Biological sciences

  • Article
    | Open Access

    The polycomb repressive complex 2 (PRC2) is a histone methyltransferase regulating cell differentiation and identity. Here, the authors show that the vertebrate-specific PRC2 accessory subunit PALI1 facilitates substrate binding by the complex and elucidate the allosteric mechanism of PALI1- mediated PRC2 activation.

    • Qi Zhang
    • , Samuel C. Agius
    •  & Chen Davidovich
  • Article
    | Open Access

    SAMHD1 is a cellular dNTPase proposed to inhibit HIV-1 reverse transcription in non-cycling immune cells by limiting dNTP substrate supply; its anti-viral but not dNTPase function is downregulated by phosphorylation of T592. Here, Martinat et al. describe an additional SUMOylation at residue K595, which promotes the dNTPase-independent restriction activity.

    • Charlotte Martinat
    • , Arthur Cormier
    •  & Alessia Zamborlini
  • Article
    | Open Access

    Multifocal imaging suffers from a number of limitations. Here the authors report an open-source 3D reconstruction algorithm to enable label-free tracking of spherical and filamentous structures which they use to characterise fluid flow and flagellar beating of human and sea urchin sperm.

    • Jan N. Hansen
    • , An Gong
    •  & Luis Alvarez
  • Article
    | Open Access

    PARG and ARH3 are the main hydrolases to reverse serine poly(ADP-ribosylation) yet their activities in the process differ. Here, the authors synthesise linear and branched poly(ADP-ribose) molecules, perform structure-function analysis and elucidate the mechanistic differences between PARG and ARH3.

    • Johannes Gregor Matthias Rack
    • , Qiang Liu
    •  & Ivan Ahel
  • Article
    | Open Access

    Many current immunoassays require multiple washing, incubation and optimization steps. Here the authors present Ratiometric Plug-and-Play Immunodiagnostics (RAPPID), a generic assay platform that uses ratiometric bioluminescent detection to allow sandwich immunoassays to be performed directly in solution.

    • Yan Ni
    • , Bas J. H. M. Rosier
    •  & Maarten Merkx
  • Article
    | Open Access

    Mitochondrial transport toward both the plus- and minus-ends of microtubules is mediated by motor proteins linked to mitochondria by TRAK adaptor proteins. Here the authors investigate the role of TRAK2 as a bidirectional motor adaptor, and propose a model where TRAK2 coordinates the activities of opposing kinesin-1 and cytoplasmic dynein motors as a single interdependent motor complex.

    • Adam R. Fenton
    • , Thomas A. Jongens
    •  & Erika L. F. Holzbaur
  • Article
    | Open Access

    Cytokinetic ring constriction during cell division requires actin but curiously is independent of myosin in many organisms. Here, the authors show that anillin, a protein enriched in the contractile ring, is a non-motor actin crosslinker that generates contractile force in lieu of a molecular motor.

    • Ondřej Kučera
    • , Valerie Siahaan
    •  & Zdenek Lansky
  • Article
    | Open Access

    Differentiation of hPSCs to cardiomyocytes suffers from high variability. Here the authors report a label-free live cell imaging platform based on autofluorescence imaging to enable the prediction of cardiomyocyte differentiation efficiency from hPSCs.

    • Tongcheng Qian
    • , Tiffany M. Heaster
    •  & Melissa C. Skala
  • Article
    | Open Access

    The willingness to exert effort into demanding tasks often declines over time through fatigue. Here the authors provide a computational account of the moment-to-moment dynamics of fatigue and its impact on effort-based choices, and reveal the neural mechanisms that underlie such computations.

    • Tanja Müller
    • , Miriam C. Klein-Flügge
    •  & Matthew A. J. Apps
  • Article
    | Open Access

    Visual processing necessitates both extracting and discarding information. Here, the authors use a specialized set of stimuli and two complementary discrimination tasks to demonstrate the opposing perceptual implications of these two aspects of information processing.

    • Corey M. Ziemba
    •  & Eero P. Simoncelli
  • Article
    | Open Access

    S-acylation is the post-translational covalent attachment of fatty acids (FA) onto cysteines. Nuskova et al. find that exposure of cells to different FAs affects which FA is used to S-acylate GNAI proteins, thereby altering GNAI function and EGFR pathway activation, linking metabolism to signaling.

    • Hana Nůsková
    • , Marina V. Serebryakova
    •  & Aurelio A. Teleman
  • Article
    | Open Access

    COVID-19 is a critical public health threat, but molecular characterizations of patients’ immunity is still lacking. Here the authors collected blood from patients with various disease severity, and prefiltered to exclude selected comorbidity, to obtain genomic, transcriptomic, proteomic, metabolomic and lipidomic profiles to report a trans-omics landscape.

    • Peng Wu
    • , Dongsheng Chen
    •  & Gang Chen
  • Article
    | Open Access

    Endoplasmic reticulum (ER)-interorganelle membrane contact sites have emerged as key regulators of organelle dynamics. Here, the authors report that the ER-resident protein SNX19 mediates ER-endolysosome membrane contacts to maintain the perinuclear distribution of endolysosomes and restrict their motility.

    • Amra Saric
    • , Spencer A. Freeman
    •  & Juan S. Bonifacino
  • Article
    | Open Access

    Assembly of the mitoribosome requires assistance from numerous specialized factors. Here, structures of the human 39S late assembly intermediates identify several assembly factors which keep the 16S rRNA in immature conformations, and reveal deacylated tRNA in the ribosomal E-site, suggesting a role in 39S assembly.

    • Jingdong Cheng
    • , Otto Berninghausen
    •  & Roland Beckmann
  • Article
    | Open Access

    The human pathogen Neisseria meningitidis colonizes blood vessels and causes vascular damage, despite a neutrophil-rich inflammatory infiltrate. Here, Manriquez et al. use a humanized mouse model to show that pathogen colonization of capillaries and arterioles creates an intravascular niche that precludes an effective action of neutrophils.

    • Valeria Manriquez
    • , Pierre Nivoit
    •  & Guillaume Duménil
  • Article
    | Open Access

    The serine/threonine kinase WNK1 is an inhibitor of chloride efflux. Here the authors show that this inhibition is a means of negatively regulating the activation of the NLRP3 inflammasome in macrophages, leading to reduced inflammatory responses.

    • Lindsey Mayes-Hopfinger
    • , Aura Enache
    •  & Emad S. Alnemri
  • Article
    | Open Access

    Patients with Cornelia de Lange Syndrome (CdLS) often have mutations in cohesin and its regulators; however, the molecular mechanism driving CdLS phenotypes is not well established. Here the authors reveal system skeletal organization genes are downregulated and show that cohesin and its loader Nipbl have altered and decreased genome-wide localization.

    • Patricia Garcia
    • , Rita Fernandez-Hernandez
    •  & Ethel Queralt
  • Article
    | Open Access

    Environmental and genetic risk factors affect the distal airway epithelium in idiopatic pulmonary fibrosis (IPF) but the role of the epithelium in IPF remains unclear. Here the authors show that pathologic activation of the ERBB-YAP axis induces dynamic and structural dysfunction in the distal airway epithelium eliciting a pro-fibrotic phenotype in mesenchymal cells.

    • Ian T. Stancil
    • , Jacob E. Michalski
    •  & David A. Schwartz
  • Article
    | Open Access

    NEK2 is a serine-threonine kinase overexpressed in a variety of human cancers. Here the authors show that NEK2 controls the stability of PD-L1 by preventing its proteasome-mediated degradation and that NEK2 targeting restores anti-tumor immune responses in preclinical models of pancreatic cancer.

    • Xiaozhen Zhang
    • , Xing Huang
    •  & Tingbo Liang
  • Article
    | Open Access

    Nutrient status in the cell regulates autophagy via mTORC1 activity. Here, the authors show that the ubiquitous G protein subunit Gαq contributes to nutrient sensing by promoting formation of an mTOR-p62-Raptor complex in replete conditions, modulating autophagy.

    • Sofía Cabezudo
    • , Maria Sanz-Flores
    •  & Catalina Ribas
  • Article
    | Open Access

    A longitudinal analysis of SARS-CoV-2 infection in humans is challenging. Here the authors show a single cell RNA-sequencing analysis of BAL fluid cells from ferrets and characterise the time dependent recruitment of macrophage subsets to the lungs in response to SARS-CoV-2 infection.

    • Jeong Seok Lee
    • , June-Young Koh
    •  & Su-Hyung Park
  • Article
    | Open Access

    Repeating fever is a hallmark of malaria. Here, a large-scale forward genetic screen in malaria-causing Plasmodium falciparum identifies genes associated with parasite tolerance to host fever, including apicoplast targeted isoprenoid biosynthesis—sharing features with artemisinin resistance.

    • Min Zhang
    • , Chengqi Wang
    •  & John H. Adams
  • Article
    | Open Access

    We know that most splicing reactions take place co-transcriptionally, but how the transcription machinery facilitate splicing of introns is unknown. Here the authors show that the 5′ splice site remains associated with the transcription machinery during intron synthesis through U1 snRNP, providing a basis for the rapid splicing reaction of introns.

    • Yodfat Leader
    • , Galit Lev Maor
    •  & Gil Ast
  • Article
    | Open Access

    Understanding how individual niches vary can inform ecology and conservation. A study of 45 GPS-tracked white storks across three breeding populations reveals that individual environmental niches are nested, arranged along a specialist-generalist gradient that is highly consistent over time.

    • Ben S. Carlson
    • , Shay Rotics
    •  & Walter Jetz
  • Article
    | Open Access

    Chronic use of mTORC1 inhibitors produces undesirable side effects in humans which limit their value for CNS disorders treatment. The authors present a binary drug strategy to protects mTORC1 activity in the periphery and show its potential utility in preclinical models of alcohol use disorder.

    • Yann Ehinger
    • , Ziyang Zhang
    •  & Dorit Ron
  • Article
    | Open Access

    Retinoblastoma is a heritable pediatric cancer driven by mutations in RB1. Here, the authors demonstrate the first patient derived model of retinoblastoma using iPSCs from patients with germline mutations in RB1.

    • Jackie L. Norrie
    • , Anjana Nityanandam
    •  & Michael A. Dyer
  • Article
    | Open Access

    BRAF-MAPK activating mutations are reported in histiocytoses—hematological neoplasms with widespread pro-inflammatory myeloid cells. Here, the authors show that an activating mutant BRAF in haematopoietic stem and progenitor cells causes an oncogene-induced senescence response leading to myeloid restricted haematopoiesis, inflammation and histiocytosis.

    • Riccardo Biavasco
    • , Emanuele Lettera
    •  & Eugenio Montini
  • Article
    | Open Access

    Germline mutations in the DNMT3A gene can cause an overgrowth syndrome associated with behavioural and hematopoietic phenotypes. Here the authors describe a mouse model of this syndrome that recapitulates many of these features, including conserved alterations in DNA methylation in the blood cells of both species.

    • Amanda M. Smith
    • , Taylor A. LaValle
    •  & Timothy J. Ley
  • Article
    | Open Access

    Genome-wide association studies of COVID-19 have identified genetic loci affecting disease severity, but the mechanisms remain to be fully described. Here, the authors use genetically predicted transcriptome, splicing and proteome data to identify potential genes and pathways underlying COVID- 19 severity.

    • Gita A. Pathak
    • , Kritika Singh
    •  & Nicholas Mancuso
  • Article
    | Open Access

    Alcoholic hepatitis is characterized by intense liver inflammation driven by excessive cytokines and chemokines production and immune cell infiltration. Here the authors identify a super-enhancer that regulates the expression of multiple CXCL chemokines in alcoholic hepatitis and may be a potential therapeutic target.

    • Mengfei Liu
    • , Sheng Cao
    •  & Vijay H. Shah
  • Article
    | Open Access

    There is an unmet clinical need to develop therapies to alleviate metastatic bone pain, frequently observed in patients with advanced cancers. Here, using mouse models of bone cancer pain, the authors show that STING agonists not only suppress bone cancer tumor burden, but also attenuate bone pain and reduce cancer-induced bone destruction.

    • Kaiyuan Wang
    • , Christopher R. Donnelly
    •  & Ru-Rong Ji
  • Article
    | Open Access

    The bacterial thymidylate synthase ThyX catalyzes the reductive methylation of deoxyuridylate (dUMP) into deoxythymidylate (dTMP) and requires both folate and flavin for activity. Here, the authors combine biochemical experiments, spectroscopic measurements and flavin synthesis chemistry to show that formaldehyde (CH2O) can replace the natural methylene donor of ThyX in a CH2O-shunt reaction, yielding a carbinolamine intermediate with the reduced flavin coenzyme, and they present the crystal structure of this intermediate.

    • Charles Bou-Nader
    • , Frederick W. Stull
    •  & Djemel Hamdane
  • Article
    | Open Access

    Autosomal dominant polycystic kidney disease is characterized by the formation of cysts in the kidney. Here the authors show that cystic extracellular vesicles/exosomes play a critical role in regulating the biology and function of adjacent cells, including renal epithelial cells, fibroblasts and macrophages, and contribute to renal cyst growth.

    • Hao Ding
    • , Linda Xiaoyan Li
    •  & Xiaogang Li
  • Article
    | Open Access

    Human cytomegalovirus (HCMV) is the prototypical member of the β-herpesvirinae subfamily and the leading viral cause of congenital infections that can lead to birth defects and it can also cause life-threatening disease in immunocompromised individuals. Here, the authors present the in-situ cryo-EM structures of the symmetry-mismatched portal and the capsid vertex-specific components (CVSCs) of HCMV and discuss the mechanistic implications for genome package, retention and ejection.

    • Zhihai Li
    • , Jingjing Pang
    •  & Xuekui Yu
  • Article
    | Open Access

    The transmembrane protein Wntless (WLS) is essential for the secretion of Wnt proteins, which are signaling molecules of the Wnt signaling pathways. Here, the authors present the 2.2 Å cryo-EM structure of human WLS in complex with Wnt3a and discuss mechanistic implications for the palmitoleoylation of Wnt3a that is required for WLS mediated Wnt secretion.

    • Qing Zhong
    • , Yanyu Zhao
    •  & Dan Ma
  • Article
    | Open Access

    Plant and soil C:N:P ratios are critical to ecosystem functioning, but it remains uncertain how plant diversity affects terrestrial C:N:P. In this meta-analysis of 169 studies, the authors find that plant mixtures can balance plant and soil C:N:P ratios according to background soil C:N:P.

    • Xinli Chen
    •  & Han Y. H. Chen
  • Article
    | Open Access

    Here the authors show that 2-aminoethylphosphonate (2AEP) mineralisation is widespread in the global ocean, operating independently of exogenous inorganic phosphate concentration. They propose 2AEP may be a major route for the regeneration of phosphate required to support marine primary production.

    • Andrew R. J. Murphy
    • , David J. Scanlan
    •  & Ian D. E. A. Lidbury
  • Perspective
    | Open Access

    A key feature of living cells is the cell cycle. In this Perspective, the authors explore attempts to recreate this process and what is still required for an integrated synthetic cell cycle.

    • Lorenzo Olivi
    • , Mareike Berger
    •  & John van der Oost
  • Article
    | Open Access

    Currently, bidirectional control of activity in the same neurons in the same experiment is difficult. Here the authors report a Bidirectional Pair of Opsins for Light-induced Excitation and Silencing, BiPOLES, which they use in a range of organisms including worms, fruit flies, mice and ferrets.

    • Johannes Vierock
    • , Silvia Rodriguez-Rozada
    •  & J. Simon Wiegert
  • Article
    | Open Access

    To explore the nature of wild and cultivated mandarins, the authors carry out genomic analysis of diverse east Asian citrus. The discovery of a wild species Citrus ryukyuensis native to the Ryukyu islands and a new population of wild mainland Asian mandarin explains the origin and diversity of mandarins and their ability to reproduce apomictically.

    • Guohong Albert Wu
    • , Chikatoshi Sugimoto
    •  & Daniel S. Rokhsar
  • Article
    | Open Access

    How acute deoxygenation events affect tropical marine ecosystems remains poorly understood. This study integrates analyses of coral reef benthic communities with microbial community sequencing to show how a deoxygenation event rapidly altered a shallow tropical coral reef ecosystem in the Caribbean.

    • Maggie D. Johnson
    • , Jarrod J. Scott
    •  & Andrew H. Altieri