Comment in Cell. 2021 Sep 30;184(20):5084-5086.

Neural circuit assembly features simultaneous targeting of numerous neuronal processes from constituent neuron types, yet the dynamics is poorly understood. Here, we use the Drosophila olfactory circuit to investigate dynamic cellular processes by which olfactory receptor neurons (ORNs) target axons precisely to specific glomeruli in the ipsi- and contralateral antennal lobes. Time-lapse imaging of individual axons from 30 ORN types revealed a rich diversity in extension speed, innervation timing, and ipsilateral branch locations and identified that ipsilateral targeting occurs via stabilization of transient interstitial branches. Fast imaging using adaptive optics-corrected lattice light-sheet microscopy showed that upon approaching target, many ORN types exhibiting "exploring branches" consisted of parallel microtubule-based terminal branches emanating from an F-actin-rich hub. Antennal nerve ablations uncovered essential roles for bilateral axons in contralateral target selection and for ORN axons to facilitate dendritic refinement of postsynaptic partner neurons. Altogether, these observations provide cellular bases for wiring specificity establishment.

Update of medRxiv. 2021 Jul 25;:

Comment in Cell. 2021 Sep 30;184(20):5082-5084. Neuron. 2021 Oct 20;109(20):3228-3230.

Comment in Dev Cell. 2021 Nov 22;56(22):3040-3041.

Comment in Trends Parasitol. 2021 Dec;37(12):1024-1026. Cell Host Microbe. 2021 Nov 10;29(11):1601-1603.

Natural goal-directed behaviors often involve complex sequences of many stimulus-triggered components. Understanding how brain circuits organize such behaviors requires mapping the interactions between an animal, its environment, and its nervous system. Here, we use brain-wide neuronal imaging to study the full performance of mating by the C. elegans male. We show that as mating unfolds in a sequence of component behaviors, the brain operates similarly between instances of each component but distinctly between different components. When the full sensory and behavioral context is taken into account, unique roles emerge for each neuron. Functional correlations between neurons are not fixed but change with behavioral dynamics. From individual neurons to circuits, our study shows how diverse brain-wide dynamics emerge from the integration of sensory perception and motor actions in their natural context.

3' untranslated region (3'UTR) variants are strongly associated with human traits and diseases, yet few have been causally identified. We developed the massively parallel reporter assay for 3'UTRs (MPRAu) to sensitively assay 12,173 3'UTR variants. We applied MPRAu to six human cell lines, focusing on genetic variants associated with genome-wide association studies (GWAS) and human evolutionary adaptation. MPRAu expands our understanding of 3'UTR function, suggesting that simple sequences predominately explain 3'UTR regulatory activity. We adapt MPRAu to uncover diverse molecular mechanisms at base pair resolution, including an adenylate-uridylate (AU)-rich element of LEPR linked to potential metabolic evolutionary adaptations in East Asians. We nominate hundreds of 3'UTR causal variants with genetically fine-mapped phenotype associations. Using endogenous allelic replacements, we characterize one variant that disrupts a miRNA site regulating the viral defense gene TRIM14 and one that alters PILRB abundance, nominating a causal variant underlying transcriptional changes in age-related macular degeneration.

Comment on Cell. 2021 Sep 30;184(20):5089-5106.e21.

Comment on Cell. 2021 Sep 30;184(20):5215-5229.e17.

Comment in Cell. 2021 Sep 30;184(20):5086-5088.

As the SARS-CoV-2 pandemic evolves, new variants continue to emerge. Some highly transmissible variants, such as Delta, also raised concerns about the effectiveness provided by current vaccines. Understanding immunological correlates of protection and how laboratory findings correspond to clinical effectiveness is imperative to shape future vaccination strategies.

The heartbeat is initiated by voltage-gated sodium channel NaV1.5, which opens rapidly and triggers the cardiac action potential; however, the structural basis for pore opening remains unknown. Here, we blocked fast inactivation with a mutation and captured the elusive open-state structure. The fast inactivation gate moves away from its receptor, allowing asymmetric opening of pore-lining S6 segments, which bend and rotate at their intracellular ends to dilate the activation gate to ∼10 Å diameter. Molecular dynamics analyses predict physiological rates of Na+ conductance. The open-state pore blocker propafenone binds in a high-affinity pose, and drug-access pathways are revealed through the open activation gate and fenestrations. Comparison with mutagenesis results provides a structural map of arrhythmia mutations that target the activation and fast inactivation gates. These results give atomic-level insights into molecular events that underlie generation of the action potential, open-state drug block, and fast inactivation of cardiac sodium channels, which initiate the heartbeat.

We present evidence for multiple independent origins of recombinant SARS-CoV-2 viruses sampled from late 2020 and early 2021 in the United Kingdom. Their genomes carry single-nucleotide polymorphisms and deletions that are characteristic of the B.1.1.7 variant of concern but lack the full complement of lineage-defining mutations. Instead, the remainder of their genomes share contiguous genetic variation with non-B.1.1.7 viruses circulating in the same geographic area at the same time as the recombinants. In four instances, there was evidence for onward transmission of a recombinant-origin virus, including one transmission cluster of 45 sequenced cases over the course of 2 months. The inferred genomic locations of recombination breakpoints suggest that every community-transmitted recombinant virus inherited its spike region from a B.1.1.7 parental virus, consistent with a transmission advantage for B.1.1.7's set of mutations.

Comment on Cell. 2021 Sep 30;184(20):5163-5178.e24.

Comment in Cell Calcium. 2022 Mar;102:102541.

In-depth quantitative proteomic analysis of clinical specimens offers unique and invaluable insights into their protein composition and biochemical state in physiological and pathological conditions. A plethora of methodologies have been developed and customized. Here, we summarize the most common and emerging mass spectrometry (MS)-based workflows. Due to space limitations the overview cannot be complete. To view this SnapShot, open or download the PDF.

We explore the utility of bioengineered human tissues-individually or connected into physiological units-for biological research. While much smaller and simpler than their native counterparts, these tissues are complex enough to approximate distinct tissue phenotypes: molecular, structural, and functional. Unlike organoids, which form spontaneously and recapitulate development, "organs-on-a-chip" are engineered to display some specific functions of whole organs. Looking back, we discuss the key developments of this emerging technology. Thinking forward, we focus on the challenges faced to fully establish, validate, and utilize the fidelity of these models for biological research.

Immune responses to cancer are highly variable, with mismatch repair-deficient (MMRd) tumors exhibiting more anti-tumor immunity than mismatch repair-proficient (MMRp) tumors. To understand the rules governing these varied responses, we transcriptionally profiled 371,223 cells from colorectal tumors and adjacent normal tissues of 28 MMRp and 34 MMRd individuals. Analysis of 88 cell subsets and their 204 associated gene expression programs revealed extensive transcriptional and spatial remodeling across tumors. To discover hubs of interacting malignant and immune cells, we identified expression programs in different cell types that co-varied across tumors from affected individuals and used spatial profiling to localize coordinated programs. We discovered a myeloid cell-attracting hub at the tumor-luminal interface associated with tissue damage and an MMRd-enriched immune hub within the tumor, with activated T cells together with malignant and myeloid cells expressing T cell-attracting chemokines. By identifying interacting cellular programs, we reveal the logic underlying spatially organized immune-malignant cell networks.

GRN mutations cause frontotemporal dementia (GRN-FTD) due to deficiency in progranulin (PGRN), a lysosomal and secreted protein with unclear function. Here, we found that Grn-/- mice exhibit a global deficiency in bis(monoacylglycero)phosphate (BMP), an endolysosomal phospholipid we identified as a pH-dependent PGRN interactor as well as a redox-sensitive enhancer of lysosomal proteolysis and lipolysis. Grn-/- brains also showed an age-dependent, secondary storage of glucocerebrosidase substrate glucosylsphingosine. We investigated a protein replacement strategy by engineering protein transport vehicle (PTV):PGRN-a recombinant protein linking PGRN to a modified Fc domain that binds human transferrin receptor for enhanced CNS biodistribution. PTV:PGRN rescued various Grn-/- phenotypes in primary murine macrophages and human iPSC-derived microglia, including oxidative stress, lysosomal dysfunction, and endomembrane damage. Peripherally delivered PTV:PGRN corrected levels of BMP, glucosylsphingosine, and disease pathology in Grn-/- CNS, including microgliosis, lipofuscinosis, and neuronal damage. PTV:PGRN thus represents a potential biotherapeutic for GRN-FTD.

Mutations causing amyotrophic lateral sclerosis (ALS) often affect the condensation properties of RNA-binding proteins (RBPs). However, the role of RBP condensation in the specificity and function of protein-RNA complexes remains unclear. We created a series of TDP-43 C-terminal domain (CTD) variants that exhibited a gradient of low to high condensation propensity, as observed in vitro and by nuclear mobility and foci formation. Notably, a capacity for condensation was required for efficient TDP-43 assembly on subsets of RNA-binding regions, which contain unusually long clusters of motifs of characteristic types and density. These "binding-region condensates" are promoted by homomeric CTD-driven interactions and required for efficient regulation of a subset of bound transcripts, including autoregulation of TDP-43 mRNA. We establish that RBP condensation can occur in a binding-region-specific manner to selectively modulate transcriptome-wide RNA regulation, which has implications for remodeling RNA networks in the context of signaling, disease, and evolution.

Comment in Nat Rev Immunol. 2021 Sep;21(9):547.

Comment in Nat Rev Drug Discov. 2021 Oct;20(10):739. Cell Res. 2021 Dec;31(12):1228-1229.

Comment in Nat Methods. 2021 Oct;18(10):1145.

Hearing involves two fundamental processes: mechano-electrical transduction and signal amplification. Despite decades of studies, the molecular bases for both remain elusive. Here, we show how prestin, the electromotive molecule of outer hair cells (OHCs) that senses both voltage and membrane tension, mediates signal amplification by coupling conformational changes to alterations in membrane surface area. Cryoelectron microscopy (cryo-EM) structures of human prestin bound with chloride or salicylate at a common "anion site" adopt contracted or expanded states, respectively. Prestin is ensconced within a perimeter of well-ordered lipids, through which it induces dramatic deformation in the membrane and couples protein conformational changes to the bulk membrane. Together with computational studies, we illustrate how the anion site is allosterically coupled to changes in the transmembrane domain cross-sectional area and the surrounding membrane. These studies provide insight into OHC electromotility by providing a structure-based mechanism of the membrane motor prestin.

Throughout development and aging, human cells accumulate mutations resulting in genomic mosaicism and genetic diversity at the cellular level. Mosaic mutations present in the gonads can affect both the individual and the offspring and subsequent generations. Here, we explore patterns and temporal stability of clonal mosaic mutations in male gonads by sequencing ejaculated sperm. Through 300× whole-genome sequencing of blood and sperm from healthy men, we find each ejaculate carries on average 33.3 ± 12.1 (mean ± SD) clonal mosaic variants, nearly all of which are detected in serial sampling, with the majority absent from sampled somal tissues. Their temporal stability and mutational signature suggest origins during embryonic development from a largely immutable stem cell niche. Clonal mosaicism likely contributes a transmissible, predicted pathogenic exonic variant for 1 in 15 men, representing a life-long threat of transmission for these individuals and a significant burden on human population health.

The Middle East region is important to understand human evolution and migrations but is underrepresented in genomic studies. Here, we generated 137 high-coverage physically phased genome sequences from eight Middle Eastern populations using linked-read sequencing. We found no genetic traces of early expansions out-of-Africa in present-day populations but found Arabians have elevated Basal Eurasian ancestry that dilutes their Neanderthal ancestry. Population sizes within the region started diverging 15-20 kya, when Levantines expanded while Arabians maintained smaller populations that derived ancestry from local hunter-gatherers. Arabians suffered a population bottleneck around the aridification of Arabia 6 kya, while Levantines had a distinct bottleneck overlapping the 4.2 kya aridification event. We found an association between movement and admixture of populations in the region and the spread of Semitic languages. Finally, we identify variants that show evidence of selection, including polygenic selection. Our results provide detailed insights into the genomic and selective histories of the Middle East.

Author information: (1)Department of Internal Medicine, Erasmus MC, Medical Center, 3015CN Rotterdam, the Netherlands. (2)Institute of Translational Genomics, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany. (3)deCODE Genetics/Amgen Inc., 102 Reykjavik, Iceland. (4)Genomic Medicine Institute, Geisinger Health System, Danville, PA 17822, USA. (5)Department of Biomedical Data Sciences, Section Molecular Epidemiology, Postzone S05-P Leiden University Medical Center, 2333ZC Leiden, the Netherlands. (6)Department of Psychiatry, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China. (7)MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK. (8)MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK; Musculoskeletal Research Unit, Translation Health Sciences, Bristol Medical School, University of Bristol, Southmead Hospital, Bristol BS10 5NB, UK. (9)Estonian Genome Center, Institute of Genomics, University of Tartu, 51010 Tartu, Estonia. (10)K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, 7491 Trondheim, Norway. (11)Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Kanagawa 230-0045, Japan. (12)4(th) Psychiatric Department, Dromokaiteio Psychiatric Hospital, 12461 Athens, Greece. (13)1(st) Department of Orthopaedics, KAT General Hospital, 14561 Athens, Greece. (14)Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland; Department of Orthopedic Surgery, Akureyri Hospital, 600 Akureyri, Iceland. (15)K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, 7491 Trondheim, Norway; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, 0316 Oslo, Norway; Research and Communication Unit for Musculoskeletal Health (FORMI), Department of Research, Innovation and Education, Division of Clinical Neuroscience, Oslo University Hospital, 0424 Oslo, Norway. (16)Department of Medicine, Landspitali The National University Hospital of Iceland, 108 Reykjavik, Iceland; Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland. (17)Departments of Rheumatology and Clinical Epidemiology, Leiden University Medical Center, 9600, 23OORC Leiden, the Netherlands. (18)Department of Twin Research and Genetic Epidemiology, Kings College London, London SE1 7EH, UK. (19)Department of Orthopaedics, Leiden University Medical Center, 9600, 23OORC Leiden, the Netherlands. (20)Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. (21)Institute of Translational Genomics, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany; Daffodil Centre, The University of Sydney, a joint venture with Cancer Council NSW, Sydney, NSW 1340, Australia. (22)Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo 108-8639, Japan; Department of Orthopedic Surgery, Shimane University, Shimane 693-8501, Japan. (23)K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, 7491 Trondheim, Norway; Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, 7491 Trondheim, Norway; BioCore-Bioinformatics Core Facility, Norwegian University of Science and Technology, 7491 Trondheim, Norway; Clinic of Laboratory Medicine, St. Olavs Hospital, Trondheim University Hospital, 7030 Trondheim, Norway. (24)2(nd) Department of Orthopaedics, National and Kapodistrian University of Athens, Medical School, Nea Ionia General Hospital Konstantopouleio, 14233 Athens, Greece. (25)Department of Orthopaedics and Traumatology, The University of Hong Kong, Pokfulam, Hong Kong, China. (26)Department of Medicine, Brigham and Women's Hospital, 181 Longwood Ave, Boston, MA 02115, USA. (27)Department of Epidemiology, Harvard T.H. Chan School of Public Health, 677 Huntington Avenue, Boston, MA 02115, USA. (28)Musculoskeletal Institute, Geisinger Health System, Danville, PA 17822, USA. (29)Department of Orthopaedics and Traumatology, The University of Hong Kong, Pokfulam, Hong Kong, China; Department of Orthopaedic Surgery, Rush University Medical Center, Chicago, IL 60612, USA. (30)deCODE Genetics/Amgen Inc., 102 Reykjavik, Iceland; Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland. (31)Musculoskeletal Research Unit, Translation Health Sciences, Bristol Medical School, University of Bristol, Southmead Hospital, Bristol BS10 5NB, UK; MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK. (32)K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, 7491 Trondheim, Norway; Department of Research, Innovation and Education, Division of Clinical Neuroscience, Oslo University Hospital and University of Oslo, 0450 Oslo, Norway; Department of Neurology, Oslo University Hospital, 0424 Oslo, Norway. (33)K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, 7491 Trondheim, Norway; Department of Research, Innovation and Education, Division of Clinical Neuroscience, Oslo University Hospital and University of Oslo, 0450 Oslo, Norway. (34)MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol BS8 2BN, UK. (35)Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China. (36)Centre for Genetics and Genomics Versus Arthritis, Centre for Musculoskeletal Research, University of Manchester, Manchester M13 9LJ, UK. (37)Faculty of Medicine and Health Sciences, School of Medicine, University of Nottingham, Nottingham, Nottinghamshire NG5 1PB, UK. (38)Laboratory of Cytogenetics and Molecular Genetics, Faculty of Medicine, University of Thessaly, Larissa 411 10, Greece. (39)School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong, China. (40)Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo 108-8639, Japan. (41)K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, 7491 Trondheim, Norway; HUNT Research Center, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, 7600 Levanger, Norway. (42)Department of Oncology and Metabolism and Healthy Lifespan Institute, University of Sheffield, Sheffield S10 2RX, UK. (43)Genomic Medicine Institute, Geisinger Health System, Danville, PA 17822, USA; Institute of Biomedical Sciences, Academia Sinica, 115 Taipei, Taiwan. (44)Institute of Translational Genomics, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany; TUM School of Medicine, Technical University of Munich and Klinikum Rechts der Isar, 81675 Munich, Germany. Electronic address: eleftheria.zeggini@helmholtz-muenchen.de.

Speech perception is thought to rely on a cortical feedforward serial transformation of acoustic into linguistic representations. Using intracranial recordings across the entire human auditory cortex, electrocortical stimulation, and surgical ablation, we show that cortical processing across areas is not consistent with a serial hierarchical organization. Instead, response latency and receptive field analyses demonstrate parallel and distinct information processing in the primary and nonprimary auditory cortices. This functional dissociation was also observed where stimulation of the primary auditory cortex evokes auditory hallucination but does not distort or interfere with speech perception. Opposite effects were observed during stimulation of nonprimary cortex in superior temporal gyrus. Ablation of the primary auditory cortex does not affect speech perception. These results establish a distributed functional organization of parallel information processing throughout the human auditory cortex and demonstrate an essential independent role for nonprimary auditory cortex in speech processing.

Animals face both external and internal dangers: pathogens threaten from the environment, and unstable genomic elements threaten from within. C. elegans protects itself from pathogens by "reading" bacterial small RNAs, using this information to both induce avoidance and transmit memories for four generations. Here, we found that memories can be transferred from either lysed animals or from conditioned media to naive animals via Cer1 retrotransposon-encoded virus-like particles. Moreover, Cer1 functions internally at the step of transmission of information from the germline to neurons and is required for learned avoidance. The presence of the Cer1 retrotransposon in wild C. elegans strains correlates with the ability to learn and inherit small-RNA-induced pathogen avoidance. Together, these results suggest that C. elegans has co-opted a potentially dangerous retrotransposon to instead protect itself and its progeny from a common pathogen through its inter-tissue signaling ability, hijacking this genomic element for its own adaptive immunity benefit.

The hippocampus is thought to encode a "cognitive map," a structural organization of knowledge about relationships in the world. Place cells, spatially selective hippocampal neurons that have been extensively studied in rodents, are one component of this map, describing the relative position of environmental features. However, whether this map extends to abstract, cognitive information remains unknown. Using the relative reward value of cues to define continuous "paths" through an abstract value space, we show that single neurons in primate hippocampus encode this space through value place fields, much like a rodent's place neurons encode paths through physical space. Value place fields remapped when cues changed but also became increasingly correlated across contexts, allowing maps to become generalized. Our findings help explain the critical contribution of the hippocampus to value-based decision-making, providing a mechanism by which knowledge of relationships in the world can be incorporated into reward predictions for guiding decisions.

Comment on Cell. 2021 Sep 16;184(19):4919-4938.e22.

Comment on Cell. 2021 Sep 16;184(19):4904-4918.e11.

Comment on Cell. 2021 Sep 16;184(19):4874-4885.e16.

Comment in Trends Mol Med. 2021 Nov;27(11):1019-1021. Signal Transduct Target Ther. 2021 Nov 11;6(1):393.

Comment in Cancer Cell. 2021 Oct 11;39(10):1308-1310.

Author information: (1)Department of Pathology, Johns Hopkins University, Baltimore, MD 21231, USA. (2)Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. (3)Department of Medicine, Washington University in St. Louis, St. Louis, MO 631110, USA; McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO 63108, USA. (4)Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA. (5)Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA. (6)The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21287, USA. (7)Department of Oncology, Johns Hopkins University, Baltimore, MD 21205, USA. (8)Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada. (9)Sema4, a Mount Sinai venture, Stamford, CT 06902, USA. (10)Institute for Systems Genetics, NYU Grossman School of Medicine, New York, NY 10016, USA; Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY 10016, USA. (11)Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada. (12)Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA. (13)Van Andel Research Institute, Grand Rapids, MI 49503, USA. (14)Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (15)Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA. (16)Office of Cancer Clinical Proteomics Research, National Cancer Institute, Bethesda, MD 20892, USA. (17)Departments of Surgery and Oncology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada. (18)Department of Pathology, Johns Hopkins University, Baltimore, MD 21231, USA; The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21287, USA. (19)Department of Pathology, Johns Hopkins University, Baltimore, MD 21231, USA; The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21287, USA; The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD 21231, USA. (20)Department of Medicine, Washington University in St. Louis, St. Louis, MO 631110, USA; McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO 63108, USA. Electronic address: lding@wustl.edu. (21)Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: bing.zhang@bcm.edu. (22)Department of Pathology, Johns Hopkins University, Baltimore, MD 21231, USA; The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21287, USA. Electronic address: huizhang@jhu.edu.

Update of medRxiv. 2021 Feb 08;:

Comment in Trends Biochem Sci. 2022 May;47(5):369-371.

Update of bioRxiv. 2021 Mar 10;:

Comment in Cell. 2021 Sep 16;184(19):4843-4844.

Genetic perturbations of cortical development can lead to neurodevelopmental disease, including autism spectrum disorder (ASD). To identify genomic regions crucial to corticogenesis, we mapped the activity of gene-regulatory elements generating a single-cell atlas of gene expression and chromatin accessibility both independently and jointly. This revealed waves of gene regulation by key transcription factors (TFs) across a nearly continuous differentiation trajectory, distinguished the expression programs of glial lineages, and identified lineage-determining TFs that exhibited strong correlation between linked gene-regulatory elements and expression levels. These highly connected genes adopted an active chromatin state in early differentiating cells, consistent with lineage commitment. Base-pair-resolution neural network models identified strong cell-type-specific enrichment of noncoding mutations predicted to be disruptive in a cohort of ASD individuals and identified frequently disrupted TF binding sites. This approach illustrates how cell-type-specific mapping can provide insights into the programs governing human development and disease.

CD8 T cell responses against different tumor neoantigens occur simultaneously, yet little is known about the interplay between responses and its impact on T cell function and tumor control. In mouse lung adenocarcinoma, we found that immunodominance is established in tumors, wherein CD8 T cell expansion is predominantly driven by the antigen that most stably binds MHC. T cells responding to subdominant antigens were enriched for a TCF1+ progenitor phenotype correlated with response to immune checkpoint blockade (ICB) therapy. However, the subdominant T cell response did not preferentially benefit from ICB due to a dysfunctional subset of TCF1+ cells marked by CCR6 and Tc17 differentiation. Analysis of human samples and sequencing datasets revealed that CCR6+ TCF1+ cells exist across human cancers and are not correlated with ICB response. Vaccination eliminated CCR6+ TCF1+ cells and dramatically improved the subdominant response, highlighting a strategy to optimally engage concurrent neoantigen responses against tumors.

The hidden world of amyloid biology has suddenly snapped into atomic-level focus, revealing over 80 amyloid protein fibrils, both pathogenic and functional. Unlike globular proteins, amyloid proteins flatten and stack into unbranched fibrils. Stranger still, a single protein sequence can adopt wildly different two-dimensional conformations, yielding distinct fibril polymorphs. Thus, an amyloid protein may define distinct diseases depending on its conformation. At the heart of this conformational variability lies structural frustrations. In functional amyloids, evolution tunes frustration levels to achieve either stability or sensitivity according to the fibril's biological function, accounting for the vast versatility of the amyloid fibril scaffold.

Comment in Cell. 2021 Sep 16;184(19):4845-4847. Mol Ther. 2021 Nov 3;29(11):3099-3100. Nat Methods. 2021 Nov;18(11):1275.

Update of bioRxiv. 2021 Mar 30;:

Since the first reports of a novel severe acute respiratory syndrome (SARS)-like coronavirus in December 2019 in Wuhan, China, there has been intense interest in understanding how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in the human population. Recent debate has coalesced around two competing ideas: a "laboratory escape" scenario and zoonotic emergence. Here, we critically review the current scientific evidence that may help clarify the origin of SARS-CoV-2.

Comment in Cell. 2021 Sep 16;184(19):4841-4842. Nature. 2021 Nov;599(7884):209-210.