Comment in Nat Rev Neurol. 2022 Aug;18(8):453.

Ferroptosis, a form of cell death driven by iron-dependent lipid peroxidation, was identified as a distinct phenomenon and named a decade ago. Ferroptosis has been implicated in a broad set of biological contexts, from development to aging, immunity, and cancer. This review describes key regulators of this form of cell death within a framework of metabolism, ROS biology, and iron biology. Key concepts and major unanswered questions in the ferroptosis field are highlighted. The next decade promises to yield further breakthroughs in the mechanisms governing ferroptosis and additional ways of harnessing ferroptosis for therapeutic benefit.

Melanoma brain metastasis (MBM) frequently occurs in patients with advanced melanoma; yet, our understanding of the underlying salient biology is rudimentary. Here, we performed single-cell/nucleus RNA-seq in 22 treatment-naive MBMs and 10 extracranial melanoma metastases (ECMs) and matched spatial single-cell transcriptomics and T cell receptor (TCR)-seq. Cancer cells from MBM were more chromosomally unstable, adopted a neuronal-like cell state, and enriched for spatially variably expressed metabolic pathways. Key observations were validated in independent patient cohorts, patient-derived MBM/ECM xenograft models, RNA/ATAC-seq, proteomics, and multiplexed imaging. Integrated spatial analyses revealed distinct geography of putative cancer immune evasion and evidence for more abundant intra-tumoral B to plasma cell differentiation in lymphoid aggregates in MBM. MBM harbored larger fractions of monocyte-derived macrophages and dysfunctional TOX+CD8+ T cells with distinct expression of immune checkpoints. This work provides comprehensive insights into MBM biology and serves as a foundational resource for further discovery and therapeutic exploration.

Comment in Nat Rev Genet. 2022 Aug;23(8):459.

Author information: (1)Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK. (2)Division of Structural Biology, Nuffield Department of Medicine, University of Oxford, The Wellcome Centre for Human Genetics, Oxford, UK; Chinese Academy of Medical Science (CAMS) Oxford Institute (COI), University of Oxford, Oxford, UK. (3)Diamond Light Source Ltd, Harwell Science & Innovation Campus, Didcot, UK. (4)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. (5)Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK; Oxford University Hospitals NHS Foundation Trust, Oxford, UK. (6)Division of Structural Biology, Nuffield Department of Medicine, University of Oxford, The Wellcome Centre for Human Genetics, Oxford, UK. (7)Oxford University Hospitals NHS Foundation Trust, Oxford, UK; Peter Medawar Building for Pathogen Research, Oxford, UK; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK. (8)Oxford University Hospitals NHS Foundation Trust, Oxford, UK. (9)Oxford University Hospitals NHS Foundation Trust, Oxford, UK; Peter Medawar Building for Pathogen Research, Oxford, UK; Translational Gastroenterology Unit, University of Oxford, Oxford, UK. (10)Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK. (11)Nuffield Department of Medicine, University of Oxford, Oxford, UK. (12)Viral Pseudotype Unit, Medway School of Pharmacy, University of Kent and Greenwich Chatham Maritime, Kent, UK. (13)Oxford University Hospitals NHS Foundation Trust, Oxford, UK; Peter Medawar Building for Pathogen Research, Oxford, UK; Translational Gastroenterology Unit, University of Oxford, Oxford, UK; NIHR Oxford Biomedical Research Centre, Oxford, UK. (14)Oxford University Hospitals NHS Foundation Trust, Oxford, UK; Peter Medawar Building for Pathogen Research, Oxford, UK; Centre For Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK; Mahidol-Oxford Tropical Medicine Research Unit, Department of Medicine, University of Oxford, Oxford, UK. (15)Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK; NIHR Oxford Biomedical Research Centre, Oxford, UK. (16)Chinese Academy of Medical Science (CAMS) Oxford Institute (COI), University of Oxford, Oxford, UK; Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK. (17)Peter Medawar Building for Pathogen Research, Oxford, UK; Department of Paediatrics, University of Oxford, Oxford, UK. (18)Division of Structural Biology, Nuffield Department of Medicine, University of Oxford, The Wellcome Centre for Human Genetics, Oxford, UK. Electronic address: liz@strubi.ox.ac.uk. (19)Division of Structural Biology, Nuffield Department of Medicine, University of Oxford, The Wellcome Centre for Human Genetics, Oxford, UK. Electronic address: dongdong.imm.ox.ac.uk@gmail.com. (20)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. Electronic address: juthathip.mongkolsapaya@well.ox.ac.uk. (21)Division of Structural Biology, Nuffield Department of Medicine, University of Oxford, The Wellcome Centre for Human Genetics, Oxford, UK. Electronic address: ren@strubi.ox.ac.uk. (22)Division of Structural Biology, Nuffield Department of Medicine, University of Oxford, The Wellcome Centre for Human Genetics, Oxford, UK; Chinese Academy of Medical Science (CAMS) Oxford Institute (COI), University of Oxford, Oxford, UK; Diamond Light Source Ltd, Harwell Science & Innovation Campus, Didcot, UK. Electronic address: dave@strubi.ox.ac.uk. (23)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. Electronic address: gavin.screaton@medsci.ox.ac.uk.

Update of bioRxiv. 2022 Mar 21;:

Comment in Cell. 2022 Jul 7;185(14):2398-2400.

Comment in Nat Rev Endocrinol. 2022 Aug;18(8):455. Nat Rev Gastroenterol Hepatol. 2022 Aug;19(8):486. Cell Res. 2022 Aug;32(8):711-712. Gastroenterology. 2023 Jan;164(1):161.

Acute mild respiratory SARS-CoV-2 infection can lead to a more chronic cognitive syndrome known as "COVID fog." New findings from Fernández-Castañeda et al. reveal how glial dysregulation and consequent neural circuit dysfunction may contribute to cognitive impairments in long COVID.

Autoantibodies targeting neuronal membrane proteins can cause encephalitis, seizures, and severe behavioral abnormalities. While antibodies for several neuronal targets have been identified, structural details on how they regulate function are unknown. Here we determined cryo-electron microscopy structures of antibodies derived from an encephalitis patient bound to the γ-aminobutyric acid type A (GABAA) receptor. These antibodies induced severe encephalitis by directly inhibiting GABAA function, resulting in nervous-system hyperexcitability. The structures reveal mechanisms of GABAA inhibition and pathology. One antibody directly competes with a neurotransmitter and locks the receptor in a resting-like state. The second antibody targets the subunit interface involved in binding benzodiazepines and antagonizes diazepam potentiation. We identify key residues in these antibodies involved in specificity and affinity and confirm structure-based hypotheses for functional effects using electrophysiology. Together these studies define mechanisms of direct functional antagonism of neurotransmission underlying autoimmune encephalitis in a human patient.

Stem cell research endeavors to generate specific subtypes of classically defined "cell types." Here, we generate >90% pure human artery or vein endothelial cells from pluripotent stem cells within 3-4 days. We specified artery cells by inhibiting vein-specifying signals and vice versa. These cells modeled viral infection of human vasculature by Nipah and Hendra viruses, which are extraordinarily deadly (∼57%-59% fatality rate) and require biosafety-level-4 containment. Generating pure populations of artery and vein cells highlighted that Nipah and Hendra viruses preferentially infected arteries; arteries expressed higher levels of their viral-entry receptor. Virally infected artery cells fused into syncytia containing up to 23 nuclei, which rapidly died. Despite infecting arteries and occupying ∼6%-17% of their transcriptome, Nipah and Hendra largely eluded innate immune detection, minimally eliciting interferon signaling. We thus efficiently generate artery and vein cells, introduce stem-cell-based toolkits for biosafety-level-4 virology, and explore the arterial tropism and cellular effects of Nipah and Hendra viruses.

Erratum in Cell. 2022 Aug 4;185(16):3056-3057.

Mouse germline cysts, on average, develop into six oocytes supported by 24 nurse cells that transfer cytoplasm and organelles to generate a Balbiani body. We showed that between E14.5 and P5, cysts periodically activate some nurse cells to begin cytoplasmic transfer, which causes them to shrink and turnover within 2 days. Nurse cells die by a programmed cell death (PCD) pathway involving acidification, similar to Drosophila nurse cells, and only infrequently by apoptosis. Prior to initiating transfer, nurse cells co-cluster by scRNA-seq with their pro-oocyte sisters, but during their final 2 days, they cluster separately. The genes promoting oocyte development and nurse cell PCD are upregulated, whereas the genes that repress transfer, such as Tex14, and oocyte factors, such as Nobox and Lhx8, are under-expressed. The transferred nurse cell centrosomes build a cytocentrum that establishes a large microtubule aster in the primordial oocyte that organizes the Balbiani body, defining the earliest oocyte polarity.

Comment on Cell. 2022 Jun 28;:null.

Comment on Cell. 2022 Jul 7;185(14):2542-2558.e18.

The ileal brake is an important reflex that ensures proper absorption of nutrients. This involves intestinal GLP-1 release, which recruits an enteric-sympathetic-spinal pathway to inhibit gastric motility and appetite. This visceral alarm system could be targeted to treat obesity and gastrointestinal dysfunction.

Microbial culturing and meta-omic profiling technologies have significantly advanced our understanding of the taxonomic and functional variation of the human microbiome and its impact on host processes. The next increase in resolution will come by understanding the role of low-abundant and less-prevalent bacteria and the study of individual cell behaviors that underlie the complexity of microbial ecosystems. To this aim, single-cell techniques are being rapidly developed to isolate, culture, and characterize the genomes and transcriptomes of individual microbes in complex communities. Here, we discuss how these single-cell technologies are providing unique insights into the biology and behavior of human microbiomes.

In vivo gene editing therapies offer the potential to treat the root causes of many genetic diseases. Realizing the promise of therapeutic in vivo gene editing requires the ability to safely and efficiently deliver gene editing agents to relevant organs and tissues in vivo. Here, we review current delivery technologies that have been used to enable therapeutic in vivo gene editing, including viral vectors, lipid nanoparticles, and virus-like particles. Since no single delivery modality is likely to be appropriate for every possible application, we compare the benefits and drawbacks of each method and highlight opportunities for future improvements.

Antibody therapeutics are a large and rapidly expanding drug class providing major health benefits. We provide a snapshot of current antibody therapeutics including their formats, common targets, therapeutic areas, and routes of administration. Our focus is on selected emerging directions in antibody design where progress may provide a broad benefit. These topics include enhancing antibodies for cancer, antibody delivery to organs such as the brain, gastrointestinal tract, and lungs, plus antibody developability challenges including immunogenicity risk assessment and mitigation and subcutaneous delivery. Machine learning has the potential, albeit as yet largely unrealized, for a transformative future impact on antibody discovery and engineering.

Cell types are the basic functional units of an organism. Cell types exhibit diverse phenotypic properties at multiple levels, making them challenging to define, categorize, and understand. This review provides an overview of the basic principles of cell types rooted in evolution and development and discusses approaches to characterize and classify cell types and investigate how they contribute to the organism's function, using the mammalian brain as a primary example. I propose a roadmap toward a conceptual framework and knowledge base of cell types that will enable a deeper understanding of the dynamic changes of cellular function under healthy and diseased conditions.

Copyright © 2022 Elsevier Inc. All rights reserved.

Synthetic genomics is the construction of viruses, bacteria, and eukaryotic cells with synthetic genomes. It involves two basic processes: synthesis of complete genomes or chromosomes and booting up of those synthetic nucleic acids to make viruses or living cells. The first synthetic genomics efforts resulted in the construction of viruses. This led to a revolution in viral reverse genetics and improvements in vaccine design and manufacture. The first bacterium with a synthetic genome led to construction of a minimal bacterial cell and recoded Escherichia coli strains able to incorporate multiple non-standard amino acids in proteins and resistant to phage infection. Further advances led to a yeast strain with a synthetic genome and new approaches for animal and plant artificial chromosomes. On the horizon there are dramatic advances in DNA synthesis that will enable extraordinary new opportunities in medicine, industry, agriculture, and research.

Metabolic anomalies contribute to tissue dysfunction. Current metabolism research spans from organelles to populations, and new technologies can accommodate investigation across these scales. Here, we review recent advancements in metabolic analysis, including small-scale metabolomics techniques amenable to organelles and rare cell types, functional screening to explore how cells respond to metabolic stress, and imaging approaches to non-invasively assess metabolic perturbations in diseases. We discuss how metabolomics provides an informative phenotypic dimension that complements genomic analysis in Mendelian and non-Mendelian disorders. We also outline pressing challenges and how addressing them may further clarify the biochemical basis of human disease.

Single-cell transcriptomic analysis has facilitated cell type identification in the brain and mapping of cell type-specific connectomes, helping to elucidate neural circuits underlying brain functions and to treat brain disorders by neuromodulation. Yet, we lack a consensual definition of neuronal types/subtypes and clear distinction between cause and effect within interconnected networks.

For decades, insight into fundamental principles of human biology and disease has been obtained primarily by experiments in animal models. While this has allowed researchers to understand many human biological processes in great detail, some developmental and disease mechanisms have proven difficult to study due to inherent species differences. The advent of organoid technology more than 10 years ago has established laboratory-grown organ tissues as an additional model system to recapitulate human-specific aspects of biology. The use of human 3D organoids, as well as other advances in single-cell technologies, has revealed unprecedented insights into human biology and disease mechanisms, especially those that distinguish humans from other species. This review highlights novel advances in organoid biology with a focus on how organoid technology has generated a better understanding of human-specific processes in development and disease.

Spatially resolved transcriptomics methodologies using RNA sequencing principles have and will continue to contribute to decode the molecular landscape of tissues. Linking quantitative sequencing data with tissue morphology empowers profiling of cellular morphology and transcription over time and space in health and disease. To view this SnapShot, open or download the PDF.

As a major event in human civilization, wild plants were successfully domesticated to be crops, largely owing to continuing artificial selection. Here, we summarize new discoveries made during the past decade in crop domestication and breeding. The construction of crop genome maps and the functional characterization of numerous trait genes provide foundational information. Approaches to read, interpret, and write complex genetic information are being leveraged in many plants for highly efficient de novo or re-domestication. Understanding the underlying mechanisms of crop microevolution and applying the knowledge to agricultural productions will give possible solutions for future challenges in food security.

Cellular carbohydrates or glycans are critical mediators of biological function. Their remarkably diverse structures and varied activities present exciting opportunities for understanding many areas of biology. In this primer, we discuss key methods and recent breakthrough technologies for identifying, monitoring, and manipulating glycans in mammalian systems.

Bioprinting merges additive manufacturing and tissue engineering to generate functional tissues and organs. The field has experienced tremendous growth over the past few years. Here, we highlight recent breakthroughs in bioprinting and discuss the challenges that are yet to be addressed before this technology can be widely utilized in biology and medicine.

Innovations in soft materials bridge electronic conduction in conventional electronics and ionic conduction in biology. In a recent issue of Science, Dobashi et al. describe a hydrogel that generates large ionic currents in response to applied force. The technology could enable sensors and energy generators for wearable and implantable devices.

Over the last decade, the artificial intelligence (AI) has undergone a revolution that is poised to transform the economy, society, and science. The pace of progress is staggering, and problems that seemed intractable just a few years ago have now been solved. The intersection between neuroscience and AI is particularly exciting.

Nearly half of the human genome is comprised of diverse repetitive sequences ranging from satellite repeats to retrotransposable elements. Such sequences are susceptible to stepwise expansions, duplications, inversions, and recombination events which can compromise genome function. In this review, we discuss the higher-order folding mechanisms of compartmentalization and loop extrusion and how they shape, and are shaped by, heterochromatin. Using primarily mammalian model systems, we contrast mechanisms governing H3K9me3-mediated heterochromatinization of the repetitive genome and highlight emerging links between repetitive elements and chromatin folding.

Technological advances have enabled the rapid generation of health and genomic data, though rarely do these technologies account for the values and priorities of marginalized communities. In this commentary, we conceptualize a blockchain genomics data framework built out of the concept of Indigenous Data Sovereignty.

Ancient DNA (aDNA) techniques applied to human genomics have significantly advanced in the past decade, enabling large-scale aDNA research, sometimes independent of human remains. This commentary reviews the major milestones of aDNA techniques and explores future directions to expand the scope of aDNA research and insights into present-day human health.

Generating considerable amounts of industrial waste requires rethinking chemistry for circularity in a broader picture. We discuss the study by Wołos et al. (2022) showing that the critical application of artificial intelligence on chemical reactivity can help us trace an unprecedented number of syntheses to novel responsible uses of waste.

Cryogenic electron tomography (cryo-ET) is the application of tomographic principles of data acquisition and reconstruction to frozen-hydrated biological specimens. It combines a close-to-life preservation of cellular structures with the power of high-resolution three-dimensional imaging, which allows us to study the molecular architecture of cells, or their molecular sociology, in unprecedented detail.

Cancer vaccines aim to direct the immune system to eradicate cancer cells. Here we review the essential immunologic concepts underpinning natural immunity and highlight the multiple unique challenges faced by vaccines targeting cancer. Recent technological advances in mass spectrometry, neoantigen prediction, genetically and pharmacologically engineered mouse models, and single-cell omics have revealed new biology, which can help to bridge this divide. We particularly focus on translationally relevant aspects, such as antigen selection and delivery and the monitoring of human post-vaccination responses, and encourage more aggressive exploration of novel approaches.