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Numerous studies have shown reduced performance in plants that are surrounded by neighbours of the same species1,2, a phenomenon known as conspecific negative density dependence (CNDD)3. A long-held ecological hypothesis posits that CNDD is more pronounced in tropical than in temperate forests4,5, which increases community stabilization, species coexistence and the diversity of local tree species6,7. Previous analyses supporting such a latitudinal gradient in CNDD8,9 have suffered from methodological limitations related to the use of static data10-12. Here we present a comprehensive assessment of latitudinal CNDD patterns using dynamic mortality data to estimate species-site-specific CNDD across 23 sites. Averaged across species, we found that stabilizing CNDD was present at all except one site, but that average stabilizing CNDD was not stronger toward the tropics. However, in tropical tree communities, rare and intermediate abundant species experienced stronger stabilizing CNDD than did common species. This pattern was absent in temperate forests, which suggests that CNDD influences species abundances more strongly in tropical forests than it does in temperate ones13. We also found that interspecific variation in CNDD, which might attenuate its stabilizing effect on species diversity14,15, was high but not significantly different across latitudes. Although the consequences of these patterns for latitudinal diversity gradients are difficult to evaluate, we speculate that a more effective regulation of population abundances could translate into greater stabilization of tropical tree communities and thus contribute to the high local diversity of tropical forests.

Phosphoinositide 3-kinase δ (PI3Kδ) has a key role in lymphocytes, and inhibitors that target this PI3K have been approved for treatment of B cell malignancies1-3. Although studies in mouse models of solid tumours have demonstrated that PI3Kδ inhibitors (PI3Kδi) can induce anti-tumour immunity4,5, its effect on solid tumours in humans remains unclear. Here we assessed the effects of the PI3Kδi AMG319 in human patients with head and neck cancer in a neoadjuvant, double-blind, placebo-controlled randomized phase II trial (EudraCT no. 2014-004388-20). PI3Kδ inhibition decreased the number of tumour-infiltrating regulatory T (Treg) cells and enhanced the cytotoxic potential of tumour-infiltrating T cells. At the tested doses of AMG319, immune-related adverse events (irAEs) required treatment to be discontinued in 12 out of 21 of patients treated with AMG319, suggestive of systemic effects on Treg cells. Accordingly, in mouse models, PI3Kδi decreased the number of Treg cells systemically and caused colitis. Single-cell RNA-sequencing analysis revealed a PI3Kδi-driven loss of tissue-resident colonic ST2 Treg cells, accompanied by expansion of pathogenic T helper 17 (TH17) and type 17 CD8+ T (TC17) cells, which probably contributed to toxicity; this points towards a specific mode of action for the emergence of irAEs. A modified treatment regimen with intermittent dosing of PI3Kδi in mouse models led to a significant decrease in tumour growth without inducing pathogenic T cells in colonic tissue, indicating that alternative dosing regimens might limit toxicity.

Treatment with immune checkpoint blockade (ICB) has revolutionized cancer therapy. Until now, predictive biomarkers1-10 and strategies to augment clinical response have largely focused on the T cell compartment. However, other immune subsets may also contribute to anti-tumour immunity11-15, although these have been less well-studied in ICB treatment16. A previously conducted neoadjuvant ICB trial in patients with melanoma showed via targeted expression profiling17 that B cell signatures were enriched in the tumours of patients who respond to treatment versus non-responding patients. To build on this, here we performed bulk RNA sequencing and found that B cell markers were the most differentially expressed genes in the tumours of responders versus non-responders. Our findings were corroborated using a computational method (MCP-counter18) to estimate the immune and stromal composition in this and two other ICB-treated cohorts (patients with melanoma and renal cell carcinoma). Histological evaluation highlighted the localization of B cells within tertiary lymphoid structures. We assessed the potential functional contributions of B cells via bulk and single-cell RNA sequencing, which demonstrate clonal expansion and unique functional states of B cells in responders. Mass cytometry showed that switched memory B cells were enriched in the tumours of responders. Together, these data provide insights into the potential role of B cells and tertiary lymphoid structures in the response to ICB treatment, with implications for the development of biomarkers and therapeutic targets.

Conservation, restoration and land management are increasingly implemented at landscape scales1,2. However, because species interaction data are typically habitat- and/or guild-specific, exactly how those interactions connect habitats and affect the stability and function of communities at landscape scales remains poorly understood. We combine multi-guild species interaction data (plant–pollinator and three plant–herbivore–parasitoid communities, collected from landscapes with one, two or three habitats), a field experiment and a modelling approach to show that multi-habitat landscapes support higher species and interaction evenness, more complementary species interactions and more consistent robustness to species loss. These emergent network properties drive improved pollination success in landscapes with more habitats and are not explained by simply summing component habitat webs. Linking landscape composition, through community structure, to ecosystem function, highlights mechanisms by which several contiguous habitats can support landscape-scale ecosystem services.Species interaction data, a field experiment and modelling of plant–insect communities show that landscapes with more habitat types support more even species, more complementary interactions, are more consistently robust to species loss, and confer greater pollination function. [ABSTRACT FROM AUTHOR]

Oncogenic mutations are abundant in the tissues of healthy individuals, but rarely form tumours1–3. Yet, the underlying protection mechanisms are largely unknown. To resolve these mechanisms in mouse mammary tissue, we use lineage tracing to map the fate of wild-type and Brca1−/−;Trp53−/− cells, and find that both follow a similar pattern of loss and spread within ducts. Clonal analysis reveals that ducts consist of small repetitive units of self-renewing cells that give rise to short-lived descendants. This offers a first layer of protection as any descendants, including oncogenic mutant cells, are constantly lost, thereby limiting the spread of mutations to a single stem cell-descendant unit. Local tissue remodelling during consecutive oestrous cycles leads to the cooperative and stochastic loss and replacement of self-renewing cells. This process provides a second layer of protection, leading to the elimination of most mutant clones while enabling the minority that by chance survive to expand beyond the stem cell-descendant unit. This leads to fields of mutant cells spanning large parts of the epithelial network, predisposing it for transformation. Eventually, clone expansion becomes restrained by the geometry of the ducts, providing a third layer of protection. Together, these mechanisms act to eliminate most cells that acquire somatic mutations at the expense of driving the accelerated expansion of a minority of cells, which can colonize large areas, leading to field cancerization.The authors use lineage tracing to map the fate of wild-type and Brca1−/−;Trp53−/− cells in the adult mouse mammary gland, identifying three layers of protection that limit the spread of mutant cells at the expense of allowing a minority of mutant cells to expand, which leads to field cancerization. [ABSTRACT FROM AUTHOR]

Ordering of ferroelectric polarization1 and its trajectory in response to an electric field2 are essential for the operation of non-volatile memories3, transducers4 and electro-optic devices5. However, for voltage control of capacitance and frequency agility in telecommunication devices, domain walls have long been thought to be a hindrance because they lead to high dielectric loss and hysteresis in the device response to an applied electric field6. To avoid these effects, tunable dielectrics are often operated under piezoelectric resonance conditions, relying on operation well above the ferroelectric Curie temperature7, where tunability is compromised. Therefore, there is an unavoidable trade-off between the requirements of high tunability and low loss in tunable dielectric devices, which leads to severe limitations on their figure of merit. Here we show that domain structure can in fact be exploited to obtain ultralow loss and exceptional frequency selectivity without piezoelectric resonance. We use intrinsically tunable materials with properties that are defined not only by their chemical composition, but also by the proximity and accessibility of thermodynamically predicted strain-induced, ferroelectric domain-wall variants8. The resulting gigahertz microwave tunability and dielectric loss are better than those of the best film devices by one to two orders of magnitude and comparable to those of bulk single crystals. The measured quality factors exceed the theoretically predicted zero-field intrinsic limit owing to domain-wall fluctuations, rather than field-induced piezoelectric oscillations, which are usually associated with resonance. Resonant frequency tuning across the entire L, S and C microwave bands (1-8 gigahertz) is achieved in an individual device-a range about 100 times larger than that of the best intrinsically tunable material. These results point to a rich phase space of possible nanometre-scale domain structures that can be used to surmount current limitations, and demonstrate a promising strategy for obtaining ultrahigh frequency agility and low-loss microwave devices.

SARS-CoV-2 lineage B.1.1.7, a variant that was first detected in the UK in September 2020.sup.1, has spread to multiple countries worldwide. Several studies have established that B.1.1.7 is more transmissible than pre-existing variants, but have not identified whether it leads to any change in disease severity.sup.2. Here we analyse a dataset that links 2,245,263 positive SARS-CoV-2 community tests and 17,452 deaths associated with COVID-19 in England from 1 November 2020 to 14 February 2021. For 1,146,534 (51%) of these tests, the presence or absence of B.1.1.7 can be identified because mutations in this lineage prevent PCR amplification of the spike (S) gene target (known as S gene target failure (SGTF).sup.1). On the basis of 4,945 deaths with known SGTF status, we estimate that the hazard of death associated with SGTF is 55% (95% confidence interval, 39-72%) higher than in cases without SGTF after adjustment for age, sex, ethnicity, deprivation, residence in a care home, the local authority of residence and test date. This corresponds to the absolute risk of death for a 55-69-year-old man increasing from 0.6% to 0.9% (95% confidence interval, 0.8-1.0%) within 28 days of a positive test in the community. Correcting for misclassification of SGTF and missingness in SGTF status, we estimate that the hazard of death associated with B.1.1.7 is 61% (42-82%) higher than with pre-existing variants. Our analysis suggests that B.1.1.7 is not only more transmissible than pre-existing SARS-CoV-2 variants, but may also cause more severe illness. Analysis of community-tested cases of SARS-CoV-2 indicates that the B.1.1.7 variant is not only more transmissible than pre-existing variants, but may also cause more severe illness, and is associated with a higher risk of death., Author(s): Nicholas G. Davies [sup.1] , Christopher I. Jarvis [sup.1] , Kevin van Zandvoort [sup.1] , Samuel Clifford [sup.1] , Fiona Yueqian Sun [sup.1] , Sebastian Funk [sup.1] , Graham [...]

Somatic cells acquire mutations throughout the course of an individual's life. Mutations occurring early in embryogenesis are often present in a substantial proportion of, but not all, cells in postnatal humans and thus have particular characteristics and effects. Depending on their location in the genome and the proportion of cells they are present in, these mosaic mutations can cause a wide range of genetic disease syndromes and predispose carriers to cancer. They have a high chance of being transmitted to offspring as de novo germline mutations and, in principle, can provide insights into early human embryonic cell lineages and their contributions to adult tissues. Although it is known that gross chromosomal abnormalities are remarkably common in early human embryos, our understanding of early embryonic somatic mutations is very limited. Here we use whole-genome sequences of normal blood from 241 adults to identify 163 early embryonic mutations. We estimate that approximately three base substitution mutations occur per cell per cell-doubling event in early human embryogenesis and these are mainly attributable to two known mutational signatures. We used the mutations to reconstruct developmental lineages of adult cells and demonstrate that the two daughter cells of many early embryonic cell-doubling events contribute asymmetrically to adult blood at an approximately 2:1 ratio. This study therefore provides insights into the mutation rates, mutational processes and developmental outcomes of cell dynamics that operate during early human embryogenesis.

Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height-increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.

Large-scale outflows driven by supermassive black holes are thought to have a fundamental role in suppressing star formation in massive galaxies. However, direct observational evidence for this hypothesis is still lacking, particularly in the young universe where star-formation quenching is remarkably rapid1–3, thus requiring effective removal of gas4 as opposed to slow gas heating5,6. Although outflows of ionized gas are frequently detected in massive distant galaxies7, the amount of ejected mass is too small to be able to suppress star formation8,9. Gas ejection is expected to be more efficient in the neutral and molecular phases10, but at high redshift these have only been observed in starbursts and quasars11,12. Here we report JWST spectroscopy of a massive galaxy experiencing rapid quenching at a redshift of 2.445. We detect a weak outflow of ionized gas and a powerful outflow of neutral gas, with a mass outflow rate that is sufficient to quench the star formation. Neither X-ray nor radio activity is detected; however, the presence of a supermassive black hole is suggested by the properties of the ionized gas emission lines. We thus conclude that supermassive black holes are able to rapidly suppress star formation in massive galaxies by efficiently ejecting neutral gas.JWST observations of a massive galaxy at a redshift of 2.45 show a powerful outflow of neutral gas, with a mass outflow rate that is sufficient to shut down star formation. [ABSTRACT FROM AUTHOR]

The record of past human adaptations provides crucial lessons for guiding responses to crises in the future1–3. To date, there have been no systematic global comparisons of humans’ ability to absorb and recover from disturbances through time4,5. Here we synthesized resilience across a broad sample of prehistoric population time–frequency data, spanning 30,000 years of human history. Cross-sectional and longitudinal analyses of population decline show that frequent disturbances enhance a population’s capacity to resist and recover from later downturns. Land-use patterns are important mediators of the strength of this positive association: farming and herding societies are more vulnerable but also more resilient overall. The results show that important trade-offs exist when adopting new or alternative land-use strategies.Analysis of population decline shows that frequent disturbances enhance a population’s capacity to resist and recover from downturns and that trade-offs exist when adopting new or alternative land-use strategies. [ABSTRACT FROM AUTHOR]

Niche dimensionality provides a general theoretical explanation for biodiversity-more niches, defined by more limiting factors, allow for more ways that species can coexist. Because plant species compete for the same set of limiting resources, theory predicts that addition of a limiting resource eliminates potential trade-offs, reducing the number of species that can coexist. Multiple nutrient limitation of plant production is common and therefore fertilization may reduce diversity by reducing the number or dimensionality of belowground limiting factors. At the same time, nutrient addition, by increasing biomass, should ultimately shift competition from belowground nutrients towards a one-dimensional competitive trade-off for light. Here we show that plant species diversity decreased when a greater number of limiting nutrients were added across 45 grassland sites from a multi-continent experimental network. The number of added nutrients predicted diversity loss, even after controlling for effects of plant biomass, and even where biomass production was not nutrient-limited. We found that elevated resource supply reduced niche dimensionality and diversity and increased both productivity and compositional turnover. Our results point to the importance of understanding dimensionality in ecological systems that are undergoing diversity loss in response to multiple global change factors.

Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric diseases.

The DNA-binding protein PRDM9 directs positioning of the double-strand breaks (DSBs) that initiate meiotic recombination in mice and humans. Prdm9 is the only mammalian speciation gene yet identified and is responsible for sterility phenotypes in male hybrids of certain mouse subspecies. To investigate PRDM9 binding and its role in fertility and meiotic recombination, we humanized the DNA-binding domain of PRDM9 in C57BL/6 mice. This change repositions DSB hotspots and completely restores fertility in male hybrids. Here we show that alteration of one Prdm9 allele impacts the behaviour of DSBs controlled by the other allele at chromosome-wide scales. These effects correlate strongly with the degree to which each PRDM9 variant binds both homologues at the DSB sites it controls. Furthermore, higher genome-wide levels of such 'symmetric' PRDM9 binding associate with increasing fertility measures, and comparisons of individual hotspots suggest binding symmetry plays a downstream role in the recombination process. These findings reveal that subspecies-specific degradation of PRDM9 binding sites by meiotic drive, which steadily increases asymmetric PRDM9 binding, has impacts beyond simply changing hotspot positions, and strongly support a direct involvement in hybrid infertility. Because such meiotic drive occurs across mammals, PRDM9 may play a wider, yet transient, role in the early stages of speciation.

Ever since Stephen Paget's 1889 hypothesis, metastatic organotropism has remained one of cancer's greatest mysteries. Here we demonstrate that exosomes from mouse and human lung-, liver- and brain-tropic tumour cells fuse preferentially with resident cells at their predicted destination, namely lung fibroblasts and epithelial cells, liver Kupffer cells and brain endothelial cells. We show that tumour-derived exosomes uptaken by organ-specific cells prepare the pre-metastatic niche. Treatment with exosomes from lung-tropic models redirected the metastasis of bone-tropic tumour cells. Exosome proteomics revealed distinct integrin expression patterns, in which the exosomal integrins α6β4 and α6β1 were associated with lung metastasis, while exosomal integrin αvβ5 was linked to liver metastasis. Targeting the integrins α6β4 and αvβ5 decreased exosome uptake, as well as lung and liver metastasis, respectively. We demonstrate that exosome integrin uptake by resident cells activates Src phosphorylation and pro-inflammatory S100 gene expression. Finally, our clinical data indicate that exosomal integrins could be used to predict organ-specific metastasis.

Quantum cascade lasers are compact, electrically pumped light sources in the technologically important mid-infrared and terahertz region of the electromagnetic spectrum.sup.1,2. Recently, the concept of topology.sup.3 has been expanded from condensed matter physics into photonics.sup.4, giving rise to a new type of lasing.sup.5-8 using topologically protected photonic modes that can efficiently bypass corners and defects.sup.4. Previous demonstrations of topological lasers have required an external laser source for optical pumping and have operated in the conventional optical frequency regime.sup.5-8. Here we demonstrate an electrically pumped terahertz quantum cascade laser based on topologically protected valley edge states.sup.9-11. Unlike topological lasers that rely on large-scale features to impart topological protection, our compact design makes use of the valley degree of freedom in photonic crystals.sup.10,11, analogous to two-dimensional gapped valleytronic materials.sup.12. Lasing with regularly spaced emission peaks occurs in a sharp-cornered triangular cavity, even if perturbations are introduced into the underlying structure, owing to the existence of topologically protected valley edge states that circulate around the cavity without experiencing localization. We probe the properties of the topological lasing modes by adding different outcouplers to the topological cavity. The laser based on valley edge states may open routes to the practical use of topological protection in electrically driven laser sources. A topological laser based on the valley degree of freedom in a compact photonic crystal can be pumped electrically, bringing topological physics concepts closer to real-life applications., Author(s): Yongquan Zeng [sup.1] , Udvas Chattopadhyay [sup.2] , Bofeng Zhu [sup.2] , Bo Qiang [sup.1] [sup.2] , Jinghao Li [sup.1] , Yuhao Jin [sup.1] , Lianhe Li [sup.3] , [...]

The most common causes of chronic liver disease are excess alcohol intake, viral hepatitis and non-alcoholic fatty liver disease, with the clinical spectrum ranging in severity from hepatic inflammation to cirrhosis, liver failure or hepatocellular carcinoma (HCC). The genome of HCC exhibits diverse mutational signatures, resulting in recurrent mutations across more than 30 cancer genes.sup.1-7. Stem cells from normal livers have a low mutational burden and limited diversity of signatures.sup.8, which suggests that the complexity of HCC arises during the progression to chronic liver disease and subsequent malignant transformation. Here, by sequencing whole genomes of 482 microdissections of 100-500 hepatocytes from 5 normal and 9 cirrhotic livers, we show that cirrhotic liver has a higher mutational burden than normal liver. Although rare in normal hepatocytes, structural variants, including chromothripsis, were prominent in cirrhosis. Driver mutations, such as point mutations and structural variants, affected 1-5% of clones. Clonal expansions of millimetres in diameter occurred in cirrhosis, with clones sequestered by the bands of fibrosis that surround regenerative nodules. Some mutational signatures were universal and equally active in both non-malignant hepatocytes and HCCs; some were substantially more active in HCCs than chronic liver disease; and others--arising from exogenous exposures--were present in a subset of patients. The activity of exogenous signatures between adjacent cirrhotic nodules varied by up to tenfold within each patient, as a result of clone-specific and microenvironmental forces. Synchronous HCCs exhibited the same mutational signatures as background cirrhotic liver, but with higher burden. Somatic mutations chronicle the exposures, toxicity, regeneration and clonal structure of liver tissue as it progresses from health to disease. Whole-genome sequencing of liver microdissections from five healthy individuals and nine with cirrhosis demonstrates the effects of liver disease on the genome, including increased rates of mutation, complex structural variation and different mutational signatures., Author(s): Simon F. Brunner [sup.1] , Nicola D. Roberts [sup.1] , Luke A. Wylie [sup.1] , Luiza Moore [sup.1] , Sarah J. Aitken [sup.2] [sup.3] , Susan E. Davies [sup.3] [...]

Human alterations to nutrient cycles and herbivore communities are affecting global biodiversity dramatically. Ecological theory predicts these changes should be strongly counteractive: nutrient addition drives plant species loss through intensified competition for light, whereas herbivores prevent competitive exclusion by increasing ground-level light, particularly in productive systems. Here we use experimental data spanning a globally relevant range of conditions to test the hypothesis that herbaceous plant species losses caused by eutrophication may be offset by increased light availability due to herbivory. This experiment, replicated in 40 grasslands on 6 continents, demonstrates that nutrients and herbivores can serve as counteracting forces to control local plant diversity through light limitation, independent of site productivity, soil nitrogen, herbivore type and climate. Nutrient addition consistently reduced local diversity through light limitation, and herbivory rescued diversity at sites where it alleviated light limitation. Thus, species loss from anthropogenic eutrophication can be ameliorated in grasslands where herbivory increases ground-level light.

Access to adequate housing is a fundamental human right, essential to human security, nutrition and health, and a core objective of the United Nations Sustainable Development Goals.sup.1,2. Globally, the housing need is most acute in Africa, where the population will more than double by 2050. However, existing data on housing quality across Africa are limited primarily to urban areas and are mostly recorded at the national level. Here we quantify changes in housing in sub-Saharan Africa from 2000 to 2015 by combining national survey data within a geostatistical framework. We show a marked transformation of housing in urban and rural sub-Saharan Africa between 2000 and 2015, with the prevalence of improved housing (with improved water and sanitation, sufficient living area and durable construction) doubling from 11% (95% confidence interval, 10-12%) to 23% (21-25%). However, 53 (50-57) million urban Africans (47% (44-50%) of the urban population analysed) were living in unimproved housing in 2015. We provide high-resolution, standardized estimates of housing conditions across sub-Saharan Africa. Our maps provide a baseline for measuring change and a mechanism to guide interventions during the era of the Sustainable Development Goals. The prevalence of improved housing (with improved drinking water and sanitation, sufficient living area and durable construction) in urban and rural sub-Saharan Africa doubled between 2000 and 2015., Author(s): Lucy S. Tusting [sup.1] , Donal Bisanzio [sup.2] [sup.3] , Graham Alabaster [sup.4] , Ewan Cameron [sup.5] , Richard Cibulskis [sup.6] , Michael Davies [sup.7] , Seth Flaxman [sup.8] [...]

Cyclic electron flow around photosystem I (PSI) is a mechanism by which photosynthetic organisms balance the levels of ATP and NADPH necessary for efficient photosynthesis.sup.1,2. NAD(P)H dehydrogenase-like complex (NDH) is a key component of this pathway in most oxygenic photosynthetic organisms.sup.3,4 and is the last large photosynthetic membrane-protein complex for which the structure remains unknown. Related to the respiratory NADH dehydrogenase complex (complex I), NDH transfers electrons originating from PSI to the plastoquinone pool while pumping protons across the thylakoid membrane, thereby increasing the amount of ATP produced per NADP.sup.+ molecule reduced.sup.4,5. NDH possesses 11 of the 14 core complex I subunits, as well as several oxygenic-photosynthesis-specific (OPS) subunits that are conserved from cyanobacteria to plants.sup.3,6. However, the three core complex I subunits that are involved in accepting electrons from NAD(P)H are notably absent in NDH.sup.3,5,6, and it is therefore not clear how NDH acquires and transfers electrons to plastoquinone. It is proposed that the OPS subunits--specifically NdhS--enable NDH to accept electrons from its electron donor, ferredoxin.sup.3-5,7. Here we report a 3.1 Å structure of the 0.42-MDa NDH complex from the thermophilic cyanobacterium Thermosynechococcus elongatus BP-1, obtained by single-particle cryo-electron microscopy. Our maps reveal the structure and arrangement of the principal OPS subunits in the NDH complex, as well as an unexpected cofactor close to the plastoquinone-binding site in the peripheral arm. The location of the OPS subunits supports a role in electron transfer and defines two potential ferredoxin-binding sites at the apex of the peripheral arm. These results suggest that NDH could possess several electron transfer routes, which would serve to maximize plastoquinone reduction and avoid deleterious off-target chemistry of the semi-plastoquinone radical. The structure of NDH, a photosynthetic membrane-protein complex that is related to respiratory complex I, is obtained by single-particle cryo-electron microscopy., Author(s): Thomas G. Laughlin [sup.1] [sup.2] , Andrew N. Bayne [sup.3] [sup.4] , Jean-François Trempe [sup.3] [sup.4] , David F. Savage [sup.1] , Karen M. Davies [sup.1] [sup.2] Author Affiliations: [...]

Carbon-hydrogen (C-H) bonds have long been considered unreactive and are inert to traditional chemical reagents, yet new methods for the transformation of these bonds are continually being developed.sup.1-9. However, it is challenging to achieve such transformations in a highly selective manner, especially if the C-H bonds are unactivated.sup.10 or not adjacent to a directing group.sup.11-13. Catalyst-controlled site-selectivity--in which the inherent reactivities of the substrates.sup.14 can be overcome by choosing an appropriate catalyst--is an appealing concept, and substantial effort has been made towards catalyst-controlled C-H functionalization.sup.6,15-17, in particular methylene C-H bond functionalization. However, although several new methods have targeted these bonds in cyclic alkanes, the selectivity has been relatively poor.sup.18-20. Here we illustrate an additional level of sophistication in catalyst-controlled C-H functionalization, whereby unactivated cyclohexane derivatives can be desymmetrized in a highly site- and stereoselective manner through donor/acceptor carbene insertion. These studies demonstrate the potential of catalyst-controlled site-selectivity to govern which C-H bond will react, which could enable new strategies for the production of fine chemicals.Unactivated cyclohexane derivatives can be desymmetrized by site- and stereoselective C-H functionalization using carbene-insertion chemistry., Author(s): Jiantao Fu [sup.1] , Zhi Ren [sup.1] , John Bacsa [sup.1] , Djamaladdin G. Musaev [sup.1] [sup.2] , Huw M. L. Davies [sup.1] Author Affiliations:(1) Department of Chemistry, Emory [...]

Theoretical models and numerical simulations have established a framework of galaxy evolution in which galaxies merge and create dual supermassive black holes (with separations of one to ten kiloparsecs), which eventually sink into the centre of the merger remnant, emit gravitational waves and coalesce. The merger also triggers star formation and supermassive black hole growth, and gas outflows regulate the stellar content.sup.1-3. Although this theoretical picture is supported by recent observations of starburst-driven and supermassive black hole-driven outflows.sup.4-6, it remains unclear how these outflows interact with the interstellar medium. Furthermore, the relative contributions of star formation and black hole activity to galactic feedback remain unknown.sup.7-9. Here we report observations of dual outflows in the central region of the prototypical merger NGC 6240. We find a black-hole-driven outflow of [O iii] to the northeast and a starburst-driven outflow of H[alpha] to the northwest. The orientations and positions of the outflows allow us to isolate them spatially and study their properties independently. We estimate mass outflow rates of 10 and 75 solar masses per year for the H[alpha] bubble and the [O iii] cone, respectively. Their combined mass outflow is comparable to the star formation rate.sup.10, suggesting that negative feedback on star formation is occurring.Observations of NGC 6240 show two differently driven outflows of different gases with a combined outflow rate comparable to the star formation rate, suggesting possible negative feedback on star formation., Author(s): F. Müller-Sánchez [sup.1] , R. Nevin [sup.1] , J. M. Comerford [sup.1] , R. I. Davies [sup.2] , G. C. Privon [sup.3] [sup.4] , E. Treister [sup.3] Author Affiliations:(1) [...]

Author(s): Eduardo Baados (corresponding author) [1]; Bram P. Venemans [2]; Chiara Mazzucchelli [2]; Emanuele P. Farina [2]; Fabian Walter [2]; Feige Wang [3, 4]; Roberto Decarli [2, 5]; Daniel Stern [...]

Author(s): Kuangbiao Liao [1]; Thomas C. Pickel [1]; Vyacheslav Boyarskikh [1]; John Bacsa [1]; Djamaladdin G. Musaev [2]; Huw M. L. Davies (corresponding author) [1] The synthesis of complex organic [...]

Indigenous Americans' relationships with and knowledge of animals have influenced how Europeans have thought about animals since 1492. [ABSTRACT FROM AUTHOR]

The early detection of relapse following primary surgery for non-small-cell lung cancer and the characterization of emerging subclones, which seed metastatic sites, might offer new therapeutic approaches for limiting tumour recurrence. The ability to track the evolutionary dynamics of early-stage lung cancer non-invasively in circulating tumour DNA (ctDNA) has not yet been demonstrated. Here we use a tumour-specific phylogenetic approach to profile the ctDNA of the first 100 TRACERx (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy (Rx)) study participants, including one patient who was also recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and analyse the tumour-volume detection limit. Through blinded profiling of postoperative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients who are very likely to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastasis, providing a new approach for ctDNA-driven therapeutic studies., Author(s): Christopher Abbosh [1]; Nicolai J. Birkbak [1, 2]; Gareth A. Wilson [1, 2]; Mariam Jamal-Hanjani [1]; Tudor Constantin [3]; Raheleh Salari [3]; John Le Quesne [4]; David A. Moore [...]