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B cells produce alloantibodies and activate alloreactive T cells, negatively affecting kidney transplant survival. By contrast, regulatory B cells are associated with transplant tolerance. Immunotherapies are needed that inhibit B-cell effector function, including antibody secretion, while sparing regulators and minimising infection risk. B lymphocyte stimulator (BLyS) is a cytokine that promotes B-cell activation and has not previously been targeted in kidney transplant recipients. We aimed to determine the safety and activity of an anti-BLyS antibody, belimumab, in addition to standard-of-care immunosuppression in adult kidney transplant recipients. We used an experimental medicine study design with multiple secondary and exploratory endpoints to gain further insight into the effect of belimumab on the generation of de-novo IgG and on the regulatory B-cell compartment. We undertook a double-blind, randomised, placebo-controlled phase 2 trial of belimumab, in addition to standard-of-care immunosuppression (basiliximab, mycophenolate mofetil, tacrolimus, and prednisolone) at two centres, Addenbrooke's Hospital, Cambridge, UK, and Guy's and St Thomas' Hospital, London, UK. Participants were eligible if they were aged 18–75 years and receiving a kidney transplant and were planned to receive standard-of-care immunosuppression. Participants were randomly assigned (1:1) to receive either intravenous belimumab 10 mg per kg bodyweight or placebo, given at day 0, 14, and 28, and then every 4 weeks for a total of seven infusions. The co-primary endpoints were safety and change in the concentration of naive B cells from baseline to week 24, both of which were analysed in all patients who received a transplant and at least one dose of drug or placebo (the modified intention-to-treat [mITT] population). This trial has been completed and is registered with ClinicalTrials.gov, NCT01536379, and EudraCT, 2011–006215–56. Between Sept 13, 2013, and Feb 8, 2015, of 303 patients assessed for eligibility, 28 kidney transplant recipients were randomly assigned to receive belimumab (n=14) or placebo (n=14). 25 patients (12 [86%] patients assigned to the belimumab group and 13 [93%] patients assigned to the placebo group) received a transplant and were included in the mITT population. We observed similar proportions of adverse events in the belimumab and placebo groups, including serious infections (one [8%] of 12 in the belimumab group and five [38%] of 13 in the placebo group during the 6-month on-treatment phase; and none in the belimumab group and two [15%] in the placebo group during the 6-month follow-up). In the on-treatment phase, one patient in the placebo group died because of fatal myocardial infarction and acute cardiac failure. The co-primary endpoint of a reduction in naive B cells from baseline to week 24 was not met. Treatment with belimumab did not significantly reduce the number of naive B cells from baseline to week 24 (adjusted mean difference between the belimumab and placebo treatment groups −34·4 cells per μL, 95% CI −109·5 to 40·7). Belimumab might be a useful adjunct to standard-of-care immunosuppression in renal transplantation, with no major increased risk of infection and potential beneficial effects on humoral alloimmunity. GlaxoSmithKline.

Deep neural networks have achieved impressive successes in fields ranging from object recognition to complex games such as Go . Navigation, however, remains a substantial challenge for artificial agents, with deep neural networks trained by reinforcement learning failing to rival the proficiency of mammalian spatial behaviour, which is underpinned by grid cells in the entorhinal cortex . Grid cells are thought to provide a multi-scale periodic representation that functions as a metric for coding space and is critical for integrating self-motion (path integration) and planning direct trajectories to goals (vector-based navigation) . Here we set out to leverage the computational functions of grid cells to develop a deep reinforcement learning agent with mammal-like navigational abilities. We first trained a recurrent network to perform path integration, leading to the emergence of representations resembling grid cells, as well as other entorhinal cell types . We then showed that this representation provided an effective basis for an agent to locate goals in challenging, unfamiliar, and changeable environments-optimizing the primary objective of navigation through deep reinforcement learning. The performance of agents endowed with grid-like representations surpassed that of an expert human and comparison agents, with the metric quantities necessary for vector-based navigation derived from grid-like units within the network. Furthermore, grid-like representations enabled agents to conduct shortcut behaviours reminiscent of those performed by mammals. Our findings show that emergent grid-like representations furnish agents with a Euclidean spatial metric and associated vector operations, providing a foundation for proficient navigation. As such, our results support neuroscientific theories that see grid cells as critical for vector-based navigation , demonstrating that the latter can be combined with path-based strategies to support navigation in challenging environments.

Accurate and spatially-explicit maps of tropical forest carbon stocks are needed to implement carbon offset mechanisms such as REDD+ (Reduced Deforestation and Degradation Plus). The Random Forest machine learning algorithm may aid carbon mapping applications using remotely-sensed data. However, Random Forest has never been compared to traditional and potentially more reliable techniques such as regionally stratified sampling and upscaling, and it has rarely been employed with spatial data. Here, we evaluated the performance of Random Forest in upscaling airborne LiDAR (Light Detection and Ranging)-based carbon estimates compared to the stratification approach over a 16-million hectare focal area of the Western Amazon. We considered two runs of Random Forest, both with and without spatial contextual modeling by including--in the latter case--x, and y position directly in the model. In each case, we set aside 8 million hectares (i.e., half of the focal area) for validation; this rigorous test of Random Forest went above and beyond the internal validation normally compiled by the algorithm (i.e., called \"out-of-bag\"), which proved insufficient for this spatial application. In this heterogeneous region of Northern Peru, the model with spatial context was the best preforming run of Random Forest, and explained 59% of LiDAR-based carbon estimates within the validation area, compared to 37% for stratification or 43% by Random Forest without spatial context. With the 60% improvement in explained variation, RMSE against validation LiDAR samples improved from 33 to 26 Mg C ha(-1) when using Random Forest with spatial context. Our results suggest that spatial context should be considered when using Random Forest, and that doing so may result in substantially improved carbon stock modeling for purposes of climate change mitigation.

Gene-editing technologies, which include the CRISPR-Cas nucleases and CRISPR base editors , have the potential to permanently modify disease-causing genes in patients . The demonstration of durable editing in target organs of nonhuman primates is a key step before in vivo administration of gene editors to patients in clinical trials. Here we demonstrate that CRISPR base editors that are delivered in vivo using lipid nanoparticles can efficiently and precisely modify disease-related genes in living cynomolgus monkeys (Macaca fascicularis). We observed a near-complete knockdown of PCSK9 in the liver after a single infusion of lipid nanoparticles, with concomitant reductions in blood levels of PCSK9 and low-density lipoprotein cholesterol of approximately 90% and about 60%, respectively; all of these changes remained stable for at least 8 months after a single-dose treatment. In addition to supporting a 'once-and-done' approach to the reduction of low-density lipoprotein cholesterol and the treatment of atherosclerotic cardiovascular disease (the leading cause of death worldwide ), our results provide a proof-of-concept for how CRISPR base editors can be productively applied to make precise single-nucleotide changes in therapeutic target genes in the liver, and potentially in other organs.

Terrestrial carbon conservation can provide critical environmental, social, and climate benefits. Yet, the geographically complex mosaic of threats to, and opportunities for, conserving carbon in landscapes remain largely unresolved at national scales. Using a new high-resolution carbon mapping approach applied to Peróúúú, a megadiverse country undergoing rapid land use change, we found that at least 0.8 Pg of aboveground carbon stocks are at imminent risk of emission from land use activities. Map-based information on the natural controls over carbon density, as well as current ecosystem threats and protections, revealed three biogeographically explicit strategies that fully offset forthcoming land-use emissions. High-resolution carbon mapping affords targeted interventions to reduce greenhouse gas emissions in rapidly developing tropical nations. Significance Land use is a principal driver of carbon emissions, either directly through land change processes such as deforestation or indirectly via transportation and industries supporting natural resource use. To minimize the effects of land use on the climate system, natural ecosystems are needed to offset gross emissions through carbon sequestration. Managing this critically important service must be achieved tactically if it is to be cost-effective. We have developed a high-resolution carbon mapping approach that can identify biogeographically explicit targets for carbon storage enhancement among all landholders within a country. Applying our approach to Peróúú reveals carbon threats and protections, as well as major opportunities for using ecosystems to sequester carbon. Our approach is scalable to any tropical forest country.

Media narratives can shape public opinion and actions, influencing the uptake of pediatric COVID-19 vaccines. The COVID-19 pandemic has occurred at a time where infodemics, misinformation, and disinformation are present, impacting the COVID-19 response. This study aims to investigate how narratives about pediatric COVID-19 vaccines in the media of 4 English-speaking countries: the United States, Australia, Canada, and the United Kingdom. The Narrative Policy Framework was used to guide the comparative analyses of the major print and web-based news agencies' media regarding COVID-19 vaccines for children aged 5 to 11 years. Data were sought using systematic searching on Factiva (Dow Jones) of 4 key phases of pediatric vaccine approval and rollout. A total of 400 articles (n=287, 71.8% in the United States, n=40, 10% in Australia, n=60, 15% in Canada, and n=13, 3% in the United Kingdom) met the search criteria and were included. Using the Narrative Policy Framework, the following were identified in each article: hero, villain, survivor, and plot. The United States was the earliest country to vaccinate children, and other countries' media often lauded the United States for this. Australian and Canadian media narratives about vaccines for children aged 5 to 11 years were commonly about protecting susceptible people in society, whereas the US and the UK narratives focused more on the vaccine helping children return to school. All 4 countries focused on the vaccines for children aged 5 to 11 years as being key to \"ending\" the pandemic. Australian and Canadian narratives frequently compared vaccine rollouts across states or provinces and bemoaned local progress in vaccine delivery compared with other countries globally. Canadian and US narratives highlighted the \"infodemic\" about the COVID-19 pandemic and disinformation regarding child vaccines as impeding uptake. All 4 countries-the United States, Australia, the United Kingdom, and Canada-used war imagery in reporting about COVID-19 vaccines for children. The advent of the Omicron variant demonstrated that populations were fatigued by the COVID-19 pandemic, and the media reporting increasingly blamed the unvaccinated. The UK media narrative was unique in describing vaccinating children as a distraction from adult COVID-19 vaccination efforts. The United States and Canada had narratives expressing anger about potential vaccine passports for children. In Australia, general practitioners were labelled as heroes. Finally, the Canadian narrative suggested altruistic forgoing of COVID-19 vaccine \"boosters\" as well as pediatric COVID-19 vaccines to benefit those in poorer nations. Public health emergencies require clear; compelling and accurate communication. The stories told during this pandemic are compelling because they contain the classic elements of a narrative; however, they can be reductive and inaccurate.

To understand the processes that form oceanic crust as well as the role of submarine volcanoes in exchanging heat and chemicals with the ocean and in supporting chemosynthetic biological communities, it is essential to study underwater eruptions. The world’s most advanced underwater volcano observatory—the Ocean Observatories Initiative Cabled Array at Axial Seamount—builds upon ~30 years of sustained geophysical monitoring at this site with autonomous and remote systems. In April 2015, only months after the Cabled Array’s installation, it recorded an eruption at Axial Seamount, adding to the records of two prior eruptions in 1998 and 2011. Between eruptions, magma recharge is focused beneath the southeast part of the summit caldera, leading to steady inflation and increasing rates of seismicity. During each eruption, the volcano deflates over days to weeks, coincident with high levels of seismicity as a dike is emplaced along one of the volcano’s rifts and lava erupts on the seafloor. Cabled Array seismic data show that motions on an outward-dipping ring fault beneath the caldera accommodate the inflation and deflation. Eruptions appear to occur at a predictable level of inflation; hence, it should be possible to time deployments of additional cabled and autonomous instrumentation to further enhance observations of the next eruption.

Redox cycling is an understated mechanism of toxicity associated with a plethora of xenobiotics, responsible for preventing the effective treatment of serious conditions such as malaria and cardiomyopathy. Quinone compounds are notorious redox cyclers, present in drugs such as doxorubicin, which is used to treat a host of human cancers. However, the therapeutic index of doxorubicin is undermined by dose-dependent cardiotoxicity, which may be a function of futile redox cycling. In this study, a doxorubicin-specific in silico quinone redox metabolism model is described. Doxorubicin-GSH adduct formation kinetics are thermodynamically estimated from its reduction potential, while the remainder of the model is parameterised using oxygen consumption rate data, indicative of hydroquinone auto-oxidation. The model is then combined with a comprehensive glutathione metabolism model, facilitating the simulation of quinone redox cycling, and adduct-induced GSH depletion. Simulations suggest that glutathione pools are most sensitive to exposure duration at pharmacologically and supra-pharmacologically relevant doxorubicin concentrations. The model provides an alternative method of investigating and quantifying redox cycling induced oxidative stress, circumventing the experimental difficulties of measuring and tracking radical species. This in silico framework provides a platform from which GSH depletion can be explored as a function of a compound's physicochemical properties.

Cancer cells depend on glucose metabolism via glycolysis as a primary energy source, despite the presence of oxygen and fully functioning mitochondria, in order to promote growth, proliferation and longevity. Glycolysis relies upon NAD+ to accept electrons in the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) reaction, linking the redox state of the cytosolic NAD+ pool to glycolytic rate. The free cytosolic NAD+/NADH ratio is involved in over 700 oxidoreductive enzymatic reactions and as such, the NAD+/NADH ratio is regarded as a metabolic readout of overall cellular redox state. Many experimental techniques that monitor or measure total NAD+ and NADH are unable to distinguish between protein-bound and unbound forms. Yet total NAD+/NADH measurements yield little information, since it is the free forms of NAD+ and NADH that determine the kinetic and thermodynamic influence of redox potential on glycolytic rate. Indirect estimations of free NAD+/NADH are based on the lactate/pyruvate (L/P) ratio at chemical equilibrium, but these measurements are often undermined by high lability. To elucidate the sensitivity of the free NAD+/NADH ratio to changes in extracellular substrate, an in silico model of hepatocarcinoma glycolysis was constructed and validated against in vitro data. Model simulations reveal that over experimentally relevant concentrations, changes in extracellular glucose and lactate concentration during routine cancer cell culture can lead to significant deviations in the NAD+/NADH ratio. Based on the principles of chemical equilibrium, the model provides a platform from which experimentally challenging situations may be examined, suggesting that extracellular substrates play an important role in cellular redox and bioenergetic homeostasis.

As previously summarized by Hammond et al. (2015), from 1983 to 2013, the NOAA Vents program conducted systematic and multidisciplinary exploration, discovery, and research related to hydrothermal vents, submarine volcanic eruptions, and associated ocean physical, chemical, and biological processes. In 2014, Vents divided into two programs, Earth-Ocean Interactions (EOI) and Acoustics, and considered a broader range of questions about how seafloor and subseafloor processes contribute to ocean health, biogeochemical cycles, ecosystem diversity, and climate change. Here, we highlight major accomplishments since 2014, including deep-sea technologies that EOI, Vents, and Pacific Marine Environmental Laboratory (PMEL) Engineering have developed to advance marine science. EOI research is driven by a need for better observational data on issues of global importance, including the role of continental margin seeps in the global methane/carbon cycle, benthic ecology, and fisheries habitat; the role of hydrothermal systems in global biogeochemical cycles, including carbon dioxide removal; the potential impact of deep-sea mining of metal sulfides on ecosystem services provided by hydrothermal vents; and how hydrothermal iron functions as an essential nutrient. NOAA Ocean Exploration, the Schmidt Ocean Institute, the Ocean Exploration Trust, and the National Science Foundation have supported and collaborated in this work. Global exploration of the deep sea with the purpose of understanding global ocean processes remains a cornerstone of EOI science.