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As SARS-CoV-2 continues to spread and evolve, detecting emerging variants early is critical for public health interventions. Inferring lineage prevalence by clinical testing is infeasible at scale, especially in areas with limited resources, participation, or testing and/or sequencing capacity, which can also introduce biases1-3. SARS-CoV-2 RNA concentration in wastewater successfully tracks regional infection dynamics and provides less biased abundance estimates than clinical testing4,5. Tracking virus genomic sequences in wastewater would improve community prevalence estimates and detect emerging variants. However, two factors limit wastewater-based genomic surveillance: low-quality sequence data and inability to estimate relative lineage abundance in mixed samples. Here we resolve these critical issues to perform a high-resolution, 295-day wastewater and clinical sequencing effort, in the controlled environment of a large university campus and the broader context of the surrounding county. We developed and deployed improved virus concentration protocols and deconvolution software that fully resolve multiple virus strains from wastewater. We detected emerging variants of concern up to 14 days earlier in wastewater samples, and identified multiple instances of virus spread not captured by clinical genomic surveillance. Our study provides a scalable solution for wastewater genomic surveillance that allows early detection of SARS-CoV-2 variants and identification of cryptic transmission.

Quantum many-body systems display rich phase structure in their low-temperature equilibrium states1. However, much of nature is not in thermal equilibrium. Remarkably, it was recently predicted that out-of-equilibrium systems can exhibit novel dynamical phases2-8 that may otherwise be forbidden by equilibrium thermodynamics, a paradigmatic example being the discrete time crystal (DTC)7,9-15. Concretely, dynamical phases can be defined in periodically driven many-body-localized (MBL) systems via the concept of eigenstate order7,16,17. In eigenstate-ordered MBL phases, the entire many-body spectrum exhibits quantum correlations and long-range order, with characteristic signatures in late-time dynamics from all initial states. It is, however, challenging to experimentally distinguish such stable phases from transient phenomena, or from regimes in which the dynamics of a few select states can mask typical behaviour. Here we implement tunable controlled-phase (CPHASE) gates on an array of superconducting qubits to experimentally observe an MBL-DTC and demonstrate its characteristic spatiotemporal response for generic initial states7,9,10. Our work employs a time-reversal protocol to quantify the impact of external decoherence, and leverages quantum typicality to circumvent the exponential cost of densely sampling the eigenspectrum. Furthermore, we locate the phase transition out of the DTC with an experimental finite-size analysis. These results establish a scalable approach to studying non-equilibrium phases of matter on quantum processors.

Loss of skeletal integrity during ageing and disease is associated with an imbalance in the opposing actions of osteoblasts and osteoclasts1. Here we show that intrinsic ageing of skeletal stem cells (SSCs)2 in mice alters signalling in the bone marrow niche and skews the differentiation of bone and blood lineages, leading to fragile bones that regenerate poorly. Functionally, aged SSCs have a decreased bone- and cartilage-forming potential but produce more stromal lineages that express high levels of pro-inflammatory and pro-resorptive cytokines. Single-cell RNA-sequencing studies link the functional loss to a diminished transcriptomic diversity of SSCs in aged mice, which thereby contributes to the transformation of the bone marrow niche. Exposure to a youthful circulation through heterochronic parabiosis or systemic reconstitution with young haematopoietic stem cells did not reverse the diminished osteochondrogenic activity of aged SSCs, or improve bone mass or skeletal healing parameters in aged mice. Conversely, the aged SSC lineage promoted osteoclastic activity and myeloid skewing by haematopoietic stem and progenitor cells, suggesting that the ageing of SSCs is a driver of haematopoietic ageing. Deficient bone regeneration in aged mice could only be returned to youthful levels by applying a combinatorial treatment of BMP2 and a CSF1 antagonist locally to fractures, which reactivated aged SSCs and simultaneously ablated the inflammatory, pro-osteoclastic milieu. Our findings provide mechanistic insights into the complex, multifactorial mechanisms that underlie skeletal ageing and offer prospects for rejuvenating the aged skeletal system.

Realizing the potential of quantum computing requires sufficiently low logical error rates1. Many applications call for error rates as low as 10-15 (refs. 2-9), but state-of-the-art quantum platforms typically have physical error rates near 10-3 (refs. 10-14). Quantum error correction15-17 promises to bridge this divide by distributing quantum logical information across many physical qubits in such a way that errors can be detected and corrected. Errors on the encoded logical qubit state can be exponentially suppressed as the number of physical qubits grows, provided that the physical error rates are below a certain threshold and stable over the course of a computation. Here we implement one-dimensional repetition codes embedded in a two-dimensional grid of superconducting qubits that demonstrate exponential suppression of bit-flip or phase-flip errors, reducing logical error per round more than 100-fold when increasing the number of qubits from 5 to 21. Crucially, this error suppression is stable over 50 rounds of error correction. We also introduce a method for analysing error correlations with high precision, allowing us to characterize error locality while performing quantum error correction. Finally, we perform error detection with a small logical qubit using the 2D surface code on the same device18,19 and show that the results from both one- and two-dimensional codes agree with numerical simulations that use a simple depolarizing error model. These experimental demonstrations provide a foundation for building a scalable fault-tolerant quantum computer with superconducting qubits.

The Zoonomia Project is investigating the genomics of shared and specialized traits in eutherian mammals. Here we provide genome assemblies for 131 species, of which all but 9 are previously uncharacterized, and describe a whole-genome alignment of 240 species of considerable phylogenetic diversity, comprising representatives from more than 80% of mammalian families. We find that regions of reduced genetic diversity are more abundant in species at a high risk of extinction, discern signals of evolutionary selection at high resolution and provide insights from individual reference genomes. By prioritizing phylogenetic diversity and making data available quickly and without restriction, the Zoonomia Project aims to support biological discovery, medical research and the conservation of biodiversity.

Female Aedes aegypti mosquitoes infect more than 400 million people each year with dangerous viral pathogens including dengue, yellow fever, Zika and chikungunya. Progress in understanding the biology of mosquitoes and developing the tools to fight them has been slowed by the lack of a high-quality genome assembly. Here we combine diverse technologies to produce the markedly improved, fully re-annotated AaegL5 genome assembly, and demonstrate how it accelerates mosquito science. We anchored physical and cytogenetic maps, doubled the number of known chemosensory ionotropic receptors that guide mosquitoes to human hosts and egg-laying sites, provided further insight into the size and composition of the sex-determining M locus, and revealed copy-number variation among glutathione S-transferase genes that are important for insecticide resistance. Using high-resolution quantitative trait locus and population genomic analyses, we mapped new candidates for dengue vector competence and insecticide resistance. AaegL5 will catalyse new biological insights and intervention strategies to fight this deadly disease vector.

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.

During both embryonic development and adult tissue regeneration, changes in chromatin structure driven by master transcription factors lead to stimulus-responsive transcriptional programs. A thorough understanding of how stem cells in the skeleton interpret mechanical stimuli and enact regeneration would shed light on how forces are transduced to the nucleus in regenerative processes. Here we develop a genetically dissectible mouse model of mandibular distraction osteogenesis-which is a process that is used in humans to correct an undersized lower jaw that involves surgically separating the jaw bone, which elicits new bone growth in the gap. We use this model to show that regions of newly formed bone are clonally derived from stem cells that reside in the skeleton. Using chromatin and transcriptional profiling, we show that these stem-cell populations gain activity within the focal adhesion kinase (FAK) signalling pathway, and that inhibiting FAK abolishes new bone formation. Mechanotransduction via FAK in skeletal stem cells during distraction activates a gene-regulatory program and retrotransposons that are normally active in primitive neural crest cells, from which skeletal stem cells arise during development. This reversion to a developmental state underlies the robust tissue growth that facilitates stem-cell-based regeneration of adult skeletal tissue.

Chromosomal instability is a hallmark of cancer that results from ongoing errors in chromosome segregation during mitosis. Although chromosomal instability is a major driver of tumour evolution, its role in metastasis has not been established. Here we show that chromosomal instability promotes metastasis by sustaining a tumour cell-autonomous response to cytosolic DNA. Errors in chromosome segregation create a preponderance of micronuclei whose rupture spills genomic DNA into the cytosol. This leads to the activation of the cGAS-STING (cyclic GMP-AMP synthase-stimulator of interferon genes) cytosolic DNA-sensing pathway and downstream noncanonical NF-κB signalling. Genetic suppression of chromosomal instability markedly delays metastasis even in highly aneuploid tumour models, whereas continuous chromosome segregation errors promote cellular invasion and metastasis in a STING-dependent manner. By subverting lethal epithelial responses to cytosolic DNA, chromosomally unstable tumour cells co-opt chronic activation of innate immune pathways to spread to distant organs.

According to the current understanding of cosmic structure formation, the precursors of the most massive structures in the Universe began to form shortly after the Big Bang, in regions corresponding to the largest fluctuations in the cosmic density field. Observing these structures during their period of active growth and assembly-the first few hundred million years of the Universe-is challenging because it requires surveys that are sensitive enough to detect the distant galaxies that act as signposts for these structures and wide enough to capture the rarest objects. As a result, very few such objects have been detected so far. Here we report observations of a far-infrared-luminous object at redshift 6.900 (less than 800 million years after the Big Bang) that was discovered in a wide-field survey. High-resolution imaging shows it to be a pair of extremely massive star-forming galaxies. The larger is forming stars at a rate of 2,900 solar masses per year, contains 270 billion solar masses of gas and 2.5 billion solar masses of dust, and is more massive than any other known object at a redshift of more than 6. Its rapid star formation is probably triggered by its companion galaxy at a projected separation of 8 kiloparsecs. This merging companion hosts 35 billion solar masses of stars and has a star-formation rate of 540 solar masses per year, but has an order of magnitude less gas and dust than its neighbour and physical conditions akin to those observed in lower-metallicity galaxies in the nearby Universe. These objects suggest the presence of a dark-matter halo with a mass of more than 100 billion solar masses, making it among the rarest dark-matter haloes that should exist in the Universe at this epoch.

Author(s): Boriana Kalderon-Asael [sup.1] , Joachim A. R. Katchinoff [sup.1] , Noah J. Planavsky [sup.1] , Ashleigh v. S. Hood [sup.2] , Mathieu Dellinger [sup.3] , Eric J. Bellefroid [sup.1] [...], The evolution of the global carbon and silicon cycles is thought to have contributed to the long-term stability of Earth's climate.sup.1-3. Many questions remain, however, regarding the feedback mechanisms at play, and there are limited quantitative constraints on the sources and sinks of these elements in Earth's surface environments.sup.4-12. Here we argue that the lithium-isotope record can be used to track the processes controlling the long-term carbon and silicon cycles. By analysing more than 600 shallow-water marine carbonate samples from more than 100 stratigraphic units, we construct a new carbonate-based lithium-isotope record spanning the past 3 billion years. The data suggest an increase in the carbonate lithium-isotope values over time, which we propose was driven by long-term changes in the lithium-isotopic conditions of sea water, rather than by changes in the sedimentary alterations of older samples. Using a mass-balance modelling approach, we propose that the observed trend in lithium-isotope values reflects a transition from Precambrian carbon and silicon cycles to those characteristic of the modern. We speculate that this transition was linked to a gradual shift to a biologically controlled marine silicon cycle and the evolutionary radiation of land plants.sup.13,14. Analysis of shallow-water marine carbonate samples from 101 stratigraphic units allows construction of a record of lithium isotopes from the past 3 billion years, tracking the evolution of the global carbon and silicon cycles.

Author(s): Gemma Conroy, Flynn Murphy, Sian Powell Author Affiliations: Five science stars making their mark in China China's push to strengthen its standing in science opens opportunities for exploration. These [...], With research spanning particle physics, solar power, conservation and the mechanisms of coronavirus transmission, these researchers are standouts in China's vast talent hub. With research spanning particle physics, solar power, conservation and the mechanisms of coronavirus transmission, these researchers are standouts in China's vast talent hub.

Author(s): Bo Shen [sup.1] , Alpaslan Tasdogan [sup.1] , Jessalyn M. Ubellacker [sup.1] , Jingzhu Zhang [sup.1] , Elena D. Nosyreva [sup.2] , Liming Du [sup.1] , Malea M. Murphy [...], Stromal cells in adult bone marrow that express leptin receptor (LEPR) are a critical source of growth factors, including stem cell factor (SCF), for the maintenance of haematopoietic stem cells and early restricted progenitors.sup.1-6. LEPR.sup.+ cells are heterogeneous, including skeletal stem cells and osteogenic and adipogenic progenitors.sup.7-12, although few markers have been available to distinguish these subsets or to compare their functions. Here we show that expression of an osteogenic growth factor, osteolectin.sup.13,14, distinguishes peri-arteriolar LEPR.sup.+ cells poised to undergo osteogenesis from peri-sinusoidal LEPR.sup.+ cells poised to undergo adipogenesis (but retaining osteogenic potential). Peri-arteriolar LEPR.sup.+osteolectin.sup.+ cells are rapidly dividing, short-lived osteogenic progenitors that increase in number after fracture and are depleted during ageing. Deletion of Scf from adult osteolectin.sup.+ cells did not affect the maintenance of haematopoietic stem cells or most restricted progenitors but depleted common lymphoid progenitors, impairing lymphopoiesis, bacterial clearance, and survival after acute bacterial infection. Peri-arteriolar osteolectin.sup.+ cell maintenance required mechanical stimulation. Voluntary running increased, whereas hindlimb unloading decreased, the frequencies of peri-arteriolar osteolectin.sup.+ cells and common lymphoid progenitors. Deletion of the mechanosensitive ion channel PIEZO1 from osteolectin.sup.+ cells depleted osteolectin.sup.+ cells and common lymphoid progenitors. These results show that a peri-arteriolar niche for osteogenesis and lymphopoiesis in bone marrow is maintained by mechanical stimulation and depleted during ageing. A peri-arteriolar niche in the bone marrow for osteogenesis and lymphopoiesis is maintained by mechanical stimulation and is depleted during ageing.

Author(s): Rachel Kaletsky [sup.1] [sup.2] , Rebecca S. Moore [sup.1] , Geoffrey D. Vrla [sup.1] , Lance R. Parsons [sup.2] , Zemer Gitai [sup.1] , Coleen T. Murphy [sup.1] [sup.2] [...], Caenorhabditis elegans must distinguish pathogens from nutritious food sources among the many bacteria to which it is exposed in its environment.sup.1. Here we show that a single exposure to purified small RNAs isolated from pathogenic Pseudomonas aeruginosa (PA14) is sufficient to induce pathogen avoidance in the treated worms and in four subsequent generations of progeny. The RNA interference (RNAi) and PIWI-interacting RNA (piRNA) pathways, the germline and the ASI neuron are all required for avoidance behaviour induced by bacterial small RNAs, and for the transgenerational inheritance of this behaviour. A single P. aeruginosa non-coding RNA, P11, is both necessary and sufficient to convey learned avoidance of PA14, and its C. elegans target, maco-1, is required for avoidance. Our results suggest that this non-coding-RNA-dependent mechanism evolved to survey the microbial environment of the worm, use this information to make appropriate behavioural decisions and pass this information on to its progeny. Exposing Caenorhabditis elegans to non-coding small RNAs from pathogenic Pseudomonas aeruginosa induces avoidance behaviours in treated worms and their progeny, which reveals how C. elegans discriminates between bacterial species in its microbial environment.

Author(s): Lara M. Cassidy [sup.1] , Ros Ó Maoldúin [sup.1] [sup.2] [sup.3] , Thomas Kador [sup.4] , Ann Lynch [sup.5] , Carleton Jones [sup.6] , Peter C. Woodman [sup.7] , [...], The nature and distribution of political power in Europe during the Neolithic era remains poorly understood.sup.1. During this period, many societies began to invest heavily in building monuments, which suggests an increase in social organization. The scale and sophistication of megalithic architecture along the Atlantic seaboard, culminating in the great passage tomb complexes, is particularly impressive.sup.2. Although co-operative ideology has often been emphasised as a driver of megalith construction.sup.1, the human expenditure required to erect the largest monuments has led some researchers to emphasize hierarchy.sup.3--of which the most extreme case is a small elite marshalling the labour of the masses. Here we present evidence that a social stratum of this type was established during the Neolithic period in Ireland. We sampled 44 whole genomes, among which we identify the adult son of a first-degree incestuous union from remains that were discovered within the most elaborate recess of the Newgrange passage tomb. Socially sanctioned matings of this nature are very rare, and are documented almost exclusively among politico-religious elites.sup.4--specifically within polygynous and patrilineal royal families that are headed by god-kings.sup.5,6. We identify relatives of this individual within two other major complexes of passage tombs 150 km to the west of Newgrange, as well as dietary differences and fine-scale haplotypic structure (which is unprecedented in resolution for a prehistoric population) between passage tomb samples and the larger dataset, which together imply hierarchy. This elite emerged against a backdrop of rapid maritime colonization that displaced a unique Mesolithic isolate population, although we also detected rare Irish hunter-gatherer introgression within the Neolithic population. Skeletal remains from the Neolithic passage tomb at Newgrange (Ireland) represent the adult son of a first-degree incestuous union, suggesting that a politico-religious elite may have controlled the construction of Irish sites of this type.

Author(s): Timothy R. Bedding [sup.1] [sup.2] , Simon J. Murphy [sup.1] [sup.2] , Daniel R. Hey [sup.1] [sup.2] , Daniel Huber [sup.3] , Tanda Li [sup.1] [sup.2] [sup.4] , Barry [...], Asteroseismology probes the internal structures of stars by using their natural pulsation frequencies.sup.1. It relies on identifying sequences of pulsation modes that can be compared with theoretical models, which has been done successfully for many classes of pulsators, including low-mass solar-type stars.sup.2, red giants.sup.3, high-mass stars.sup.4 and white dwarfs.sup.5. However, a large group of pulsating stars of intermediate mass--the so-called [delta] Scuti stars--have rich pulsation spectra for which systematic mode identification has not hitherto been possible.sup.6,7. This arises because only a seemingly random subset of possible modes are excited and because rapid rotation tends to spoil regular patterns.sup.8-10. Here we report the detection of remarkably regular sequences of high-frequency pulsation modes in 60 intermediate-mass main-sequence stars, which enables definitive mode identification. The space motions of some of these stars indicate that they are members of known associations of young stars, as confirmed by modelling of their pulsation spectra. The pulsation spectra of intermediate-mass stars (so-called [delta] Scuti stars) have been challenging to analyse, but new observations of 60 such stars reveal remarkably regular sequences of high-frequency pulsation modes.

Ageing and lifespan of organisms are determined by complicated interactions between their genetics and the environment, but the cellular mechanisms remain controversial. There have been a number of studies suggesting that cellular energy metabolism and free radical dynamics affect lifespan, implicating mitochondrial function. Recently, Shen et al. provided apparent mechanistic insight by reporting that mitochondrial oscillations of ‘free radical production’, called ‘mitoflashes’, in the pharynx of 3-day old Caenorhabditis elegans correlated inversely with lifespan. The interpretation of ‘mitoflashes’ as ‘bursts of superoxide’ radicals assumes that circularly permuted yellow fluorescent protein (cpYFP) is a reliable indicator of mitochondrial superoxide. This interpretation has been criticised because experiments and theoretical considerations both show that changes in cpYFP fluorescence are due to alterations in pH, not superoxide-. We now provide direct evidence that purified cpYFP is completely unresponsive to superoxide. Therefore ‘mitoflashes’ do not reflect superoxide generation and are not evidence for a link between mitochondrial free radical dynamics and lifespan.

Transmission spectroscopy has been a workhorse technique used over the past two decades to constrain the physical and chemical properties of exoplanet atmospheres1–5. One of its classical key assumptions is that the portion of the atmosphere it probes—the terminator region—is homogeneous. Several works from the past decade, however, have put this into question for highly irradiated, hot (Teq ≳ 1,000 K) gas giant exoplanets, both empirically6–10 and through three-dimensional modelling11–17. While models have predicted clear differences between the evening (day-to-night) and morning (night-to-day) terminators, direct morning and evening transmission spectra in a wide wavelength range have not been reported for an exoplanet so far. Under the assumption of precise and accurate orbital parameters for the exoplanet WASP-39 b, here we report the detection of inhomogeneous terminators on WASP-39 b, which has allowed us to retrieve its morning and evening transmission spectra in the near-infrared (2–5 μm) using the James Webb Space Telescope. We have observed larger transit depths in the evening, which are, on average, 405 ± 88 ppm larger than the morning ones, and also have qualitatively larger features than the morning spectrum. The spectra are best explained by models in which the evening terminator is hotter than the morning terminator by 17 7 − 57 + 65 K, with both terminators having C/O ratios consistent with solar. General circulation models predict temperature differences broadly consistent with the above value and point towards a cloudy morning terminator and a clearer evening terminator.The atmospheric terminator region of WASP-39 b, a hot gas giant exoplanet, is inhomogeneous, despite past assumptions, with the evening terminator being hotter and thus probably clearer, and the morning terminator probably being cloudy and consequently cooler. [ABSTRACT FROM AUTHOR]

Migration and homing of immune cells are critical for immune surveillance. Trafficking is mediated by combinations of adhesion and chemokine receptors that guide immune cells, in response to chemokine signals, to specific locations within tissues and the lymphatic system to support tissue-localized immune reactions and systemic immunity1,2. Here we show that disruption of leukaemia inhibitory factor (LIF) production from group 2 innate lymphoid cells (ILC2s) prevents immune cells leaving the lungs to migrate to the lymph nodes (LNs). In the absence of LIF, viral infection leads to plasmacytoid dendritic cells (pDCs) becoming retained in the lungs where they improve tissue-localized, antiviral immunity, whereas chronic pulmonary allergen challenge leads to marked immune cell accumulation and the formation of tertiary lymphoid structures in the lung. In both cases immune cells fail to migrate to the lymphatics, leading to highly compromised LN reactions. Mechanistically, ILC2-derived LIF induces the production of the chemokine CCL21 from lymphatic endothelial cells lining the pulmonary lymphatic vessels, thus licensing the homing of CCR7+ immune cells (including dendritic cells) to LNs. Consequently, ILC2-derived LIF dictates the egress of immune cells from the lungs to regulate tissue-localized versus systemic immunity and the balance between allergen and viral responsiveness in the lungs.Disruption of leukaemia inhibitory factor production from group 2 innate lymphoid cells prevents immune cells leaving the lungs to migrate to lymph nodes, leading to plasmacytoid dendritic cells becoming retained in the lungs following viral infection. [ABSTRACT FROM AUTHOR]

Interactions between exoplanetary atmospheres and internal properties have long been proposed to be drivers of the inflation mechanisms of gaseous planets and apparent atmospheric chemical disequilibrium conditions1. However, transmission spectra of exoplanets have been limited in their ability to observationally confirm these theories owing to the limited wavelength coverage of the Hubble Space Telescope (HST) and inferences of single molecules, mostly H2O (ref. 2). In this work, we present the panchromatic transmission spectrum of the approximately 750 K, low-density, Neptune-sized exoplanet WASP-107b using a combination of HST Wide Field Camera 3 (WFC3) and JWST Near-Infrared Camera (NIRCam) and Mid-Infrared Instrument (MIRI). From this spectrum, we detect spectroscopic features resulting from H2O (21σ), CH4 (5σ), CO (7σ), CO2 (29σ), SO2 (9σ) and NH3 (6σ). The presence of these molecules enables constraints on the atmospheric metal enrichment (M/H is 10–18× solar3), vertical mixing strength (log10Kzz = 8.4–9.0 cm2 s−1) and internal temperature (>345 K). The high internal temperature is suggestive of tidally driven inflation4 acting on a Neptune-like internal structure, which can naturally explain the large radius and low density of the planet. These findings suggest that eccentricity-driven tidal heating is a critical process governing atmospheric chemistry and interior-structure inferences for most of the cool (<1,000 K) super-Earth-to-Saturn-mass exoplanet population.Analysis of the panchromatic transmission spectrum of the warm, low-density, Neptune-sized exoplanet WASP-107b from instruments aboard the HST and JWST suggests that tidal interaction with its host star led to changes in its atmospheric chemistry. [ABSTRACT FROM AUTHOR]

Author(s): Alpaslan Tasdogan [sup.1] , Brandon Faubert [sup.1] , Vijayashree Ramesh [sup.1] , Jessalyn M. Ubellacker [sup.1] , Bo Shen [sup.1] , Ashley Solmonson [sup.1] , Malea M. Murphy [sup.1] [...], Metastasis requires cancer cells to undergo metabolic changes that are poorly understood.sup.1-3. Here we show that metabolic differences among melanoma cells confer differences in metastatic potential as a result of differences in the function of the MCT1 transporter. In vivo isotope tracing analysis in patient-derived xenografts revealed differences in nutrient handling between efficiently and inefficiently metastasizing melanomas, with circulating lactate being a more prominent source of tumour lactate in efficient metastasizers. Efficient metastasizers had higher levels of MCT1, and inhibition of MCT1 reduced lactate uptake. MCT1 inhibition had little effect on the growth of primary subcutaneous tumours, but resulted in depletion of circulating melanoma cells and reduced the metastatic disease burden in patient-derived xenografts and in mouse melanomas. In addition, inhibition of MCT1 suppressed the oxidative pentose phosphate pathway and increased levels of reactive oxygen species. Antioxidants blocked the effects of MCT1 inhibition on metastasis. MCT1.sup.high and MCT1.sup.-/low cells from the same melanomas had similar capacities to form subcutaneous tumours, but MCT1.sup.high cells formed more metastases after intravenous injection. Metabolic differences among cancer cells thus confer differences in metastatic potential as metastasizing cells depend on MCT1 to manage oxidative stress. Differences in MCT1 function among melanoma cells confer differences in oxidative stress resistance and metastatic potential.

Performing genetic studies in multiple human populations can identify disease risk alleles that are common in one population but rare in others, with the potential to illuminate pathophysiology, health disparities, and the population genetic origins of disease alleles. Here we analysed 9.2 million single nucleotide polymorphisms (SNPs) in each of 8,214 Mexicans and other Latin Americans: 3,848 with type 2 diabetes and 4,366 non-diabetic controls. In addition to replicating previous findings, we identified a novel locus associated with type 2 diabetes at genome-wide significance spanning the solute carriers SLC16A11 and SLC16A13 (P = 3.9 × 10(-13); odds ratio (OR) = 1.29). The association was stronger in younger, leaner people with type 2 diabetes, and replicated in independent samples (P = 1.1 × 10(-4); OR = 1.20). The risk haplotype carries four amino acid substitutions, all in SLC16A11; it is present at ~50% frequency in Native American samples and ~10% in east Asian, but is rare in European and African samples. Analysis of an archaic genome sequence indicated that the risk haplotype introgressed into modern humans via admixture with Neanderthals. The SLC16A11 messenger RNA is expressed in liver, and V5-tagged SLC16A11 protein localizes to the endoplasmic reticulum. Expression of SLC16A11 in heterologous cells alters lipid metabolism, most notably causing an increase in intracellular triacylglycerol levels. Despite type 2 diabetes having been well studied by genome-wide association studies in other populations, analysis in Mexican and Latin American individuals identified SLC16A11 as a novel candidate gene for type 2 diabetes with a possible role in triacylglycerol metabolism.

Recombination, together with mutation, gives rise to genetic variation in populations. Here we leverage the recent mixture of people of African and European ancestry in the Americas to build a genetic map measuring the probability of crossing over at each position in the genome, based on about 2.1 million crossovers in 30,000 unrelated African Americans. At intervals of more than three megabases it is nearly identical to a map built in Europeans. At finer scales it differs significantly, and we identify about 2,500 recombination hotspots that are active in people of West African ancestry but nearly inactive in Europeans. The probability of a crossover at these hotspots is almost fully controlled by the alleles an individual carries at PRDM9 (P value

Author(s): Jakub Gruszczyk [sup.1] , Rick K. Huang [sup.2] , Li-Jin Chan [sup.1] [sup.3] , Sébastien Menant [sup.1] , Chuan Hong [sup.2] , James M. Murphy [sup.1] [sup.3] , Yee-Foong [...], Plasmodium vivax is the most widely distributed malaria parasite that infects humans.sup.1. P. vivax invades reticulocytes exclusively, and successful entry depends on specific interactions between the P. vivax reticulocyte-binding protein 2b (PvRBP2b) and transferrin receptor 1 (TfR1).sup.2. TfR1-deficient erythroid cells are refractory to invasion by P. vivax, and anti-PvRBP2b monoclonal antibodies inhibit reticulocyte binding and block P. vivax invasion in field isolates.sup.2. Here we report a high-resolution cryo-electron microscopy structure of a ternary complex of PvRBP2b bound to human TfR1 and transferrin, at 3.7 Å resolution. Mutational analyses show that PvRBP2b residues involved in complex formation are conserved; this suggests that antigens could be designed that act across P. vivax strains. Functional analyses of TfR1 highlight how P. vivax hijacks TfR1, an essential housekeeping protein, by binding to sites that govern host specificity, without affecting its cellular function of transporting iron. Crystal and solution structures of PvRBP2b in complex with antibody fragments characterize the inhibitory epitopes. Our results establish a structural framework for understanding how P. vivax reticulocyte-binding protein engages its receptor and the molecular mechanism of inhibitory monoclonal antibodies, providing important information for the design of novel vaccine candidates. Structural studies show that conserved residues in Plasmodium vivax reticulocyte-binding protein 2b determine interactions with transferrin receptor 1 that are essential for host invasion, suggesting avenues for designing vaccines that work across P. vivax strains.