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The global aim to move away from fossil fuels requires efficient, inexpensive and sustainable energy storage to fully use renewable energy sources. Thermal energy storage materials1,2in combination with a Carnot battery3, 4–5could revolutionize the energy storage sector. However, a lack of stable, inexpensive and energy-dense thermal energy storage materials impedes the advancement of this technology. Here we report the first, to our knowledge, ‘trimodal’ material that synergistically stores large amounts of thermal energy by integrating three distinct energy storage modes—latent, thermochemical and sensible. The eutectic mixture of boric and succinic acids undergoes a transition at around 150 °C, with a record high reversible thermal energy uptake of 394 ± 5% J g−1. We show that the transition involves melting of the boric acid component, which simultaneously undergoes dehydration into metaboric acid and water that dissolve into the liquid. Being retained in the liquid state allows the metaboric acid to readily rehydrate to re-form boric acid on cooling. Thermal stability is demonstrated over 1,000 heating–cooling cycles. The material is very low cost, environmentally friendly and sustainable. This combination of a solid–liquid phase transition and a chemical reaction demonstrated here opens new pathways in the development of high energy capacity materials.

Directed cell migration is driven by the front–back polarization of intracellular signalling1–3. Receptor tyrosine kinases and other inputs activate local signals that trigger membrane protrusions at the front2,4–6. Equally important is a long-range inhibitory mechanism that suppresses signalling at the back to prevent the formation of multiple fronts7–9. However, the identity of this mechanism is unknown. Here we report that endoplasmic reticulum–plasma membrane (ER–PM) contact sites are polarized in single and collectively migrating cells. The increased density of these ER–PM contacts at the back provides the ER-resident PTP1B phosphatase more access to PM substrates, which confines receptor signalling to the front and directs cell migration. Polarization of the ER–PM contacts is due to microtubule-regulated polarization of the ER, with more RTN4-rich curved ER at the front and more CLIMP63-rich flattened ER at the back. The resulting ER curvature gradient leads to small and unstable ER–PM contacts only at the front. These contacts flow backwards and grow to large and stable contacts at the back to form the front–back ER–PM contact gradient. Together, our study suggests that the structural polarity mediated by ER–PM contact gradients polarizes cell signalling, directs cell migration and prolongs cell migration.

Antibody and chimeric antigen receptor (CAR) T cell-mediated targeted therapies have improved survival in patients with solid and haematologic malignancies1–9. Adults with T cell leukaemias and lymphomas, collectively called T cell cancers, have short survival10,11and lack such targeted therapies. Thus, T cell cancers particularly warrant the development of CAR T cells and antibodies to improve patient outcomes. Preclinical studies showed that targeting T cell receptor β-chain constant region 1 (TRBC1) can kill cancerous T cells while preserving sufficient healthy T cells to maintain immunity12, making TRBC1 an attractive target to treat T cell cancers. However, the first-in-human clinical trial of anti-TRBC1 CAR T cells reported a low response rate and unexplained loss of anti-TRBC1 CAR T cells13,14. Here we demonstrate that CAR T cells are lost due to killing by the patient’s normal T cells, reducing their efficacy. To circumvent this issue, we developed an antibody–drug conjugate that could kill TRBC1+cancer cells in vitro and cure human T cell cancers in mouse models. The anti-TRBC1 antibody–drug conjugate may provide an optimal format for TRBC1 targeting and produce superior responses in patients with T cell cancers.

Fusobacterium nucleatum(Fn), a bacterium present in the human oral cavity and rarely found in the lower gastrointestinal tract of healthy individuals1, is enriched in human colorectal cancer (CRC) tumours2–5. High intratumoural Fnloads are associated with recurrence, metastases and poorer patient prognosis5–8. Here, to delineate Fngenetic factors facilitating tumour colonization, we generated closed genomes for 135 Fnstrains; 80 oral strains from individuals without cancer and 55 unique cancer strains cultured from tumours from 51 patients with CRC. Pangenomic analyses identified 483 CRC-enriched genetic factors. Tumour-isolated strains predominantly belong to Fnsubspecies animalis(Fna). However, genomic analyses reveal that Fna, considered a single subspecies, is instead composed of two distinct clades (FnaC1 and FnaC2). Of these, only FnaC2 dominates the CRC tumour niche. Inter-Fnaanalyses identified 195 FnaC2-associated genetic factors consistent with increased metabolic potential and colonization of the gastrointestinal tract. In support of this, FnaC2-treated mice had an increased number of intestinal adenomas and altered metabolites. Microbiome analysis of human tumour tissue from 116 patients with CRC demonstrated FnaC2 enrichment. Comparison of 62 paired specimens showed that only FnaC2 is tumour enriched compared to normal adjacent tissue. This was further supported by metagenomic analysis of stool samples from 627 patients with CRC and 619 healthy individuals. Collectively, our results identify the Fnaclade bifurcation, show that specifically FnaC2 drives the reported Fnenrichment in human CRC and reveal the genetic underpinnings of pathoadaptation of FnaC2 to the CRC niche.

Tiragolumab, an anti-TIGIT antibody with an active IgG1κ Fc, demonstrated improved outcomes in the phase 2 CITYSCAPE trial (ClinicalTrials.gov: NCT03563716) when combined with atezolizumab (anti-PD-L1) versus atezolizumab alone1. However, there remains little consensus on the mechanism(s) of response with this combination2. Here we find that a high baseline of intratumoural macrophages and regulatory T cells is associated with better outcomes in patients treated with atezolizumab plus tiragolumab but not with atezolizumab alone. Serum sample analysis revealed that macrophage activation is associated with a clinical benefit in patients who received the combination treatment. In mouse tumour models, tiragolumab surrogate antibodies inflamed tumour-associated macrophages, monocytes and dendritic cells through Fcγ receptors (FcγR), in turn driving anti-tumour CD8+T cells from an exhausted effector-like state to a more memory-like state. These results reveal a mechanism of action through which TIGIT checkpoint inhibitors can remodel immunosuppressive tumour microenvironments, and suggest that FcγR engagement is an important consideration in anti-TIGIT antibody development.

Wildfires are thought to be increasing in severity and frequency as a result of climate change1–5. Air pollution from landscape fires can negatively affect human health4–6, but human exposure to landscape fire-sourced (LFS) air pollution has not been well characterized at the global scale7–23. Here, we estimate global daily LFS outdoor fine particulate matter (PM2.5) and surface ozone concentrations at 0.25° × 0.25° resolution during the period 2000–2019 with the help of machine learning and chemical transport models. We found that overall population-weighted average LFS PM2.5and ozone concentrations were 2.5 µg m−3(6.1% of all-source PM2.5) and 3.2 µg m−3(3.6% of all-source ozone), respectively, in 2010–2019, with a slight increase for PM2.5, but not for ozone, compared with 2000–2009. Central Africa, Southeast Asia, South America and Siberia experienced the highest LFS PM2.5and ozone concentrations. The concentrations of LFS PM2.5and ozone were about four times higher in low-income countries than in high-income countries. During the period 2010–2019, 2.18 billion people were exposed to at least 1 day of substantial LFS air pollution per year, with each person in the world having, on average, 9.9 days of exposure per year. These two metrics increased by 6.8% and 2.1%, respectively, compared with 2000–2009. Overall, we find that the global population is increasingly exposed to LFS air pollution, with socioeconomic disparities.

The tumour-associated microbiota is an intrinsic component of the tumour microenvironment across human cancer types1,2. Intratumoral host–microbiota studies have so far largely relied on bulk tissue analysis1–3, which obscures the spatial distribution and localized effect of the microbiota within tumours. Here, by applying in situ spatial-profiling technologies4and single-cell RNA sequencing5to oral squamous cell carcinoma and colorectal cancer, we reveal spatial, cellular and molecular host–microbe interactions. We adapted 10x Visium spatial transcriptomics to determine the identity and in situ location of intratumoral microbial communities within patient tissues. Using GeoMx digital spatial profiling6, we show that bacterial communities populate microniches that are less vascularized, highly immuno‑suppressive and associated with malignant cells with lower levels of Ki-67 as compared to bacteria-negative tumour regions. We developed a single-cell RNA-sequencing method that we name INVADEseq (invasion–adhesion-directed expression sequencing) and, by applying this to patient tumours, identify cell-associated bacteria and the host cells with which they interact, as well as uncovering alterations in transcriptional pathways that are involved in inflammation, metastasis, cell dormancy and DNA repair. Through functional studies, we show that cancer cells that are infected with bacteria invade their surrounding environment as single cells and recruit myeloid cells to bacterial regions. Collectively, our data reveal that the distribution of the microbiota within a tumour is not random; instead, it is highly organized in microniches with immune and epithelial cell functions that promote cancer progression.

Low levels of social interaction across class lines have generated widespread concern1–4and are associated with worse outcomes, such as lower rates of upward income mobility4–7. Here we analyse the determinants of cross-class interaction using data from Facebook, building on the analysis in our companion paper7. We show that about half of the social disconnection across socioeconomic lines—measured as the difference in the share of high-socioeconomic status (SES) friends between people with low and high SES—is explained by differences in exposure to people with high SES in groups such as schools and religious organizations. The other half is explained by friending bias—the tendency for people with low SES to befriend people with high SES at lower rates even conditional on exposure. Friending bias is shaped by the structure of the groups in which people interact. For example, friending bias is higher in larger and more diverse groups and lower in religious organizations than in schools and workplaces. Distinguishing exposure from friending bias is helpful for identifying interventions to increase cross-SES friendships (economic connectedness). Using fluctuations in the share of students with high SES across high school cohorts, we show that increases in high-SES exposure lead low-SES people to form more friendships with high-SES people in schools that exhibit low levels of friending bias. Thus, socioeconomic integration can increase economic connectedness in communities in which friending bias is low. By contrast, when friending bias is high, increasing cross-SES interactions among existing members may be necessary to increase economic connectedness. To support such efforts, we release privacy-protected statistics on economic connectedness, exposure and friending bias for each ZIP (postal) code, high school and college in the United States at https://www.socialcapital.org.

Social capital—the strength of an individual’s social network and community—has been identified as a potential determinant of outcomes ranging from education to health1–8. However, efforts to understand what types of social capital matter for these outcomes have been hindered by a lack of social network data. Here, in the first of a pair of papers9, we use data on 21 billion friendships from Facebook to study social capital. We measure and analyse three types of social capital by ZIP (postal) code in the United States: (1) connectedness between different types of people, such as those with low versus high socioeconomic status (SES); (2) social cohesion, such as the extent of cliques in friendship networks; and (3) civic engagement, such as rates of volunteering. These measures vary substantially across areas, but are not highly correlated with each other. We demonstrate the importance of distinguishing these forms of social capital by analysing their associations with economic mobility across areas. The share of high-SES friends among individuals with low SES—which we term economic connectedness—is among the strongest predictors of upward income mobility identified to date10,11. Other social capital measures are not strongly associated with economic mobility. If children with low-SES parents were to grow up in counties with economic connectedness comparable to that of the average child with high-SES parents, their incomes in adulthood would increase by 20% on average. Differences in economic connectedness can explain well-known relationships between upward income mobility and racial segregation, poverty rates, and inequality12–14. To support further research and policy interventions, we publicly release privacy-protected statistics on social capital by ZIP code at https://www.socialcapital.org.

International policy is focused on increasing the proportion of the Earth’s surface that is protected for nature1,2. Although studies show that protected areas prevent habitat loss3–6, there is a lack of evidence for their effect on species’ populations: existing studies are at local scale or use simple designs that lack appropriate controls7–13. Here we explore how 1,506 protected areas have affected the trajectories of 27,055 waterbird populations across the globe using a robust before–after control–intervention study design, which compares protected and unprotected populations in the years before and after protection. We show that the simpler study designs typically used to assess protected area effectiveness (before–after or control–intervention) incorrectly estimate effects for 37–50% of populations—for instance misclassifying positively impacted populations as negatively impacted, and vice versa. Using our robust study design, we find that protected areas have a mixed impact on waterbirds, with a strong signal that areas managed for waterbirds or their habitat are more likely to benefit populations, and a weak signal that larger areas are more beneficial than smaller ones. Calls to conserve 30% of the Earth’s surface by 2030 are gathering pace14, but we show that protection alone does not guarantee good biodiversity outcomes. As countries gather to agree the new Global Biodiversity Framework, targets must focus on creating and supporting well-managed protected and conserved areas that measurably benefit populations.

Reconstructing the building blocks that made Earth and the Moon is critical to constrain their formation and compositional evolution to the present. Neodymium (Nd) isotopes identify these building blocks by fingerprinting nucleosynthetic components. In addition, the 146Sm–142Nd and 147Sm–143Nd decay systems, with half-lives of 103 million years and 108 billion years, respectively, track potential differences in their samarium (Sm)/Nd ratios. The difference in Earth’s present-day 142Nd/144Nd ratio compared with chondrites1,2, and in particular enstatite chondrites, is interpreted as nucleosynthetic isotope variation in the protoplanetary disk. This necessitates that chondrite parent bodies have the same Sm/Nd ratio as Earth’s precursor materials2. Here we show that Earth and the Moon instead had a Sm/Nd ratio approximately 2.4 ± 0.5 per cent higher than the average for chondrites and that the initial 142Nd/144Nd ratio of Earth’s precursor materials is more similar to that of enstatite chondrites than previously proposed1,2. The difference in the Sm/Nd ratio between Earth and chondrites probably reflects the mineralogical distribution owing to mixing processes within the inner protoplanetary disk. This observation simplifies lunar differentiation to a single stage from formation to solidification of a lunar magma ocean3. This also indicates that no Sm/Nd fractionation occurred between the materials that made Earth and the Moon in the Moon-forming giant impact.

The evolution of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus leads to new variants that warrant timely epidemiological characterization. Here we use the dense genomic surveillance data generated by the COVID-19 Genomics UK Consortium to reconstruct the dynamics of 71 different lineages in each of 315 English local authorities between September 2020 and June 2021. This analysis reveals a series of subepidemics that peaked in early autumn 2020, followed by a jump in transmissibility of the B.1.1.7/Alpha lineage. The Alpha variant grew when other lineages declined during the second national lockdown and regionally tiered restrictions between November and December 2020. A third more stringent national lockdown suppressed the Alpha variant and eliminated nearly all other lineages in early 2021. Yet a series of variants (most of which contained the spike E484K mutation) defied these trends and persisted at moderately increasing proportions. However, by accounting for sustained introductions, we found that the transmissibility of these variants is unlikely to have exceeded the transmissibility of the Alpha variant. Finally, B.1.617.2/Delta was repeatedly introduced in England and grew rapidly in early summer 2021, constituting approximately 98% of sampled SARS-CoV-2 genomes on 26 June 2021.

Light-emitting diodes (LEDs) based on perovskite quantum dots have shown external quantum efficiencies (EQEs) of over 23% and narrowband emission, but suffer from limited operating stability1. Reduced-dimensional perovskites (RDPs) consisting of quantum wells (QWs) separated by organic intercalating cations show high exciton binding energies and have the potential to increase the stability and the photoluminescence quantum yield2,3. However, until now, RDP-based LEDs have exhibited lower EQEs and inferior colour purities4–6. We posit that the presence of variably confined QWs may contribute to non-radiative recombination losses and broadened emission. Here we report bright RDPs with a more monodispersed QW thickness distribution, achieved through the use of a bifunctional molecular additive that simultaneously controls the RDP polydispersity while passivating the perovskite QW surfaces. We synthesize a fluorinated triphenylphosphine oxide additive that hydrogen bonds with the organic cations, controlling their diffusion during RDP film deposition and suppressing the formation of low-thickness QWs. The phosphine oxide moiety passivates the perovskite grain boundaries via coordination bonding with unsaturated sites, which suppresses defect formation. This results in compact, smooth and uniform RDP thin films with narrowband emission and high photoluminescence quantum yield. This enables LEDs with an EQE of 25.6% with an average of 22.1 ±1.2% over 40 devices, and an operating half-life of two hours at an initial luminance of 7,200 candela per metre squared, indicating tenfold-enhanced operating stability relative to the best-known perovskite LEDs with an EQE exceeding 20%1,4–6.

Baleen whales influence their ecosystems through immense prey consumption and nutrient recycling1–3. It is difficult to accurately gauge the magnitude of their current or historic ecosystem role without measuring feeding rates and prey consumed. To date, prey consumption of the largest species has been estimated using metabolic models3–9based on extrapolations that lack empirical validation. Here, we used tags deployed on seven baleen whale (Mysticeti) species (n= 321 tag deployments) in conjunction with acoustic measurements of prey density to calculate prey consumption at daily to annual scales from the Atlantic, Pacific, and Southern Oceans. Our results suggest that previous studies3–9have underestimated baleen whale prey consumption by threefold or more in some ecosystems. In the Southern Ocean alone, we calculate that pre-whaling populations of mysticetes annually consumed 430 million tonnes of Antarctic krill (Euphausia superba), twice the current estimated total biomass of E. superba10, and more than twice the global catch of marine fisheries today11. Larger whale populations may have supported higher productivity in large marine regions through enhanced nutrient recycling: our findings suggest mysticetes recycled 1.2 × 104tonnes iron yr−1in the Southern Ocean before whaling compared to 1.2 × 103tonnes iron yr−1recycled by whales today. The recovery of baleen whales and their nutrient recycling services2,3,7could augment productivity and restore ecosystem function lost during 20th century whaling12,13.

Myocardial infarction is a major cause of premature death in adults. Compromised cardiac function after myocardial infarction leads to chronic heart failure with systemic health complications and a high mortality rate1. Effective therapeutic strategies are needed to improve the recovery of cardiac function after myocardial infarction. More specifically, there is a major unmet need for a new class of drugs that can improve cardiomyocyte contractility, because inotropic therapies that are currently available have been associated with high morbidity and mortality in patients with systolic heart failure2,3or have shown a very modest reduction of risk of heart failure4. Microtubule detyrosination is emerging as an important mechanism for the regulation of cardiomyocyte contractility5. Here we show that deficiency of microtubule-affinity regulating kinase 4 (MARK4) substantially limits the reduction in the left ventricular ejection fraction after acute myocardial infarction in mice, without affecting infarct size or cardiac remodelling. Mechanistically, we provide evidence that MARK4 regulates cardiomyocyte contractility by promoting phosphorylation of microtubule-associated protein 4 (MAP4), which facilitates the access of vasohibin 2 (VASH2)—a tubulin carboxypeptidase—to microtubules for the detyrosination of α-tubulin. Our results show how the detyrosination of microtubules in cardiomyocytes is finely tuned by MARK4 to regulate cardiac inotropy, and identify MARK4 as a promising therapeutic target for improving cardiac function after myocardial infarction.

The rise of atmospheric oxygen fundamentally changed the chemistry of surficial environments and the nature of Earth’s habitability1. Early atmospheric oxygenation occurred over a protracted period of extreme climatic instability marked by multiple global glaciations2,3, with the initial rise of oxygen concentration to above 10−5of the present atmospheric level constrained to about 2.43 billion years ago4,5. Subsequent fluctuations in atmospheric oxygen levels have, however, been reported to have occurred until about 2.32 billion years ago4, which represents the estimated timing of irreversible oxygenation of the atmosphere6,7. Here we report a high-resolution reconstruction of atmospheric and local oceanic redox conditions across the final two glaciations of the early Palaeoproterozoic era, as documented by marine sediments from the Transvaal Supergroup, South Africa. Using multiple sulfur isotope and iron–sulfur–carbon systematics, we demonstrate continued oscillations in atmospheric oxygen levels after about 2.32 billion years ago that are linked to major perturbations in ocean redox chemistry and climate. Oxygen levels thus fluctuated across the threshold of 10−5of the present atmospheric level for about 200 million years, with permanent atmospheric oxygenation finally arriving with the Lomagundi carbon isotope excursion at about 2.22 billion years ago, some 100 million years later than currently estimated.

Compound acts by novel mechanism and is effective in mice.

Method uses core carbohydrate to build variations of ubiquitous but enigmatic biomolecules.

Thor's hero shrew is only second species found to have interlocking vertebrae.

Once-forgotten 'tar pitch' experiment yields results after seven decades.

Researchers detail structure and workings of mouse and fruit fly retinal circuits.

Co-inhibitory immune receptors can contribute to T cell dysfunction in patients with cancer1,2. Blocking antibodies against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death 1 (PD-1) partially reverse this effect and are becoming standard of care in an increasing number of malignancies3. However, many of the other axes by which tumours become inhospitable to T cells are not fully understood. Here we report that V-domain immunoglobulin suppressor of T cell activation (VISTA) engages and suppresses T cells selectively at acidic pH such as that found in tumour microenvironments. Multiple histidine residues along the rim of the VISTA extracellular domain mediate binding to the adhesion and co-inhibitory receptor P-selectin glycoprotein ligand-1 (PSGL-1). Antibodies engineered to selectively bind and block this interaction in acidic environments were sufficient to reverse VISTA-mediated immune suppression in vivo. These findings identify a mechanism by which VISTA may engender resistance to anti-tumour immune responses, as well as an unexpectedly determinative role for pH in immune co-receptor engagement.

Increasing human populations around the global coastline have caused extensive loss, degradation and fragmentation of coastal ecosystems, threatening the delivery of important ecosystem services1. As a result, alarming losses of mangrove, coral reef, seagrass, kelp forest and coastal marsh ecosystems have occurred1–6. However, owing to the difficulty of mapping intertidal areas globally, the distribution and status of tidal flats—one of the most extensive coastal ecosystems—remain unknown7. Here we present an analysis of over 700,000 satellite images that maps the global extent of and change in tidal flats over the course of 33 years (1984–2016). We find that tidal flats, defined as sand, rock or mud flats that undergo regular tidal inundation7, occupy at least 127,921 km2(124,286–131,821 km2, 95% confidence interval). About 70% of the global extent of tidal flats is found in three continents (Asia (44% of total), North America (15.5% of total) and South America (11% of total)), with 49.2% being concentrated in just eight countries (Indonesia, China, Australia, the United States, Canada, India, Brazil and Myanmar). For regions with sufficient data to develop a consistent multi-decadal time series—which included East Asia, the Middle East and North America—we estimate that 16.02% (15.62–16.47%, 95% confidence interval) of tidal flats were lost between 1984 and 2016. Extensive degradation from coastal development1, reduced sediment delivery from major rivers8,9, sinking of riverine deltas8,10, increased coastal erosion and sea-level rise11signal a continuing negative trajectory for tidal flat ecosystems around the world. Our high-spatial-resolution dataset delivers global maps of tidal flats, which substantially advances our understanding of the distribution, trajectory and status of these poorly known coastal ecosystems.

Female Aedes aegyptimosquitoes 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.

Our Galaxy is thought to have an active evolutionary history, dominated over the past ten billion years or so by star formation, the accretion of cold gas and, in particular, the merging of clumps of baryonic and dark matter. The stellar halo—the faint, roughly spherical component of the Galaxy—reveals rich ‘fossil’ evidence of these interactions, in the form of stellar streams, substructures and chemically distinct stellar components. The effects of interactions with dwarf galaxies on the content and morphology of the Galactic disk are still being explored. Recent studies have identified kinematically distinct stellar substructures and moving groups of stars in our Galaxy, which may have extragalactic origins. There is also mounting evidence that stellar overdensities (regions with greater-than-average stellar density) at the interface between the outer disk and the halo could have been caused by the interaction of a dwarf galaxy with the disk. Here we report a spectroscopic analysis of 14 stars from two stellar overdensities, each lying about five kiloparsecs above or below the Galactic plane—locations suggestive of an association with the stellar halo. We find that the chemical compositions of these two groups of stars are almost identical, both within and between these overdensities, and closely match the abundance patterns of stars in the Galactic disk. We conclude that these stars came from the disk, and that the overdensities that they are part of were created by tidal interactions of the disk with passing or merging dwarf galaxies.

Elucidating the material culture of early people in arid Australia and the nature of their environmental interactions is essential for understanding the adaptability of populations and the potential causes of megafaunal extinctions 50–40 thousand years ago (ka). Humans colonized the continent by 50 ka, but an apparent lack of cultural innovations compared to people in Europe and Africa has been deemed a barrier to early settlement in the extensive arid zone. Here we present evidence from Warratyi rock shelter in the southern interior that shows that humans occupied arid Australia by around 49 ka, 10 thousand years (kyr) earlier than previously reported. The site preserves the only reliably dated, stratified evidence of extinct Australian megafauna, including the giant marsupial Diprotodon optatum, alongside artefacts more than 46 kyr old. We also report on the earliest-known use of ochre in Australia and Southeast Asia (at or before 49–46 ka), gypsum pigment (40–33 ka), bone tools (40–38 ka), hafted tools (38–35 ka), and backed artefacts (30–24 ka), each up to 10 kyr older than any other known occurrence. Thus, our evidence shows that people not only settled in the arid interior within a few millennia of entering the continent, but also developed key technologies much earlier than previously recorded for Australia and Southeast Asia.

In the past 50 years, cross-coupling reactions mediated by transition metals have changed the way in which complex organic molecules are synthesized. The predictable and chemoselective nature of these transformations has led to their widespread adoption across many areas of chemical research. However, the construction of a bond between two sp3-hybridized carbon atoms, a fundamental unit of organic chemistry, remains an important yet elusive objective for engineering cross-coupling reactions. In comparison to related procedures with sp2-hybridized species, the development of methods for sp3–sp3bond formation via transition metal catalysis has been hampered historically by deleterious side-reactions, such as β-hydride elimination with palladium catalysis or the reluctance of alkyl halides to undergo oxidative addition. To address this issue, nickel-catalysed cross-coupling processes can be used to form sp3–sp3bonds that utilize organometallic nucleophiles and alkyl electrophiles. In particular, the coupling of alkyl halides with pre-generated organozinc, Grignard and organoborane species has been used to furnish diverse molecular structures. However, the manipulations required to produce these activated structures is inefficient, leading to poor step- and atom-economies. Moreover, the operational difficulties associated with making and using these reactive coupling partners, and preserving them through a synthetic sequence, has hindered their widespread adoption. A generically useful sp3–sp3coupling technology that uses bench-stable, native organic functional groups, without the need for pre-functionalization or substrate derivatization, would therefore be valuable. Here we demonstrate that the synergistic merger of photoredox and nickel catalysis enables the direct formation of sp3–sp3bonds using only simple carboxylic acids and alkyl halides as the nucleophilic and electrophilic coupling partners, respectively. This metallaphotoredox protocol is suitable for many primary and secondary carboxylic acids. The merit of this coupling strategy is illustrated by the synthesis of the pharmaceutical tirofiban in four steps from commercially available starting materials.

In recent years, millisecond-duration radio signals originating in distant galaxies appear to have been discovered in the so-called fast radio bursts. These signals are dispersed according to a precise physical law and this dispersion is a key observable quantity, which, in tandem with a redshift measurement, can be used for fundamental physical investigations. Every fast radio burst has a dispersion measurement, but none before now have had a redshift measurement, because of the difficulty in pinpointing their celestial coordinates. Here we report the discovery of a fast radio burst and the identification of a fading radio transient lasting ~6 days after the event, which we use to identify the host galaxy; we measure the galaxy’s redshift to be z = 0.492 ± 0.008. The dispersion measure and redshift, in combination, provide a direct measurement of the cosmic density of ionized baryons in the intergalactic medium of ΩIGM= 4.9 ± 1.3 per cent, in agreement with the expectation from the Wilkinson Microwave Anisotropy Probe, and including all of the so-called ‘missing baryons’. The ~6-day radio transient is largely consistent with the radio afterglow of a short γ-ray burst, and its existence and timescale do not support progenitor models such as giant pulses from pulsars, and supernovae. This contrasts with the interpretation of another recently discovered fast radio burst, suggesting that there are at least two classes of bursts.

The Ebola virus disease epidemic in West Africa is the largest on record, responsible for over 28,599 cases and more than 11,299 deaths. Genome sequencing in viral outbreaks is desirable to characterize the infectious agent and determine its evolutionary rate. Genome sequencing also allows the identification of signatures of host adaptation, identification and monitoring of diagnostic targets, and characterization of responses to vaccines and treatments. The Ebola virus (EBOV) genome substitution rate in the Makona strain has been estimated at between 0.87 × 10−3and 1.42 × 10−3mutations per site per year. This is equivalent to 16–27 mutations in each genome, meaning that sequences diverge rapidly enough to identify distinct sub-lineages during a prolonged epidemic. Genome sequencing provides a high-resolution view of pathogen evolution and is increasingly sought after for outbreak surveillance. Sequence data may be used to guide control measures, but only if the results are generated quickly enough to inform interventions. Genomic surveillance during the epidemic has been sporadic owing to a lack of local sequencing capacity coupled with practical difficulties transporting samples to remote sequencing facilities. To address this problem, here we devise a genomic surveillance system that utilizes a novel nanopore DNA sequencing instrument. In April 2015 this system was transported in standard airline luggage to Guinea and used for real-time genomic surveillance of the ongoing epidemic. We present sequence data and analysis of 142 EBOV samples collected during the period March to October 2015. We were able to generate results less than 24 h after receiving an Ebola-positive sample, with the sequencing process taking as little as 15–60 min. We show that real-time genomic surveillance is possible in resource-limited settings and can be established rapidly to monitor outbreaks.

Males and females share many traits that have a common genetic basis; however, selection on these traits often differs between the sexes, leading to sexual conflict. Under such sexual antagonism, theory predicts the evolution of genetic architectures that resolve this sexual conflict. Yet, despite intense theoretical and empirical interest, the specific loci underlying sexually antagonistic phenotypes have rarely been identified, limiting our understanding of how sexual conflict impacts genome evolution and the maintenance of genetic diversity. Here we identify a large effect locus controlling age at maturity in Atlantic salmon (Salmo salar), an important fitness trait in which selection favours earlier maturation in males than females, and show it is a clear example of sex-dependent dominance that reduces intralocus sexual conflict and maintains adaptive variation in wild populations. Using high-density single nucleotide polymorphism data across 57 wild populations and whole genome re-sequencing, we find that the vestigial-like family member 3 gene (VGLL3) exhibits sex-dependent dominance in salmon, promoting earlier and later maturation in males and females, respectively. VGLL3, an adiposity regulator associated with size and age at maturity in humans, explained 39% of phenotypic variation, an unexpectedly large proportion for what is usually considered a highly polygenic trait. Such large effects are predicted under balancing selection from either sexually antagonistic or spatially varying selection. Our results provide the first empirical example of dominance reversal allowing greater optimization of phenotypes within each sex, contributing to the resolution of sexual conflict in a major and widespread evolutionary trade-off between age and size at maturity. They also provide key empirical evidence for how variation in reproductive strategies can be maintained over large geographical scales. We anticipate these findings will have a substantial impact on population management in a range of harvested species where trends towards earlier maturation have been observed.

Studies of human development in vitroare on a collision course with an international policy that limits embryo research to the first two weeks of development, warn Insoo Hyun, Amy Wilkerson and Josephine Johnston.

The circulation of lymph is apparently controlled partly by the pressure of fluid entering the lymphatic capillaries, aided by external forces such as skeletal muscle contraction and gut peristalsis1,2, but lymphatic vessels themselves also contract rhythmically when distended in vivo or in vitro and this may be of major importance in the propulsion of lymph3–8. We have studied the effects of biochemical mediators on isolated sheep and bovine lymphatic segments and on pressure pulses from indwelling lymphatic cannulae and report here that nanomolar concentrations of prostaglandin (PG) H2endoperoxide and a stable PGH2analogue elicited rhythmical contractions and increased the tone of isolated quiescent lymphatic segments. Some segments showed spontaneous rhythmic activity, and these spontaneous contractions could be inhibited not only by aspirin (a cyclo-oxygenase inhibitor) but also by inhibitors of thromboxane synthase (imidazole and compound UK 37248). The pulsatile pressure changes measured from indwelling lymphatic cannulae in conscious sheep were also suppressed by aspirin or imidazole infused directly into the lymphatic circulation. Our results suggest that endogenous thromboxane production is mainly responsible for spontaneous lymphatic contractions but that PGH2also has contractile activity. An unknown product of arachidonate and PGH2, which could be formed non-enzymatically, inhibited both spontaneous and induced contractions.

VLA observations of SS433 at 1,465, 4,885, and 15,035 MHz between 8 September 1979 and 20 June 1980 show structure with size scales between 0.1 and 5 arc s which changes significantly on time scales of 1–2 weeks. Jets with 8–20% linear polarization are ejected on both sides of the central radio source which is coincident with the optical image, along position angles between 80° and 120° with a mean position angle for ejected material of 100°. Features in linear polarized intensity maps can be identified in four successive epochs spanning 196 days, and the resulting proper motions for identifiable clouds are 0.0088 arc s per day. If the feature velocities are equal to that of the optical emission lines, the distance to SS433 is 5.1 kpc. The position angles of identifiable features correlate well with the known precessing optical jets if one extrapolates back to the time of ejection using the observed transverse speeds. The equipartition magnetic field strengths of 0.001–0.01 G indicate synchrotron lifetimes of 109–1011s; therefore synchrotron losses are not a dominant factor in the evolution of the extended radio emission. The evolution of radio jets indicates that the relativistic electrons and magnetic fields seen as synchrotron emission may be generated by flows along the rotation axis of the accretion disk of the SS433 star system.

Homozygous (di/di) Brattleboro rats have normal hypothalamic levels of oxytocin and neurophysin I, but undetectable levels of neurophysin II and arginine-vasopressin (AVP)1. This defect has been presumed to be at the genomic or transcriptional level, as AVP messenger is reported to be drastically reduced, if not absent, from the hypothalamus of Brattleboro rats2. Recent studies suggest de novo production of various neuropeptides in the mammalian gonad3–7, including AVP7. We report here the detection and localization of immunoreactive (ir) AVP in the luteal cells of adult homozygous Brattleboro rats, and the modulation of this ovarian ir-AVP by gonadotropins. These findings are thus consistent with a tissue-specific defect of AVP expression in the magnocellular neurones of the Brattleboro rat, and suggest that a comparable defect does not occur in the ovaries of such animals.

The decapentaplegic gene complex (DPP-C) has been implicated in several events in pattern formation during Drosophila development1–3. During embryogenesis, the DPP-C participates in the establishment of dorsal-ventral specification. Later, it is required for the correct morphogenesis of the imaginal disks, which will form much of the adult epidermis. We have undertaken a molecular analysis of the DPP-C to determine what role it plays in positional information. It appears to be a large genetic unit (>40 kilobases (kb)) consisting mostly of cis-regulatory information controlling the expression of a set of overlapping transcripts that differ at their 5' ends, but share the bulk of their transcribed sequences. Here, we describe the sequence analysis of two complementary DNAs comprising 4.0 kb of a 4.5-kb transcript. The C-terminus of the protein thereby deduced exhibits strong sequence homology (25–38% amino-acid identity) to the C-termini of a class of mammalian proteins that includes transforming growth factor-β (TGF-β)4,5, inhibin6–9and Müllerian inhibiting substance (MIS)10,11. These proteins act on target cells to produce a variety of responses, such as stimulation or inhibition of cell division or differentiation. The homology suggests that the DPP-C protein contributes to correct morphogenesis as a secreted factor involved in the differential regulation of cell growth. This is the first report of a member of the TGF-β gene family in a non-mammalian organism, and indicates that one or more members of this gene family existed before arthropod and vertebrate lineages diverged.

Explanations of how earthquake lights might arise have failed to show how large charge densities can be concentrated and sustained in a conductive Earth. A physical model is proposed, based on frictional heating of the fault, that solves this and related problems.

Neurones in the intact retina are interconnected by a complex network of chemical and electrical synapses. The electrical interactions between many types of retinal neurones make it difficult to determine the active and passive membrane properties of the individual cells. A direct way to examine such properties is to dissociate the retina into single cells1–3and to record intracellularly from identified, isolated neurones in the absence of neural connections. Such an approach has been used to study the electrophysiological properties of several classes of neurones in the vertebrate retina3–5. We have combined the method developed previously for examining the neurochemistry of individual retinal cells1,2with a single-electrode clamp technique6,7to investigate the biophysical properties of isolated horizontal cells from the teleost retina. Our results suggest that the specific membrane capacity of these cells is ∼1 µF cm−2, and that the specific membrane resistivity ranges from ∼5,000 to 20,000 Ω cm2. In isolation, these cells can show regenerative voltage responses which are most probably calcium-dependent.