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Oncogenes are commonly amplified on particles of extrachromosomal DNA (ecDNA) in cancer1,2, but our understanding of the structure of ecDNA and its effect on gene regulation is limited. Here, by integrating ultrastructural imaging, long-range optical mapping and computational analysis of whole-genome sequencing, we demonstrate the structure of circular ecDNA. Pan-cancer analyses reveal that oncogenes encoded on ecDNA are among the most highly expressed genes in the transcriptome of the tumours, linking increased copy number with high transcription levels. Quantitative assessment of the chromatin state reveals that although ecDNA is packaged into chromatin with intact domain structure, it lacks higher-order compaction that is typical of chromosomes and displays significantly enhanced chromatin accessibility. Furthermore, ecDNA is shown to have a significantly greater number of ultra-long-range interactions with active chromatin, which provides insight into how the structure of circular ecDNA affects oncogene function, and connects ecDNA biology with modern cancer genomics and epigenetics.

Transformative technologies are enabling the construction of threedimensional (3D) maps of tissues with unprecedented spatial and molecularresolution. Over the next seven years, the NIH Common Fund Human BiomolecularAtlas Program (HuBMAP) intends to develop a widely accessible framework forcomprehensively mapping the human body at single-cell resolution by supportingtechnology development, data acquisition, and detailed spatial mapping. HuBMAPwill integrate its efforts with other funding agencies, programs, consortia,and the biomedical research community at large towards the shared vision of acomprehensive, accessible 3D molecular and cellular atlas of the human body, inhealth and various disease settings.

How the genomic features of a patient's cancer relate to individual disease kinetics remains poorly understood. Here we used the indolent growth dynamics of chronic lymphocytic leukaemia (CLL) to analyse the growth rates and corresponding genomic patterns of leukaemia cells from 107 patients with CLL, spanning decades-long disease courses. We found that CLL commonly demonstrates not only exponential expansion but also logistic growth, which is sigmoidal and reaches a certain steady-state level. Each growth pattern was associated with marked differences in genetic composition, the pace of disease progression and the extent of clonal evolution. In a subset of patients, whose serial samples underwent next-generation sequencing, we found that dynamic changes in the disease course of CLL were shaped by the genetic events that were already present in the early slow-growing stages. Finally, by analysing the growth rates of subclones compared with their parental clones, we quantified the growth advantage conferred by putative CLL drivers in vivo.

Most adult carcinomas develop from noninvasive precursor lesions, a progression that is supported by genetic analysis. However, the evolutionary and genetic relationships among co-existing lesions are unclear. Here we analysed the somatic variants of pancreatic cancers and precursor lesions sampled from distinct regions of the same pancreas. After inferring evolutionary relationships, we found that the ancestral cell had initiated and clonally expanded to form one or more lesions, and that subsequent driver gene mutations eventually led to invasive pancreatic cancer. We estimate that this multi-step progression generally spans many years. These new data reframe the step-wise progression model of pancreatic cancer by illustrating that independent, high-grade pancreatic precursor lesions observed in a single pancreas often represent a single neoplasm that has colonized the ductal system, accumulating spatial and genetic divergence over time.

To build a universal quantum computer from fragile physical qubits, effective implementation of quantum error correction (QEC).sup.1 is an essential requirement and a central challenge. Existing demonstrations of QEC are based on an active schedule of error-syndrome measurements and adaptive recovery operations.sup.2,3,4,5,6,7 that are hardware intensive and prone to introducing and propagating errors. In principle, QEC can be realized autonomously and continuously by tailoring dissipation within the quantum system.sup.1,8,9,10,11,12,13,14, but so far it has remained challenging to achieve the specific form of dissipation required to counter the most prominent errors in a physical platform. Here we encode a logical qubit in Schrödinger cat-like multiphoton states.sup.15 of a superconducting cavity, and demonstrate a corrective dissipation process that stabilizes an error-syndrome operator: the photon number parity. Implemented with continuous-wave control fields only, this passive protocol protects the quantum information by autonomously correcting single-photon-loss errors and boosts the coherence time of the bosonic qubit by over a factor of two. Notably, QEC is realized in a modest hardware setup with neither high-fidelity readout nor fast digital feedback, in contrast to the technological sophistication required for prior QEC demonstrations. Compatible with additional phase-stabilization and fault-tolerant techniques.sup.16,17,18, our experiment suggests quantum dissipation engineering as a resource-efficient alternative or supplement to active QEC in future quantum computing architectures. A logical qubit encoded in multi-photon states of a superconducting cavity is protected with autonomous correction of certain quantum errors by tailoring the dissipation it is exposed to., Author(s): Jeffrey M. Gertler [sup.1] , Brian Baker [sup.2] , Juliang Li [sup.1] , Shruti Shirol [sup.1] , Jens Koch [sup.2] , Chen Wang [sup.1] Author Affiliations: (1) Department of [...]

From Fortran to arXiv.org, these advances in programming and platforms sent biology, climate science and physics into warp speed. From Fortran to arXiv.org, these advances in programming and platforms sent biology, climate science and physics into warp speed., Author(s): Jeffrey M. Perkel Author Affiliations: Ten computer codes that transformed science Illustration by Pawel Jonca cartoon of a researcher sitting in front of a giant computer screen showing lines [...]

Sleep disconnects animals from the external world, at considerable risks and costs that must be offset by a vital benefit. Insight into this mysterious benefit will come from understanding sleep homeostasis: to monitor sleep need, an internal bookkeeper must track physiological changes that are linked to the core function of sleep. In Drosophila, a crucial component of the machinery for sleep homeostasis is a cluster of neurons innervating the dorsal fan-shaped body (dFB) of the central complex. Artificial activation of these cells induces sleep, whereas reductions in excitability cause insomnia. dFB neurons in sleep-deprived flies tend to be electrically active, with high input resistances and long membrane time constants, while neurons in rested flies tend to be electrically silent. Correlative evidence thus supports the simple view that homeostatic sleep control works by switching sleep-promoting neurons between active and quiescent states. Here we demonstrate state switching by dFB neurons, identify dopamine as a neuromodulator that operates the switch, and delineate the switching mechanism. Arousing dopamine caused transient hyperpolarization of dFB neurons within tens of milliseconds and lasting excitability suppression within minutes. Both effects were transduced by Dop1R2 receptors and mediated by potassium conductances. The switch to electrical silence involved the downregulation of voltage-gated A-type currents carried by Shaker and Shab, and the upregulation of voltage-independent leak currents through a two-pore-domain potassium channel that we term Sandman. Sandman is encoded by the CG8713 gene and translocates to the plasma membrane in response to dopamine. dFB-restricted interference with the expression of Shaker or Sandman decreased or increased sleep, respectively, by slowing the repetitive discharge of dFB neurons in the ON state or blocking their entry into the OFF state. Biophysical changes in a small population of neurons are thus linked to the control of sleep-wake state.

Data transport across short electrical wires is limited by both bandwidth and power density, which creates a performance bottleneck for semiconductor microchips in modern computer systems--from mobile phones to large-scale data centres. These limitations can be overcome by using optical communications based on chip-scale electronic-photonic systems enabled by silicon-based nanophotonic devices. However, combining electronics and photonics on the same chip has proved challenging, owing to microchip manufacturing conflicts between electronics and photonics. Consequently, current electronic-photonic chips are limited to niche manufacturing processes and include only a few optical devices alongside simple circuits. Here we report an electronic-photonic system on a single chip integrating over 70 million transistors and 850 photonic components that work together to provide logic, memory, and interconnect functions. This system is a realization of a microprocessor that uses on-chip photonic devices to directly communicate with other chips using light. To integrate electronics and photonics at the scale of a microprocessor chip, we adopt a 'zero-change' approach to the integration of photonics. Instead of developing a custom process to enable the fabrication of photonics, which would complicate or eliminate the possibility of integration with state-of-the-art transistors at large scale and at high yield, we design optical devices using a standard microelectronics foundry process that is used for modern microprocessors. This demonstration could represent the beginning of an era of chip-scale electronic-photonic systems with the potential to transform computing system architectures, enabling more powerful computers, from network infrastructure to data centres and supercomputers.

Structural variants are implicated in numerous diseases and make up the majority of varying nucleotides among human genomes. Here we describe an integrated set of eight structural variant classes comprising both balanced and unbalanced variants, which we constructed using short-read DNA sequencing data and statistically phased onto haplotype blocks in 26 human populations. Analysing this set, we identify numerous gene-intersecting structural variants exhibiting population stratification and describe naturally occurring homozygous gene knockouts that suggest the dispensability of a variety of human genes. We demonstrate that structural variants are enriched on haplotypes identified by genome-wide association studies and exhibit enrichment for expression quantitative trait loci. Additionally, we uncover appreciable levels of structural variant complexity at different scales, including genic loci subject to clusters of repeated rearrangement and complex structural variants with multiple breakpoints likely to have formed through individual mutational events. Our catalogue will enhance future studies into structural variant demography, functional impact and disease association.

Deducing the full protein complement of individual cells has long played second fiddle to transcriptomics. That's about to change. Deducing the full protein complement of individual cells has long played second fiddle to transcriptomics. That's about to change., Author(s): Jeffrey M. Perkel Author Affiliations: Chemist Ying Zhu places a nanoPOTS chip containing protein samples into an automated analysis system. Credit: Andrea Starr/PNNL Ying Zhu places a chip containing [...]

A rapidly growing collection of software tools is helping researchers to analyse multiple huge '-omics' data sets. A rapidly growing collection of software tools is helping researchers to analyse multiple huge '-omics' data sets., Author(s): Jeffrey M. Perkel Author Affiliations: Single-cell analysis enters the multiomics age Single-cell data (top) increasingly are being combined with spatial information (bottom). Credit: 10x Genomics Two sheets of visual [...]

Most great ape genetic variation remains uncharacterized; however, its study is critical for understanding population history, recombination, selection and susceptibility to disease. Here we sequence to high coverage a total of 79 wild- and captive-born individuals representing all six great ape species and seven subspecies and report 88.8 million single nucleotide polymorphisms. Our analysis provides support for genetically distinct populations within each species, signals of gene flow, and the split of common chimpanzees into two distinct groups: Nigeria-Cameroon/western and central/eastern populations. We find extensive inbreeding in almost all wild populations, with eastern gorillas being the most extreme. Inferred effective population sizes have varied radically over time in different lineages and this appears to have a profound effect on the genetic diversity at, or close to, genes in almost all species. We discover and assign 1,982 loss-of-function variants throughout the human and great ape lineages, determining that the rate of gene loss has not been different in the human branch compared to other internal branches in the great ape phylogeny. This comprehensive catalogue of great ape genome diversity provides a framework for understanding evolution and a resource for more effective management of wild and captive great ape populations.

Genomic structural variants (SVs) are abundant in humans, differing from other forms of variation in extent, origin and functional impact. Despite progress in SV characterization, the nucleotide resolution architecture of most SVs remains unknown. We constructed a map of unbalanced SVs (that is, copy number variants) based on whole genome DNA sequencing data from 185 human genomes, integrating evidence from complementary SV discovery approaches with extensive experimental validations. Our map encompassed 22,025 deletions and 6,000 additional SVs, including insertions and tandem duplications. Most SVs (53%) were mapped to nucleotide resolution, which facilitated analysing their origin and functional impact. We examined numerous whole and partial gene deletions with a genotyping approach and observed a depletion of gene disruptions amongst high frequency deletions. Furthermore, we observed differences in the size spectra of SVs originating from distinct formation mechanisms, and constructed a map of SV hotspots formed by common mechanisms. Our analytical framework and SV map serves as a resource for sequencing-based association studies.

Missing documentation and obsolete environments force participants in the Ten Years Reproducibility Challenge to get creative. Missing documentation and obsolete environments force participants in the Ten Years Reproducibility Challenge to get creative., Author(s): Jeffrey M. Perkel Author Affiliations: Illustration by The Project Twins Cartoon based on the style of an Apple II interface, showing archaeology type strata layers with buried computer icons. [...]

Microscopy has been a trade-off until now: the bigger the sample, the lower the resolution. But picking out cellular detail in mouse brains and more is becoming increasingly possible. Microscopy has been a trade-off until now: the bigger the sample, the lower the resolution. But picking out cellular detail in mouse brains and more is becoming increasingly possible., Author(s): Jeffrey M. Perkel Author Affiliations: The microscope makers putting ever-larger biological samples under the spotlight Long-term functional imaging of an entire Drosophila embryo, captured using light-sheet microscopy. Credit: Raghav [...]

A new breed of protein engineers is finding that the best way to create a molecule is to build it from scratch. A new breed of protein engineers is finding that the best way to create a molecule is to build it from scratch., Author(s): Jeffrey M. Perkel Author Affiliations: The computational protein designers By designing a protein from the ground up, researchers can create molecules with forms and functions not found in nature. [...]

A simple software toolset can help to ease the pain of reproducing computational analyses.A simple software toolset can help to ease the pain of reproducing computational analyses., Author(s): Jeffrey M. PerkelAuthor Affiliations:A toolkit for data transparency takes shape Credit: Mehau Kulyk/SPL/Getty [see PDF for image]Julia Stewart Lowndes studied metre-long Humboldt squid (Dosidicus gigas ), tagging them to [...]

Outdated genome-sequencing machines need not die -- researchers can repurpose them to drive next-generation biochemistry studies.Outdated DNA-sequencing machines need not die -- researchers can repurpose them to drive next-generation biochemistry studies., Author(s): Jeffrey M. PerkelAuthor Affiliations:The hackers teaching old DNA sequencers new tricks This next-generation biochemistry platform, dubbed 'Serenity', was assembled from the components of an old Illumina DNA sequencer. [see [...]

Author(s): Erica N. Borducchi [1]; Crystal Cabral [1]; Kathryn E. Stephenson [1]; Jinyan Liu [1]; Peter Abbink [1]; David Nganga [1]; Joseph P. Nkolola [1]; Amanda L. Brinkman [1]; Lauren [...]

Activation of glucose-sensing neurons in the ventromedial hypothalamic nucleus using radio waves or magnetic fields remotely and non-invasively in vivo increases plasma glucose and glucagon, and suppresses plasma insulin; conversely, remote inhibition of glucose-sensing neurons decreased blood glucose and increased plasma insulin. Remote control of animal behaviour This study describes a new technology that allows neurons to be activated or inhibited remotely in freely moving animals using radio waves or magnetic fields. Jeffrey Friedman and colleagues used an iron-binding protein tethered to a heat-sensitive protein to excite or inhibit neurons in the ventromedial hypothalamic nucleus in mice. Activation of glucose-sensing neurons increased plasma glucose and glucagon, suppressed plasma insulin and increased feeding. Inhibition decreased blood glucose, increased plasma insulin and suppressed the response to hypoglycaemia. As well as enabling remote control of cellular activity in basic research, this approach has potential therapeutic implications as a minimally invasive alternative to deep brain stimulation. Targeted, temporally regulated neural modulation is invaluable in determining the physiological roles of specific neural populations or circuits. Here we describe a system for non-invasive, temporal activation or inhibition of neuronal activity in vivo and its use to study central nervous system control of glucose homeostasis and feeding in mice. We are able to induce neuronal activation remotely using radio waves or magnetic fields via Cre-dependent expression of a GFP-tagged ferritin fusion protein tethered to the cation-conducting transient receptor potential vanilloid 1 (TRPV1) by a camelid anti-GFP antibody (anti-GFP-TRPV1).sup.1. Neuronal inhibition via the same stimuli is achieved by mutating the TRPV1 pore, rendering the channel chloride-permeable. These constructs were targeted to glucose-sensing neurons in the ventromedial hypothalamus in glucokinase-Cre mice, which express Cre in glucose-sensing neurons.sup.2. Acute activation of glucose-sensing neurons in this region increases plasma glucose and glucagon, lowers insulin levels and stimulates feeding, while inhibition reduces blood glucose, raises insulin levels and suppresses feeding. These results suggest that pancreatic hormones function as an effector mechanism of central nervous system circuits controlling blood glucose and behaviour. The method we employ obviates the need for permanent implants and could potentially be applied to study other neural processes or used to regulate other, even dispersed, cell types., Author(s): Sarah A. Stanley [sup.1] , Leah Kelly [sup.1] , Kaamashri N. Latcha [sup.1] , Sarah F. Schmidt [sup.1] , Xiaofei Yu [sup.1] , Alexander R. Nectow [sup.1] , Jeremy [...]

Combining the data-analysis tool Starfish with technologies to pinpoint RNA's cellular locations can add spatial detail to in situ transcriptomics. Combining the data-analysis tool Starfish with technologies to pinpoint RNA's cellular locations can add spatial detail to in situ transcriptomics., Author(s): Jeffrey M. Perkel Author Affiliations: Starfish enterprise: finding RNA patterns in single cells Each point is an individual RNA molecule, localized by its proximity to other RNAs. This imaging [...]