John F Brooks, Cassie L Behrendt, Kelly A Ruhn, Syann Lee, Prithvi Raj, Joseph S Takahashi, Lora V Hooper
Environmental light cycles entrain circadian feeding behaviors in animals that produce rhythms in exposure to foodborne bacteria. Here, we show that the intestinal microbiota generates diurnal rhythms in innate immunity that synchronize with feeding rhythms to anticipate microbial exposure. Rhythmic expression of antimicrobial proteins was driven by daily rhythms in epithelial attachment by segmented filamentous bacteria (SFB), members of the mouse intestinal microbiota. Rhythmic SFB attachment was driven by the circadian clock through control of feeding rhythms...
July 21, 2021: Cell
Kathryn R Bowles, M Catarina Silva, Kristen Whitney, Taylor Bertucci, Joshua E Berlind, Jesse D Lai, Jacob C Garza, Nathan C Boles, Sidhartha Mahali, Kevin H Strang, Jacob A Marsh, Cynthia Chen, Derian A Pugh, Yiyuan Liu, Ronald E Gordon, Susan K Goderie, Rebecca Chowdhury, Steven Lotz, Keith Lane, John F Crary, Stephen J Haggarty, Celeste M Karch, Justin K Ichida, Alison M Goate, Sally Temple
Frontotemporal dementia (FTD) because of MAPT mutation causes pathological accumulation of tau and glutamatergic cortical neuronal death by unknown mechanisms. We used human induced pluripotent stem cell (iPSC)-derived cerebral organoids expressing tau-V337M and isogenic corrected controls to discover early alterations because of the mutation that precede neurodegeneration. At 2 months, mutant organoids show upregulated expression of MAPT, glutamatergic signaling pathways, and regulators, including the RNA-binding protein ELAVL4, and increased stress granules...
July 21, 2021: Cell
Yang Liu, Hugo Bisio, Chelsea Marie Toner, Sandra Jeudy, Nadege Philippe, Keda Zhou, Samuel Bowerman, Alison White, Garrett Edwards, Chantal Abergel, Karolin Luger
The organization of genomic DNA into defined nucleosomes has long been viewed as a hallmark of eukaryotes. This paradigm has been challenged by the identification of "minimalist" histones in archaea and more recently by the discovery of genes that encode fused remote homologs of the four eukaryotic histones in Marseilleviridae, a subfamily of giant viruses that infect amoebae. We demonstrate that viral doublet histones are essential for viral infectivity, localize to cytoplasmic viral factories after virus infection, and ultimately are found in the mature virions...
July 21, 2021: Cell
Manuel J Ferreira-Pinto, Harsh Kanodia, Antonio Falasconi, Markus Sigrist, Maria S Esposito, Silvia Arber
The mesencephalic locomotor region (MLR) is a key midbrain center with roles in locomotion. Despite extensive studies and clinical trials aimed at therapy-resistant Parkinson's disease (PD), debate on its function remains. Here, we reveal the existence of functionally diverse neuronal populations with distinct roles in control of body movements. We identify two spatially intermingled glutamatergic populations separable by axonal projections, mouse genetics, neuronal activity profiles, and motor functions. Most spinally projecting MLR neurons encoded the full-body behavior rearing...
July 20, 2021: Cell
Sridevi Challa, Beman R Khulpateea, Tulip Nandu, Cristel V Camacho, Keun W Ryu, Hao Chen, Yan Peng, Jayanthi S Lea, W Lee Kraus
Defects in translation lead to changes in the expression of proteins that can serve as drivers of cancer formation. Here, we show that cytosolic NAD+ synthesis plays an essential role in ovarian cancer by regulating translation and maintaining protein homeostasis. Expression of NMNAT-2, a cytosolic NAD+ synthase, is highly upregulated in ovarian cancers. NMNAT-2 supports the catalytic activity of the mono(ADP-ribosyl) transferase (MART) PARP-16, which mono(ADP-ribosyl)ates (MARylates) ribosomal proteins. Depletion of NMNAT-2 or PARP-16 leads to inhibition of MARylation, increased polysome association and enhanced translation of specific mRNAs, aggregation of their translated protein products, and reduced growth of ovarian cancer cells...
July 19, 2021: Cell
Neri Amara, Madison P Cooper, Maria A Voronkova, Bradley A Webb, Eric M Lynch, Justin M Kollman, Taylur Ma, Kebing Yu, Zijuan Lai, Dewakar Sangaraju, Nobuhiko Kayagaki, Kim Newton, Matthew Bogyo, Steven T Staben, Vishva M Dixit
In neutrophils, nicotinamide adenine dinucleotide phosphate (NADPH) generated via the pentose phosphate pathway fuels NADPH oxidase NOX2 to produce reactive oxygen species for killing invading pathogens. However, excessive NOX2 activity can exacerbate inflammation, as in acute respiratory distress syndrome (ARDS). Here, we use two unbiased chemical proteomic strategies to show that small-molecule LDC7559, or a more potent designed analog NA-11, inhibits the NOX2-dependent oxidative burst in neutrophils by activating the glycolytic enzyme phosphofructokinase-1 liver type (PFKL) and dampening flux through the pentose phosphate pathway...
July 17, 2021: Cell
Barbara Bosch, Michael A DeJesus, Nicholas C Poulton, Wenzhu Zhang, Curtis A Engelhart, Anisha Zaveri, Sophie Lavalette, Nadine Ruecker, Carolina Trujillo, Joshua B Wallach, Shuqi Li, Sabine Ehrt, Brian T Chait, Dirk Schnappinger, Jeremy M Rock
Antibacterial agents target the products of essential genes but rarely achieve complete target inhibition. Thus, the all-or-none definition of essentiality afforded by traditional genetic approaches fails to discern the most attractive bacterial targets: those whose incomplete inhibition results in major fitness costs. In contrast, gene "vulnerability" is a continuous, quantifiable trait that relates the magnitude of gene inhibition to the effect on bacterial fitness. We developed a CRISPR interference-based functional genomics method to systematically titrate gene expression in Mycobacterium tuberculosis (Mtb) and monitor fitness outcomes...
July 16, 2021: Cell
Xinzheng Guo, Jing Zhou, Christopher Starr, Ethan J Mohns, Yidong Li, Earnest P Chen, Yonejung Yoon, Christopher P Kellner, Kohichi Tanaka, Hongbing Wang, Wei Liu, Louis R Pasquale, Jonathan B Demb, Michael C Crair, Bo Chen
Retinal ganglion cells (RGCs) are the sole output neurons that transmit visual information from the retina to the brain. Diverse insults and pathological states cause degeneration of RGC somas and axons leading to irreversible vision loss. A fundamental question is whether manipulation of a key regulator of RGC survival can protect RGCs from diverse insults and pathological states, and ultimately preserve vision. Here, we report that CaMKII-CREB signaling is compromised after excitotoxic injury to RGC somas or optic nerve injury to RGC axons, and reactivation of this pathway robustly protects RGCs from both injuries...
July 14, 2021: Cell
Charles L Evavold, Iva Hafner-Bratkovič, Pascal Devant, Jasmin M D'Andrea, Elsy M Ngwa, Elvira Boršić, John G Doench, Martin W LaFleur, Arlene H Sharpe, Jay R Thiagarajah, Jonathan C Kagan
The process of pyroptosis is mediated by inflammasomes and a downstream effector known as gasdermin D (GSDMD). Upon cleavage by inflammasome-associated caspases, the N-terminal domain of GSDMD forms membrane pores that promote cytolysis. Numerous proteins promote GSDMD cleavage, but none are known to be required for pore formation after GSDMD cleavage. Herein, we report a forward genetic screen that identified the Ragulator-Rag complex as being necessary for GSDMD pore formation and pyroptosis in macrophages...
July 14, 2021: Cell
Florencia Pratto, Kevin Brick, Gang Cheng, Kwan-Wood Gabriel Lam, Jeffrey M Cloutier, Daisy Dahiya, Stephen R Wellard, Philip W Jordan, R Daniel Camerini-Otero
Genetic recombination generates novel trait combinations, and understanding how recombination is distributed across the genome is key to modern genetics. The PRDM9 protein defines recombination hotspots; however, megabase-scale recombination patterning is independent of PRDM9. The single round of DNA replication, which precedes recombination in meiosis, may establish these patterns; therefore, we devised an approach to study meiotic replication that includes robust and sensitive mapping of replication origins...
July 8, 2021: Cell
Lin Kang, Guijuan He, Amanda K Sharp, Xiaofeng Wang, Anne M Brown, Pawel Michalak, James Weger-Lucarelli
The coronavirus disease 2019 (COVID-19) pandemic underscores the need to better understand animal-to-human transmission of coronaviruses and adaptive evolution within new hosts. We scanned more than 182,000 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genomes for selective sweep signatures and found a distinct footprint of positive selection located around a non-synonymous change (A1114G; T372A) within the spike protein receptor-binding domain (RBD), predicted to remove glycosylation and increase binding to human ACE2 (hACE2), the cellular receptor...
July 7, 2021: Cell
Hannah C Wastyk, Gabriela K Fragiadakis, Dalia Perelman, Dylan Dahan, Bryan D Merrill, Feiqiao B Yu, Madeline Topf, Carlos G Gonzalez, William Van Treuren, Shuo Han, Jennifer L Robinson, Joshua E Elias, Erica D Sonnenburg, Christopher D Gardner, Justin L Sonnenburg
Diet modulates the gut microbiome, which in turn can impact the immune system. Here, we determined how two microbiota-targeted dietary interventions, plant-based fiber and fermented foods, influence the human microbiome and immune system in healthy adults. Using a 17-week randomized, prospective study (n = 18/arm) combined with -omics measurements of microbiome and host, including extensive immune profiling, we found diet-specific effects. The high-fiber diet increased microbiome-encoded glycan-degrading carbohydrate active enzymes (CAZymes) despite stable microbial community diversity...
July 6, 2021: Cell
Seth R Taylor, Gabriel Santpere, Alexis Weinreb, Alec Barrett, Molly B Reilly, Chuan Xu, Erdem Varol, Panos Oikonomou, Lori Glenwinkel, Rebecca McWhirter, Abigail Poff, Manasa Basavaraju, Ibnul Rafi, Eviatar Yemini, Steven J Cook, Alexander Abrams, Berta Vidal, Cyril Cros, Saeed Tavazoie, Nenad Sestan, Marc Hammarlund, Oliver Hobert, David M Miller
We have produced gene expression profiles of all 302 neurons of the C. elegans nervous system that match the single-cell resolution of its anatomy and wiring diagram. Our results suggest that individual neuron classes can be solely identified by combinatorial expression of specific gene families. For example, each neuron class expresses distinct codes of ∼23 neuropeptide genes and ∼36 neuropeptide receptors, delineating a complex and expansive "wireless" signaling network. To demonstrate the utility of this comprehensive gene expression catalog, we used computational approaches to (1) identify cis-regulatory elements for neuron-specific gene expression and (2) reveal adhesion proteins with potential roles in process placement and synaptic specificity...
July 2, 2021: Cell
Anusha Nathan, Elizabeth J Rossin, Clarety Kaseke, Ryan J Park, Ashok Khatri, Dylan Koundakjian, Jonathan M Urbach, Nishant K Singh, Arman Bashirova, Rhoda Tano-Menka, Fernando Senjobe, Michael T Waring, Alicja Piechocka-Trocha, Wilfredo F Garcia-Beltran, A John Iafrate, Vivek Naranbhai, Mary Carrington, Bruce D Walker, Gaurav D Gaiha
The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants that escape convalescent and vaccine-induced antibody responses has renewed focus on the development of broadly protective T-cell-based vaccines. Here, we apply structure-based network analysis and assessments of HLA class I peptide stability to define mutationally constrained CD8+ T cell epitopes across the SARS-CoV-2 proteome. Highly networked residues are conserved temporally among circulating variants and sarbecoviruses and disproportionately impair spike pseudotyped lentivirus infectivity when mutated...
June 30, 2021: Cell
Krystelle Nganou-Makamdop, Aarthi Talla, Ashish Arunkumar Sharma, Sam Darko, Amy Ransier, Farida Laboune, Jeffrey G Chipman, Gregory J Beilman, Torfi Hoskuldsson, Slim Fourati, Thomas E Schmidt, Sahaana Arumugam, Noemia S Lima, Damee Moon, Samuel Callisto, Jordan Schoephoerster, Jeffery Tomalka, Peter Mugyenyi, Francis Ssali, Proscovia Muloma, Patrick Ssengendo, Ana R Leda, Ryan K Cheu, Jacob K Flynn, Antigoni Morou, Elsa Brunet-Ratnasingham, Benigno Rodriguez, Michael M Lederman, Daniel E Kaufmann, Nichole R Klatt, Cissy Kityo, Jason M Brenchley, Timothy W Schacker, Rafick P Sekaly, Daniel C Douek
The impact of the microbiome on HIV disease is widely acknowledged although the mechanisms downstream of fluctuations in microbial composition remain speculative. We detected rapid, dynamic changes in translocated microbial constituents during two years after cART initiation. An unbiased systems biology approach revealed two distinct pathways driven by changes in the abundance ratio of Serratia to other bacterial genera. Increased CD4 T cell numbers over the first year were associated with high Serratia abundance, pro-inflammatory innate cytokines, and metabolites that drive Th17 gene expression signatures and restoration of mucosal integrity...
June 30, 2021: Cell
Yanniv Dorone, Steven Boeynaems, Eduardo Flores, Benjamin Jin, Shannon Hateley, Flavia Bossi, Elena Lazarus, Janice G Pennington, Emiel Michiels, Mathias De Decker, Katlijn Vints, Pieter Baatsen, George W Bassel, Marisa S Otegui, Alex S Holehouse, Moises Exposito-Alonso, Shahar Sukenik, Aaron D Gitler, Seung Y Rhee
Many organisms evolved strategies to survive desiccation. Plant seeds protect dehydrated embryos from various stressors and can lay dormant for millennia. Hydration is the key trigger to initiate germination, but the mechanism by which seeds sense water remains unresolved. We identified an uncharacterized Arabidopsis thaliana prion-like protein we named FLOE1, which phase separates upon hydration and allows the embryo to sense water stress. We demonstrate that biophysical states of FLOE1 condensates modulate its biological function in vivo in suppressing seed germination under unfavorable environments...
June 30, 2021: Cell
Emilia Favuzzi, Shuhan Huang, Giuseppe A Saldi, Loïc Binan, Leena A Ibrahim, Marian Fernández-Otero, Yuqing Cao, Ayman Zeine, Adwoa Sefah, Karen Zheng, Qing Xu, Elizaveta Khlestova, Samouil L Farhi, Richard Bonneau, Sandeep Robert Datta, Beth Stevens, Gord Fishell
Microglia, the resident immune cells of the brain, have emerged as crucial regulators of synaptic refinement and brain wiring. However, whether the remodeling of distinct synapse types during development is mediated by specialized microglia is unknown. Here, we show that GABA-receptive microglia selectively interact with inhibitory cortical synapses during a critical window of mouse postnatal development. GABA initiates a transcriptional synapse remodeling program within these specialized microglia, which in turn sculpt inhibitory connectivity without impacting excitatory synapses...
June 29, 2021: Cell
Jennifer Allouche, Inbal Rachmin, Kaustubh Adhikari, Luba M Pardo, Ju Hee Lee, Alicia M McConnell, Shinichiro Kato, Shaohua Fan, Akinori Kawakami, Yusuke Suita, Kazumasa Wakamatsu, Vivien Igras, Jianming Zhang, Paula P Navarro, Camila Makhlouta Lugo, Haley R Noonan, Kathleen A Christie, Kaspar Itin, Nisma Mujahid, Jennifer A Lo, Chong Hyun Won, Conor L Evans, Qing Yu Weng, Hequn Wang, Sam Osseiran, Alyssa Lovas, István Németh, Antonio Cozzio, Alexander A Navarini, Jennifer J Hsiao, Nhu Nguyen, Lajos V Kemény, Othon Iliopoulos, Carola Berking, Thomas Ruzicka, Rolando Gonzalez-José, Maria-Cátira Bortolini, Samuel Canizales-Quinteros, Victor Acuna-Alonso, Carla Gallo, Giovanni Poletti, Gabriel Bedoya, Francisco Rothhammer, Shosuke Ito, Maria Vittoria Schiaffino, Luke H Chao, Benjamin P Kleinstiver, Sarah Tishkoff, Leonard I Zon, Tamar Nijsten, Andrés Ruiz-Linares, David E Fisher, Elisabeth Roider
Ultraviolet (UV) light and incompletely understood genetic and epigenetic variations determine skin color. Here we describe an UV- and microphthalmia-associated transcription factor (MITF)-independent mechanism of skin pigmentation. Targeting the mitochondrial redox-regulating enzyme nicotinamide nucleotide transhydrogenase (NNT) resulted in cellular redox changes that affect tyrosinase degradation. These changes regulate melanosome maturation and, consequently, eumelanin levels and pigmentation. Topical application of small-molecule inhibitors yielded skin darkening in human skin, and mice with decreased NNT function displayed increased pigmentation...
June 29, 2021: Cell
Allon Wagner, Chao Wang, Johannes Fessler, David DeTomaso, Julian Avila-Pacheco, James Kaminski, Sarah Zaghouani, Elena Christian, Pratiksha Thakore, Brandon Schellhaass, Elliot Akama-Garren, Kerry Pierce, Vasundhara Singh, Noga Ron-Harel, Vivian Paraskevi Douglas, Lloyd Bod, Alexandra Schnell, Daniel Puleston, Raymond A Sobel, Marcia Haigis, Erika L Pearce, Manoocher Soleimani, Clary Clish, Aviv Regev, Vijay K Kuchroo, Nir Yosef
Metabolism is a major regulator of immune cell function, but it remains difficult to study the metabolic status of individual cells. Here, we present Compass, an algorithm to characterize cellular metabolic states based on single-cell RNA sequencing and flux balance analysis. We applied Compass to associate metabolic states with T helper 17 (Th17) functional variability (pathogenic potential) and recovered a metabolic switch between glycolysis and fatty acid oxidation, akin to known Th17/regulatory T cell (Treg) differences, which we validated by metabolic assays...
June 29, 2021: Cell
Mark J Wagner, Joan Savall, Oscar Hernandez, Gabriel Mel, Hakan Inan, Oleg Rumyantsev, Jérôme Lecoq, Tony Hyun Kim, Jin Zhong Li, Charu Ramakrishnan, Karl Deisseroth, Liqun Luo, Surya Ganguli, Mark J Schnitzer
In motor neuroscience, state changes are hypothesized to time-lock neural assemblies coordinating complex movements, but evidence for this remains slender. We tested whether a discrete change from more autonomous to coherent spiking underlies skilled movement by imaging cerebellar Purkinje neuron complex spikes in mice making targeted forelimb-reaches. As mice learned the task, millimeter-scale spatiotemporally coherent spiking emerged ipsilateral to the reaching forelimb, and consistent neural synchronization became predictive of kinematic stereotypy...
June 28, 2021: Cell
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