintenance in mammals.
AU  - Tischfield, M.A.*
AU  - Baris, H.N.*
AU  - Wu, C.*
AU  - Rudolph, G.*
AU  - van Maldergem, L.*
AU  - He, W.*
AU  - Chan, W.M.*
AU  - Andrews, C.*
AU  - Demer, J.L.*
AU  - Robertson, R.L.*
AU  - Mackey, D.A.*
AU  - Ruddle, J.B.*
AU  - Bird, T.D.*
AU  - Gottlob, I.*
AU  - Pieh, C.*
AU  - Traboulsi, E.I.*
AU  - Pomeroy, S.L.*
AU  - Hunter, D.G.*
AU  - Soul, J.S.*
AU  - Newlin, A.*
AU  - Sabol, L.J.*
AU  - Doherty, E.J.*
AU  - de Uzcátegui, C.E.*
AU  - de Uzcátegui, N.*
AU  - Collins, M.L.Z.*
AU  - Sener, E.C.*
AU  - Wabbels, B.*
AU  - Hellebrand, H.*
AU  - Meitinger, T.
AU  - de Berardinis, T.*
AU  - Magli, A.*
AU  - Schiavi, C.*
AU  - Pastore-Trossello, M.*
AU  - Koc, F.*
AU  - Wong, A.M.*
AU  - Levin, A.V.*
AU  - Geraghty, M.T.*
AU  - Descartes, M.*
AU  - Flaherty, M.*
AU  - Jamieson, R.V.*
AU  - Møller, H.U.*
AU  - Meuthen, I.*
AU  - Callen, D.F.*
AU  - Kerwin, J.*
AU  - Lindsay, S.*
AU  - Meindl, A.*
AU  - Gupta, M.L.*
AU  - Pellman, D.*
AU  - Engle, E.C.*
C1  - 1633
C2  - 27158
SP  - 74-87
TI  - Human TUBB3 mutations perturb microtubule dynamics, kinesin interactions, and axon guidance.
JO  - Cell
VL  - 140
IS  - 1
PB  - Cell Press
PY  - 2010
SN  - 0092-8674
ER  - 

TY  - JOUR
AB  - It has been proposed that two amino acid substitutions in the transcription factor FOXP2 have been positively selected during human evolution due to effects on aspects of speech and language. Here, we introduce these substitutions into the endogenous Foxp2 gene of mice. Although these mice are generally healthy, they have qualitatively different ultrasonic vocalizations, decreased exploratory behavior and decreased dopamine concentrations in the brain suggesting that the humanized Foxp2 allele affects basal ganglia. In the striatum, a part of the basal ganglia affected in humans with a speech deficit due to a nonfunctional FOXP2 allele, we find that medium spiny neurons have increased dendrite lengths and increased synaptic plasticity. Since mice carrying one nonfunctional Foxp2 allele show opposite effects, this suggests that alterations in cortico-basal ganglia circuits might have been important for the evolution of speech and language in humans. For a video summary of this article, see the Paper-Flick file available with the online Supplemental Data.
AU  - Enard, W.*
AU  - Gehre, S.*
AU  - Hammerschmidt, K.*
AU  - Hölter, S.M.
AU  - Blass, T.*
AU  - Somel, M.*
AU  - Brückner, M.K.*
AU  - Schreiweis, C.*
AU  - Winter, C.*
AU  - Sohr, R.*
AU  - Becker, L.
AU  - Wiebe, V.*
AU  - Nickel, B.*
AU  - Giger, T.*
AU  - Müller, U.*
AU  - Groszer, M.*
AU  - Adler, T.
AU  - Aguilar, A.*
AU  - Bolle, I.
AU  - Calzada-Wack, J.
AU  - Dalke, C.
AU  - Ehrhardt, N.*
AU  - Favor, J.
AU  - Fuchs, H.
AU  - Gailus-Durner, V.
AU  - Hans, W.
AU  - Hölzlwimmer, G.
AU  - Javaheri, A.
AU  - Kalaydjiev, S.*
AU  - Kallnik, M.
AU  - Kling, E.
AU  - Kunder, S.
AU  - Moßbrugger, I.
AU  - Naton, B.
AU  - Rácz, I.*
AU  - Rathkolb, B.
AU  - Rozman, J.
AU  - Schrewe, A.
AU  - Busch, D.H.*
AU  - Graw, J.
AU  - Ivandic, B.*
AU  - Klingenspor, M.*
AU  - Klopstock, T.*
AU  - Ollert, M.*
AU  - Quintanilla-Martinez, L.
AU  - Schulz, S.
AU  - Wolf, E.*
AU  - Wurst, W.
AU  - Zimmer, A.*
AU  - Fisher, S.E.*
AU  - Morgenstern, R.*
AU  - Arendt, T.*
AU  - Hrabě de Angelis, M.
AU  - Fischer, J.*
AU  - Schwarz, J.*
AU  - Pääbo, S.*
C1  - 1102
C2  - 26178
SP  - 961-971
TI  - A humanized version of Foxp2 affects cortico-basal ganglia circuits in mice.
JO  - Cell
VL  - 137
IS  - 5
PB  - Cell Press
PY  - 2009
SN  - 0092-8674
ER  - 

TY  - JOUR
AB  - Small regulatory RNAs including small interfering RNAs (siRNAs) and microRNAs ( miRNAs) guide Argonaute ( Ago) proteins to specific target RNAs leading to mRNA destabilization or translational repression. Here, we report the identification of Importin 8 (Imp8) as a component of miRNA-guided regulatory pathways. We show that Imp8 interacts with Ago proteins and localizes to cytoplasmic processing bodies ( P bodies), structures involved in RNA metabolism. Furthermore, we detect Ago2 in the nucleus of HeLa cells, and knockdown of Imp8 reduces the nuclear Ago2 pool. Using immunoprecipitations of Ago2-associated mRNAs followed by microarray analysis, we further demonstrate that Imp8 is required for the recruitment of Ago protein complexes to a large set of Ago2-associated target mRNAs, allowing for efficient and specific gene silencing. Therefore, we provide evidence that Imp8 is required for cytoplasmic miRNA-guided gene silencing and affects nuclear localization of Ago proteins.
AU  - Weinmann, L.*
AU  - Höck, J.*
AU  - Ivacevic, T.*
AU  - Ohrt, T.*
AU  - Mütze, J.*
AU  - Schwille, P.*
AU  - Kremmer, E.
AU  - Benes, V.*
AU  - Urlaub, H.*
AU  - Meister, G.*
C1  - 2899
C2  - 26523
SP  - 496-507
TI  - Importin 8 is a gene silencing factor that targets argonaute proteins to distinct mRNAs.
JO  - Cell
VL  - 136
IS  - 3
PB  - Cell Press
PY  - 2009
SN  - 0092-8674
ER  - 

TY  - JOUR
AU  - Collins, F.C.*
AU  - Finnell, R.H.*
AU  - Rossant, J.*
AU  - Wurst, W.
C1  - 1182
C2  - 24431
SP  - 235 S.
TI  - A new partner for the International Knockout Mouse Consortium.
JO  - Cell
VL  - 129
IS  - 2
PB  - Cell Press
PY  - 2007
SN  - 0092-8674
ER  - 

TY  - JOUR
AB  - Three major mouse knockout programs are underway worldwide, working together to mutate all protein-encoding genes in the mouse using a combination of gene trapping and gene targeting in mouse embryonic stem (ES) cells. Although the current emphasis is on production of this valuable resource, there are significant efforts to facilitate program coordination, to enhance the availability of this resource, and to plan for future efforts in mouse genetics research.
AU  - Collins, F.S.*
AU  - Rossant, J.*
AU  - Wurst, W.
C1  - 2588
C2  - 24320
SP  - 9-13
TI  - A mouse for all reasons.
JO  - Cell
VL  - 128
PB  - Cell Press
PY  - 2007
SN  - 0092-8674
ER  - 

TY  - JOUR
AB  - In vertebrates, ß cells are aggregated in the form of pancreatic islets. Within these islets, communication between ß cells inhibits basal insulin secretion and enhances glucose-stimulated insulin secretion, thus contributing to glucose homeostasis during fasting and feeding. In the search for the underlying molecular mechanism, we have discovered that ß cells communicate via ephrin-As and EphAs. We provide evidence that ephrin-A5 is required for glucose-stimulated insulin secretion. We further show that EphA-ephrin-A-mediated ß cell communication is bidirectional: EphA forward signaling inhibits insulin secretion, whereas ephrin-A reverse signaling stimulates insulin secretion. EphA forward signaling is downregulated in response to glucose, which indicates that, under basal conditions, ß cells use EphA forward signaling to suppress insulin secretion and that, under stimulatory conditions, they shift to ephrin-A reverse signaling to enhance insulin secretion. Thus, we explain how ß cell communication in pancreatic islets conversely affects basal and glucose-stimulated insulin secretion to improve glucose homeostasis.
AU  - Konstantinova, I.*
AU  - Nikolova, G.*
AU  - Ohara-Imaizumi, M.*
AU  - Meda, P.*
AU  - Kucera, T.*
AU  - Zarbalis, K.
AU  - Wurst, W.
AU  - Nagamatsu, S.*
AU  - Lammert, E.*
C1  - 1183
C2  - 24432
SP  - 359-370
TI  - EphA-Ephrin-A-Mediated ß cell communication regulates insulin secretion from pancreatic islets.
JO  - Cell
VL  - 129
PB  - Cell Press
PY  - 2007
SN  - 0092-8674
ER  - 

TY  - JOUR
AB  - Antigen stimulation of immune cells activates the transcription factor NFAT, a key regulator of T cell activation and anergy. NFAT forms cooperative complexes with the AP-1 family of transcription factors and regulates T cell activation-associated genes. Here we show that regulatory T cell (Treg) function is mediated by an analogous cooperative complex of NFAT with the forkhead transcription factor FOXP3, a lineage specification factor for Tregs. The crystal structure of an NFAT:FOXP2:DNA complex reveals an extensive protein-protein interaction interface between NFAT and FOXP2. Structure-guided mutations of FOXP3, predicted to progressively disrupt its interaction with NFAT, interfere in a graded manner with the ability of FOXP3 to repress expression of the cytokine IL2, upregulate expression of the Treg markers CTLA4 and CD25, and confer suppressor function in a murine model of autoimmune diabetes. Thus by switching transcriptional partners, NFAT converts the acute T cell activation program into the suppressor program of Tregs.
AU  - Wu, Y.*
AU  - Borde, M.*
AU  - Heissmeyer, V.
AU  - Feuerer, M.*
AU  - Lapan, A.D.*
AU  - Stroud, J.C.*
AU  - Bates, D.L.*
AU  - Guo, L.*
AU  - Han, A.*
AU  - Ziegler, S.F.*
AU  - Mathis, D.*
AU  - Benoist, C.*
AU  - Chen, L.*
AU  - Rao, A.*
C1  - 4930
C2  - 23819
SP  - 375-387
TI  - FOXP3 controls regulatory T cell function through cooperation with NFAT.
JO  - Cell
VL  - 126
IS  - 2
PY  - 2006
SN  - 0092-8674
ER  - 

TY  - JOUR
AB  - The E. coli chaperonin GroEL and its cofactor GroES promote protein folding by sequestering nonnative polypeptides in a cage-like structure. Here we define the contribution of this system to protein folding across the entire E. coli proteome. Approximately 250 different proteins interact with GroEL, but most of these can utilize either GroEL or the upstream chaperones trigger factor (TF) and DnaK for folding. Obligate GroEL-dependence is limited to only ∼85 substrates, including 13 essential proteins, and occupying more than 75% of GroEL capacity. These proteins appear to populate kinetically trapped intermediates during folding; they are stabilized by TF/DnaK against aggregation but reach native state only upon transfer to GroEL/GroES. Interestingly, substantially enriched among the GroEL substrates are proteins with (βα)8 TIM-barrel domains. We suggest that the chaperonin system may have facilitated the evolution of this fold into a versatile platform for the implementation of numerous enzymatic functions.
AU  - Kerner, M.J.*
AU  - Naylor, D.J.*
AU  - Ishihama, Y.*
AU  - Maier, T.*
AU  - Chang, H.-Ch.*
AU  - Stines, A.P.*
AU  - Georgopoulos, C.*
AU  - Frishman, D.
AU  - Hayer-Hartl, M.*
AU  - Mann, M.*
AU  - Hartl, U.*
C1  - 2636
C2  - 23410
SP  - 209-220
TI  - Proteome-wide analysis of chaperonin-dependent protein folding in Escherichia coli.
JO  - Cell
VL  - 122
IS  - 2
PY  - 2005
SN  - 0092-8674
ER  - 

TY  - JOUR
AB  - The proper function of immune surveillance requires well-coordinated mechanisms in order to guide the patrolling immune cells through peripheral tissues and into secondary lymphoid organs. Analyzing gene-targeted mice, we identified the chemokine receptor CCR7 as an important organizer of the primary immune response. CCR7-deficient mice show severely delayed kinetics regarding the antibody response and lack contact sensitivity and delayed type hypersensitivity reactions. Due to the impaired migration of lymphocytes, these animals reveal profound morphological alterations in all secondary lymphoid organs. Upon activation, mature skin dendritic cells fail to migrate into the draining lymph nodes. Thus, in order to bring together lymphocytes and dendritic cells to form the characteristic microarchitecture of secondary lymphoid organs, CCR7 is required to rapidly initiate an adoptive immune response.
AU  - Forster, R.*
AU  - Schubel, A.*
AU  - Breitfeld, D.*
AU  - Kremmer, E.
AU  - Renner-Müller, I.*
AU  - Wolf, E.*
AU  - Lipp, M.*
C1  - 21061
C2  - 19091
SP  - 23-33
TI  - CCR7 Coordinates the Primary Immune Response by Establishing Functional Microenvironments in Secondary Lymphoid Organs.
JO  - Cell
VL  - 99
IS  - 1
PY  - 1999
SN  - 0092-8674
ER  -