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Ca 2+ coordinates diverse cellular processes, yet how function-specific signals arise is enigmatic. We describe a cell-wide network of distinct cytoplasmic nanocourses with the nucleus at its centre, demarcated by sarcoplasmic reticulum (SR) junctions (≤400 nm across) that restrict Ca 2+ diffusion and by nanocourse-specific Ca 2+ -pumps that facilitate signal segregation. Ryanodine receptor subtype 1 (RyR1) supports relaxation of arterial myocytes by unloading Ca 2+ into peripheral nanocourses delimited by plasmalemma-SR junctions, fed by sarco/endoplasmic reticulum Ca 2+ ATPase 2b (SERCA2b). Conversely, stimulus-specified increases in Ca 2+ flux through RyR2/3 clusters selects for rapid propagation of Ca 2+ signals throughout deeper extraperinuclear nanocourses and thus myocyte contraction. Nuclear envelope invaginations incorporating SERCA1 in their outer nuclear membranes demarcate further diverse networks of cytoplasmic nanocourses that receive Ca 2+ signals through discrete RyR1 clusters, impacting gene expression through epigenetic marks segregated by their associated invaginations. Critically, this circuit is not hardwired and remodels for different outputs during cell proliferation. Although calcium signals are known to be critical for many cellular processes, how signaling elicits specific functions remains unclear. In visually striking work, Duan et al. reveal that networks of cytoplasmic nanocourses orchestrate cell activity by directing site-specific calcium signals.

Ca coordinates diverse cellular processes, yet how function-specific signals arise is enigmatic. We describe a cell-wide network of distinct cytoplasmic nanocourses with the nucleus at its centre, demarcated by sarcoplasmic reticulum (SR) junctions (≤400 nm across) that restrict Ca diffusion and by nanocourse-specific Ca -pumps that facilitate signal segregation. Ryanodine receptor subtype 1 (RyR1) supports relaxation of arterial myocytes by unloading Ca into peripheral nanocourses delimited by plasmalemma-SR junctions, fed by sarco/endoplasmic reticulum Ca ATPase 2b (SERCA2b). Conversely, stimulus-specified increases in Ca flux through RyR2/3 clusters selects for rapid propagation of Ca signals throughout deeper extraperinuclear nanocourses and thus myocyte contraction. Nuclear envelope invaginations incorporating SERCA1 in their outer nuclear membranes demarcate further diverse networks of cytoplasmic nanocourses that receive Ca signals through discrete RyR1 clusters, impacting gene expression through epigenetic marks segregated by their associated invaginations. Critically, this circuit is not hardwired and remodels for different outputs during cell proliferation.

While BRAF inhibitor combinations with EGFR and/or MEK inhibitors have improved clinical efficacy in BRAF V600E colorectal cancer (CRC), response rates remain low and lack durability. Preclinical data suggest that BRAF/MAPK pathway inhibition may augment the tumor immune response. We performed a proof-of-concept single-arm phase 2 clinical trial of combined PD-1, BRAF and MEK inhibition with sparatlizumab (PDR001), dabrafenib and trametinib in 37 patients with BRAF V600E CRC. The primary end point was overall response rate, and the secondary end points were progression-free survival, disease control rate, duration of response and overall survival. The study met its primary end point with a confirmed response rate (24.3% in all patients; 25% in microsatellite stable patients) and durability that were favorable relative to historical controls of BRAF-targeted combinations alone. Single-cell RNA sequencing of 23 paired pretreatment and day 15 on-treatment tumor biopsies revealed greater induction of tumor cell-intrinsic immune programs and more complete MAPK inhibition in patients with better clinical outcome. Immune program induction in matched patient-derived organoids correlated with the degree of MAPK inhibition. These data suggest a potential tumor cell-intrinsic mechanism of cooperativity between MAPK inhibition and immune response, warranting further clinical evaluation of optimized targeted and immune combinations in CRC. ClinicalTrials.gov registration: NCT03668431. Patients with BRAF V600E -mutated colorectal cancer have encouraging overall response rates to inhibition of PD-1, BRAF and MEK, with translational analyses suggesting that induction of tumor-intrinsic programs and immune programs contributes to improved outcomes via MAPK inhibition.

Human activity in the last century has led to a significant increase in nitrogen (N) emissions and atmospheric deposition. This N deposition has reached a level that has caused or is likely to cause alterations to the structure and function of many ecosystems across the United States. One approach for quantifying the deposition of pollution that would be harmful to ecosystems is the determination of critical loads. A critical load is defined as the input of a pollutant below which no detrimental ecological effects occur over the long-term according to present knowledge. The objectives of this project were to synthesize current research relating atmospheric N deposition to effects on terrestrial and freshwater ecosystems in the United States, and to estimate associated empirical N critical loads. The receptors considered included freshwater diatoms, mycorrhizal fungi, lichens, bryophytes, herbaceous plants, shrubs, and trees. Ecosystem impacts included: (1) biogeochemical responses and (2) individual species, population, and community responses. Biogeochemical responses included increased N mineralization and nitrification (and N availability for plant and microbial uptake), increased gaseous N losses (ammonia volatilization, nitric and nitrous oxide from nitrification and denitrification), and increased N leaching. Individual species, population, and community responses included increased tissue N, physiological and nutrient imbalances, increased growth, altered root  :  shoot ratios, increased susceptibility to secondary stresses, altered fire regime, shifts in competitive interactions and community composition, changes in species richness and other measures of biodiversity, and increases in invasive species. The range of critical loads for nutrient N reported for U.S. ecoregions, inland surface waters, and freshwater wetlands is 1-39 kg N·ha −1 ·yr −1 , spanning the range of N deposition observed over most of the country. The empirical critical loads for N tend to increase in the following sequence for different life forms: diatoms, lichens and bryophytes, mycorrhizal fungi, herbaceous plants and shrubs, and trees. The critical load approach is an ecosystem assessment tool with great potential to simplify complex scientific information and communicate effectively with the policy community and the public. This synthesis represents the first comprehensive assessment of empirical critical loads of N for major ecoregions across the United States.

1. Animals produce sounds for diverse biological functions such as defending territories, attracting mates, deterring predators, navigation, finding food and maintaining contact with members of their social group. Biologists can take advantage of these acoustic behaviours to gain valuable insights into the spatial and temporal scales over which individuals and populations interact. Advances in bioacoustic technology, including the development of autonomous cabled and wireless recording arrays, permit data collection at multiple locations over time. These systems are transforming the way we study individuals and populations of animals and are leading to significant advances in our understandings of the complex interactions between animals and their habitats. 2. Here, we review questions that can be addressed using bioacoustic approaches, by providing a primer on technologies and approaches used to study animals at multiple organizational levels by ecologists, behaviourists and conservation biologists. 3. Spatially dispersed groups of microphones (arrays) enable users to study signal directionality on a small scale or to locate animals and track their movements on a larger scale. 4. Advances in algorithm development can allow users to discriminate among species, sexes, age groups and individuals. 5. With such technology, users can remotely and non-invasively survey populations, describe the soundscape, quantify anthropogenic noise, study species interactions, gain new insights into the social dynamics of sound-producing animals and track the effects of factors such as climate change and habitat fragmentation on phenology and biodiversity. 6. There remain many challenges in the use of acoustic monitoring, including the difficulties in performing signal recognition across taxa. The bioacoustics community should focus on developing a common framework for signal recognition that allows for various species' data to be analysed by any recognition system supporting a set of common standards. 7. Synthesis and applications. Microphone arrays are increasingly used to remotely monitor acoustically active animals. We provide examples from a variety of taxa where acoustic arrays have been used for ecological, behavioural and conservation studies. We discuss the technologies used, the methodologies for automating signal recognition and some of the remaining challenges. We also make recommendations for using this technology to aid in wildlife management.

Significance Suitable habitats for forest trees may be shifting fast with recent climate change. Studies tracking the shift in suitable habitat for forests have been inconclusive, in part because responses in tree fecundity and seedling establishment can diverge. Analysis of both components at a continental scale reveals a poleward migration of northern species that is in progress now. Recruitment and fecundity both contribute to poleward spread in the West, while fecundity limits spread in the East, despite a fecundity hotspot in the Southeast. Fecundity limitation on population spread can confront conservation and management efforts with persistent disequilibrium between forest diversity and rapid climate change.

Non-communicable diseases (NCDs) like cardiovascular disease, chronic respiratory diseases, cancers, diabetes, and neuropsychiatric diseases cause significant global morbidity and mortality which disproportionately affect those living in low resource regions including low- and middle-income countries (LMICs). In order to reduce NCD morbidity and mortality in LMIC it is imperative to understand risk factors associated with the development of NCDs. Certain infections are known risk factors for many NCDs. Several parasitic helminth infections, which occur most commonly in LMICs, have been identified as potential drivers of NCDs in parasite-endemic regions. Though understudied, the impact of helminth infections on the development of NCDs is likely related to helminth-specific factors, including species, developmental stage and disease burden. Mechanical and chemical damage induced by the helminth in combination with pathologic host immune responses contribute to the long-term inflammation that increases risk for NCD development. Robust studies from animal models and human clinical trials are needed to understand the immunologic mechanisms of helminth-induced NCDs. Understanding the complex connection between helminths and NCDs will aid in targeted public health programs to reduce helminth-induced NCDs and reduce the high rates of morbidity that affects millions of people living in parasite-endemic, LMICs globally.

The challenge of meeting human development needs while protecting the earth's life support systems confronts scientists, technologists, policy makers, and communities from local to global levels. Many believe that science and technology (S&T) must play a more central role in sustainable development, yet little systematic scholarship exists on how to create institutions that effectively harness S&T for sustainability. This study suggests that efforts to mobilize S&T for sustainability are more likely to be effective when they manage boundaries between knowledge and action in ways that simultaneously enhance the salience, credibility, and legitimacy of the information they produce. Effective systems apply a variety of institutional mechanisms that facilitate communication, translation and mediation across boundaries.

Widely administered efficacious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines are the safest and most efficient way to achieve individual- and population-level immunity, making SARS-CoV-2 vaccination the most viable strategy for controlling the coronavirus disease 2019 (COVID-19) pandemic in the United States. To this end, the US government has invested more than $10 billion in \"Operation Warp Speed,\" a public-private partnership including the Centers for Disease Control and Prevention (CDC), the US Food and Drug Administration (FDA), and the US Department of Defense. Operation Warp Speed funded the development of several SARS-CoV-2 vaccines and aimed to deliver 300 million doses of a vaccine by the ambitious date of January 2021. Broad vaccine uptake (i.e., an estimated 55% to 82% of the population) is necessary to achieve population-level immunity.1 However, the advent of safe and efficacious vaccines alone will not guarantee their acceptability or uptake within US communities. Surveys of the US population indicate that a large proportion of Americans may choose not to undergo SARS-CoV-2 vaccination; 20% of Americans do not plan to get the SARS-CoV-2 vaccine, and another 31% are unsure if they will get it, according to an Associated Press poll conducted in May 2020. Another survey published in August 2020 found that 67% of those surveyed would accept a SARS-CoV-2 vaccine \"if it is recommended for them,\" but results showed significant geographic and demographic differences in vaccine acceptance.2 Such data suggest that SARS-CoV-2 vaccine hesitancy among the general public is largely a result of concerns about possible vaccine side effects, misconceptions about contracting SARS-CoV-2 from the vaccine, and indifference to SARS-CoV-2 infection risk. It is essential to confront the barriers to vaccination now-before SARS-CoV-2 vaccines are distributed-to achieve broad vaccine acceptance.

DNA-based vaccines have been safe but weakly immunogenic in humans to date. We sought to determine the safety, tolerability, and immunogenicity of ADVAX, a multigenic HIV-1 DNA vaccine candidate, injected intramuscularly by in vivo electroporation (EP) in a Phase-1, double-blind, randomized placebo-controlled trial in healthy volunteers. Eight volunteers each received 0.2 mg, 1 mg, or 4 mg ADVAX or saline placebo via EP, or 4 mg ADVAX via standard intramuscular injection at weeks 0 and 8. A third vaccination was administered to eleven volunteers at week 36. EP was safe, well-tolerated and considered acceptable for a prophylactic vaccine. EP delivery of ADVAX increased the magnitude of HIV-1-specific cell mediated immunity by up to 70-fold over IM injection, as measured by gamma interferon ELISpot. The number of antigens to which the response was detected improved with EP and increasing dosage. Intracellular cytokine staining analysis of ELISpot responders revealed both CD4+ and CD8+ T cell responses, with co-secretion of multiple cytokines. This is the first demonstration in healthy volunteers that EP is safe, tolerable, and effective in improving the magnitude, breadth and durability of cellular immune responses to a DNA vaccine candidate. ClinicalTrials.gov NCT00545987.