Erratum in Cell. 2021 Dec 9;184(25):6211.

Comment in Trends Pharmacol Sci. 2022 Jun;43(6):461-463.

Erratum in Cell. 2022 Jan 6;185(1):218.

Anosmia, the loss of smell, is a common and often the sole symptom of COVID-19. The onset of the sequence of pathobiological events leading to olfactory dysfunction remains obscure. Here, we have developed a postmortem bedside surgical procedure to harvest endoscopically samples of respiratory and olfactory mucosae and whole olfactory bulbs. Our cohort of 85 cases included COVID-19 patients who died a few days after infection with SARS-CoV-2, enabling us to catch the virus while it was still replicating. We found that sustentacular cells are the major target cell type in the olfactory mucosa. We failed to find evidence for infection of olfactory sensory neurons, and the parenchyma of the olfactory bulb is spared as well. Thus, SARS-CoV-2 does not appear to be a neurotropic virus. We postulate that transient insufficient support from sustentacular cells triggers transient olfactory dysfunction in COVID-19. Olfactory sensory neurons would become affected without getting infected.

Comment in Cell. 2021 Nov 24;184(24):5842-5844.

Comment in Nat Methods. 2022 Feb;19(2):140.

Comment on Cell. 2021 Nov 24;184(24):5902-5915.e17.

Diversity within science, technology, engineering, and mathematics (STEM) remains disturbingly low. Relative to larger, highly funded universities, smaller schools harbor more diverse student demographics and more limited resources. Here, we propose four strategies leveraging the unique advantages of smaller institutions to advance underrepresented scholars along STEM pathways.

Comment on Cell. 2021 Jun 24;184(13):3394-3409.e20. Cell. 2021 Nov 24;184(24):5839-5841.

Numerous DNA double-strand breaks (DSBs) arise during meiosis to initiate homologous recombination. These DSBs are usually repaired faithfully, but here, we uncover a distinct type of mutational event in which deletions form via joining of ends from two closely spaced DSBs (double cuts) within a single hotspot or at adjacent hotspots on the same or different chromatids. Deletions occur in normal meiosis but are much more frequent when DSB formation is dysregulated in the absence of the ATM kinase. Events between chromosome homologs point to multi-chromatid damage and aborted gap repair. Some deletions contain DNA from other hotspots, indicating that double cutting at distant sites creates substrates for insertional mutagenesis. End joining at double cuts can also yield tandem duplications or extrachromosomal circles. Our findings highlight the importance of DSB regulation and reveal a previously hidden potential for meiotic mutagenesis that is likely to affect human health and genome evolution.

Current catalogs of regulatory sequences in the human genome are still incomplete and lack cell type resolution. To profile the activity of gene regulatory elements in diverse cell types and tissues in the human body, we applied single-cell chromatin accessibility assays to 30 adult human tissue types from multiple donors. We integrated these datasets with previous single-cell chromatin accessibility data from 15 fetal tissue types to reveal the status of open chromatin for ∼1.2 million candidate cis-regulatory elements (cCREs) in 222 distinct cell types comprised of >1.3 million nuclei. We used these chromatin accessibility maps to delineate cell-type-specificity of fetal and adult human cCREs and to systematically interpret the noncoding variants associated with complex human traits and diseases. This rich resource provides a foundation for the analysis of gene regulatory programs in human cell types across tissues, life stages, and organ systems.

Comment in Nat Rev Microbiol. 2022 Feb;20(2):63. Nat Rev Gastroenterol Hepatol. 2022 Jan;19(1):6. Cell Metab. 2021 Dec 7;33(12):2311-2313. Nat Neurosci. 2022 Jan;25(1):2. Cell Host Microbe. 2022 Jan 12;30(1):5-7. Cell Rep Med. 2022 Jan 18;3(1):100505.

The biogenesis of mammalian autophagosomes remains to be fully defined. Here, we used cellular and in vitro membrane fusion analyses to show that autophagosomes are formed from a hitherto unappreciated hybrid membrane compartment. The autophagic precursors emerge through fusion of FIP200 vesicles, derived from the cis-Golgi, with endosomally derived ATG16L1 membranes to generate a hybrid pre-autophagosomal structure, HyPAS. A previously unrecognized apparatus defined here controls HyPAS biogenesis and mammalian autophagosomal precursor membranes. HyPAS can be modulated by pharmacological agents whereas its formation is inhibited upon severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or by expression of SARS-CoV-2 nsp6. These findings reveal the origin of mammalian autophagosomal membranes, which emerge via convergence of secretory and endosomal pathways, and show that this process is targeted by microbial factors such as coronaviral membrane-modulating proteins.

Comment in Nat Rev Genet. 2022 Jan;23(1):1. Cell. 2021 Dec 9;184(25):6019-6021.

Comment in Cell Res. 2022 Feb;32(2):113-114.

Dynein-decorated doublet microtubules (DMTs) are critical components of the oscillatory molecular machine of cilia, the axoneme, and have luminal surfaces patterned periodically by microtubule inner proteins (MIPs). Here we present an atomic model of the 48-nm repeat of a mammalian DMT, derived from a cryoelectron microscopy (cryo-EM) map of the complex isolated from bovine respiratory cilia. The structure uncovers principles of doublet microtubule organization and features specific to vertebrate cilia, including previously unknown MIPs, a luminal bundle of tektin filaments, and a pentameric dynein-docking complex. We identify a mechanism for bridging 48- to 24-nm periodicity across the microtubule wall and show that loss of the proteins involved causes defective ciliary motility and laterality abnormalities in zebrafish and mice. Our structure identifies candidate genes for diagnosis of ciliopathies and provides a framework to understand their functions in driving ciliary motility.

Comment in Nat Rev Microbiol. 2022 Jan;20(1):2.

Author information: (1)Translational and Clinical Research Institute Immunity and Inflammation Theme, Newcastle University, Newcastle, UK. Electronic address: rebecca.payne2@newcastle.ac.uk. (2)Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK. (3)NIHR Health Protection Research Unit in Emerging and Zoonotic Infections, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK. (4)Peter Medawar Building for Pathogen Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK; Oxford University Hospitals NHS Foundation Trust, Oxford, UK; Nuffield Department of Clinical Neuroscience, University of Oxford, Oxford, UK. (5)Peter Medawar Building for Pathogen Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK. (6)Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK. (7)Institute of Immunology and Immunotherapy, College of Medical and Dental Science, University of Birmingham, Birmingham, UK. (8)Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK. (9)Translational and Clinical Research Institute Immunity and Inflammation Theme, Newcastle University, Newcastle, UK. (10)Public Health England, Colindale, London, UK. (11)Oxford University Hospitals NHS Foundation Trust, Oxford, UK; Translational Gastroenterology Unit, University of Oxford, Oxford, UK. (12)Liverpool University Hospitals NHS Foundation Trust, Liverpool, UK. (13)Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK. (14)Translational and Clinical Research Institute Immunity and Inflammation Theme, Newcastle University, Newcastle, UK; Great North Children's Hospital, Newcastle, UK. (15)Institute of Immunology and Immunotherapy, College of Medical and Dental Science, University of Birmingham, Birmingham, UK; University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK. (16)Oxford University Hospitals NHS Foundation Trust, Oxford, UK. (17)Peter Medawar Building for Pathogen Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK; Oxford University Hospitals NHS Foundation Trust, Oxford, UK; Oxford University Medical School, Medical Sciences Division, University of Oxford, Oxford, UK. (18)NIHR Health Protection Research Unit in Emerging and Zoonotic Infections, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK; Liverpool University Hospitals NHS Foundation Trust, Liverpool, UK; Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK. (19)Oxford University Hospitals NHS Foundation Trust, Oxford, UK; Oxford Centre For Global Health Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK. (20)Oxford University Hospitals NHS Foundation Trust, Oxford, UK; Radcliffe Department of Medicine, University of Oxford, Oxford, UK. (21)Peter Medawar Building for Pathogen Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK; Oxford University Hospitals NHS Foundation Trust, Oxford, UK. (22)Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK; NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UK. (23)Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK; Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK. (24)Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK; Chinese Academy of Medical Science (CAMS) Oxford Institute (COI), University of Oxford, Oxford, UK; Siriraj Center of Research Excellence in Dengue & Emerging Pathogens, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand. (25)Peter Medawar Building for Pathogen Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK; Oxford University Hospitals NHS Foundation Trust, Oxford, UK; Translational Gastroenterology Unit, University of Oxford, Oxford, UK; NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UK. (26)Public Health England, Colindale, London, UK; Faculty of Medicine, Department of Infectious Disease, Imperial College London, London, UK; NIHR Health Protection Research Unit in Healthcare Associated Infection and Antimicrobial Resistance, University of Oxford, Oxford, UK. (27)Public Health England, Colindale, London, UK; NIHR Health Protection Research Unit in Healthcare Associated Infection and Antimicrobial Resistance, University of Oxford, Oxford, UK. (28)Translational and Clinical Research Institute Immunity and Inflammation Theme, Newcastle University, Newcastle, UK; Department of Infection and Tropical Medicine, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle, UK. (29)NIHR Health Protection Research Unit in Emerging and Zoonotic Infections, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK; Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK. (30)Peter Medawar Building for Pathogen Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK; Oxford University Hospitals NHS Foundation Trust, Oxford, UK; Translational Gastroenterology Unit, University of Oxford, Oxford, UK; NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UK. Electronic address: paul.klenerman@ndm.ox.ac.uk. (31)Peter Medawar Building for Pathogen Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK; Oxford University Hospitals NHS Foundation Trust, Oxford, UK; Oxford Centre For Global Health Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK; Mahidol-Oxford Tropical Medicine Research Unit, Bangkok, Thailand.

Comment on Cell. 2021 Nov 11;184(23):5728-5739.e16.

Comment in Nat Rev Neurosci. 2022 Jan;23(1):3.

Comment on Nature. 2021 Sep;597(7878):709-714.

Comment in Cell. 2021 Nov 11;184(23):5693-5695.

Comment on Cell. 2021 Nov 11;184(23):5824-5837.e15.

Comment in Neuron. 2021 Nov 17;109(22):3545-3547. Trends Parasitol. 2022 Mar;38(3):191-192.

Comment in Nat Rev Microbiol. 2022 Jan;20(1):1. Cell. 2021 Nov 11;184(23):5691-5693.